BACTERIAL TAXONOMY

Classification, Nomenclature, Laboratory Identification

The Gram-Positive Cell As previously mentioned, Gram-positive bacteria are characterized by their blue-violet color reaction in the Gram-staining procedure . The blue-violet color reaction is caused by crystal-violet, the primary Gram-stain dye, complexing with the iodine mordant. When the decolorizer is applied, a slow dehydration of the crystal-violet iodine complex is observed due to the closing of pores running through the cell wall. !ecause the crystal-violet is still present in the cell, the counter stain is not incorporated, thus maintaining the cell"s blue-violet color. #f you recall, most cell walls contain peptidoglycan, a molecule made of amino acids and sugar. A distinguishing factor among Gram-positive bacteria is that roughly $%& of their cell wall is comprised of peptidoglycan and a Gram-positve bacteria can have more than '% layers of peptidoglycan stac(ed together to form the cell wall. That"s pretty thic()

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*xamples of common Gram-positive cells are +taphylococcus aureus and +treptococcus cremoris, a bacterium used in dairy production.

G,A--./+#T#0* 1/11# The Gram-positive cocci are grouped together based on their Gram-stain reaction, thic( cell wall composition, and spherical shape. -ost of the organisms in these groups are members of the -icrococcaceae family All of the organisms in these groups are non-endospore forming chemosynthetic heterotrophs. We will discuss only the clinically relevant bacteria from Micrococcus and Staphylococcus of the -icrococcaceae family. Streptococcus and *nterococcus2formerly a species of +treptococcus3 are discussed as well because of the many diseases they inflict on humans. The chart below shows the paths to identification of the genera discussed.

MICROCOCCUS

-icrocoocus is a Gram-positive, aerobic bacterium which is a member of the Micrococcaceae amily. -icrococcus cells can be observed under the microscope as spherical cells forming pairs or clusters. #f cultured in broth or on nutrient agar, the colonies may be red or yellow when observed unstained. Although these bacteria are a common human s(in contaminant, they are relatively harmless to humans because they maintain a saprophytic lifestyle. They can also be found in freshwater environments or in soil. Three common species of -icrococcus are -. luteus, -. roseus, and -. varians.

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o o o

4A!/,AT/,5 #67#1AT#/6+8 1atalase 9 /xidative action on glucose Growth on mannitol

ST!P"#$OCOCCUS 1linically, the most important genus of the Micrococcaceae family is +taphylococcus. The +taphylococcus genus is classified into two ma:or groups8 aureus and non-aureus. S% aureus is a leading cause of soft tissue infections, as well as to&ic shoc' syndrome (TSS) and scalded s'in syndrome. #t can be distinguished from other species of +taph by a positive result in a coagulase test2all other species are negative3. The pathogenic effects of +taph are mainly asssociated with the toxins it produces. -ost of these toxins are produced in the stationary phase of the bacterial growth curve. #n fact, it is not uncommon for an infected site to contain no viable +taph cells. The +. aureus enteroto&in causes ;uic( onset food poisoning which can lead to cramps and severe vomiting. #nfection can be traced to contaminated meats which have not been fully coo(ed. These microbes also secrete leu'ocidin, a toxin which destroys white blood cells and leads to the formation of puss and acne. .articularly, +. aureus has been found to be the causative agent in such ailments as pneumonia, meningitis, boils, arthritis, and osteomyelitis 2chronic bone infection3. -ost +. aureus are penicillin resistant, but vancomycin and nafcillin are (nown to be effective against most strains. /f the non-aureus species, +. epidermis is the most clinically significant. This bacterium is an opportunistic pathogen which is a normal resident of human s(in. Those susceptible to infection by the bacterium are #0 drug users, newborns, elderly, and those using catheters or other artificial appliances. #nfection is easily treatable with vancomycin or rifampin. 4A!/,AT/,5 #67#1AT#/6+8

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Anaerobic glucose fermentation with acid production 1atalase 9 6itrate 9 1oagulase 9

STR*PTOCOCCUS The +treptococcus genus consists of Gram-positive, aerobic bacteria which appear as chains under microscopic observation. The organisms in this genus are characterized by a coccus appearance, a thic( cell wall, and aerobic action on glucose. <our different classification systems exist for this important microorganism8 C$I+IC!$ .yogenic +treptococci /ral +treptococci *nteric +treptococci, "*MO$#S#S alpha-hemolysis beta-hemolysis gamma-hemolysis S*RO$OGIC!$-4ancefield 2A-=3, 2>-?3 ,IOC"*MIC!$2physiological3

GROUP !

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The first group in the 4ancefield classification system includes only one species of +treptococcus, +. pyogenes. This particular opportunistic pathogen is responsible for about $%& of all cases of pharyngitis. A common form of pharyngitis is @+trep throat@ which is characterized by inflamation and swelling of the throat, as well as development of pus-filled regions on the tonsils. .enicillin is usually administered to patients as soon as possible to ;uell the possibility of the infection spreading from the upper respiratory system into the lungs. /nce in the lungs, the infection could give rise to pneumonia. +ome cases also develop into rheumatic ever if left untreated. /ther diseases lin(ed to +. pyogenes are s(in infections such as impetigo, cellulitis, and erysipelas. 4A!/,AT/,5 #67#1AT#/6+8 1atalase !eta-hemolysis !acitracin sensitive GROUP , The ! classification of 4ansefield also includes only one bacterium, +. agalactiae. <or years this bacterium has been the causative agent in mastitis in cows. 1urrently, it has been found to be a cause of sexually transmitted urogenital infections in females. Although infection is easily treated with penicillin, proper diagnosis is necessary for women nearing labor because the infection can easily spread to the child via the birth canal. 4A!/,AT/,5 #67#1AT#/6+8 1A-. 9 !eta-hemolysis GROUP Type 7 +treptococcus is the next clinically important bacterium because of the multitude of diseases it is (nown to cause. Although many are harmless, the pathogenic strains cause complications of the human digestive tract. This group has recently been reclassified into two divisions8 *nterococcus and non-*nterococcus. The *nterococci include *. faecalis, a cause of urinary tract infections, and *. faecium, a bacterium resistant to many common antibiotics. 7iseases such as septicemia, endocarditis, and appendicitis have also been attributed to group 7 +trep. <ecal matter from infected individuals is a source for isolation and identification techni;ues. /nce identified, Group 7 +trep can be treated with ampicillin alone or in combination with gentamicin. 4A!/,AT/,5 #67#1AT#/6+8

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=ydrolysis of bile esculin 2dar( brown medium3 -this indicates the ability of the bacteria to tolerate bile from the liver Growth in high salt conc.

OT"*R IMPORT!+T STR*P

Streptococcus pneumoniae
!ecause its surface carbohydrate antigens do not correspond to a specific 4ancefield group, +. pneumonia is discussed separately. Although not given a letter designation, +. pneumoniae can be considered a .yogenic 2puss-producing3 strain of +trep. #t can be distinguished from other .yogenic bacteria by its high sensitivity to /ptochin 2no growth zone of inhibition3. This bacterium causes pneumonia 2obviously)3, meningitis, and otitis media. #t also demonstrates alpha-hemolytic growth on blood agar. .iridans Group The 0iridans +treptococci, consisting of +. mutans and +. mitis, are alpha-hemolytic bacteria. These bacteria inhabit the mouth. #n fact, a large percentage of tooth decay can be attributed to +. mutans. G,A--./+#T#0* ,/7+ The Gram-positive rods in this section will be divided into three distinct varieties based upon their ability to produce endospores and their morphological appearance8 *67/+./,*-</,-#6G o ,!CI$$US ,*G?4A,, 6/6-*67/+./,*-</,-#6G o $!CTO,!CI$$US o $IST*RI! o *R#SIP*$OT"RI/ #,,*G?4A,, 6/6-*67/+./,*-</,-#6G o COR#+*,!CT*RIUM

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These bacteria are ubi;uitous in nature and most are aerobic or facultatively anaerobic. ,!CI$$US

!acillus represents a genus of Gram-positive bacteria which are ubi;uitous in nature 2soil, water, and airborne dust3. +ome species are natural flora in the human intestines. When grown on blood agar, !acillus produces large, spreading, gray-white colonies with irregular margins. A uni;ue characteristic of this bacterium is its ability to produce endospores when environmental conditions are stressful. The only other (nown spore-producing bacterium is 1lostridium. Although most species of !acillus are harmless saprophytes, two species are considered medically significant8 !. anthracis and !. cereus. ,% anthracis
!. anthracis is the bacterium which causes anthra& in cows, sheep, and sometimes humans. Anthrax is transmitted to humans via direct contact with animal products or inhalation of endospores. ?nder the microscope, !. anthracis cells appear to have s;uare ends and seem to be attached by a :oint to other cells. The spores are best observed when the bacterium is cultured on artificial media. +ources of infection are usually industrial or agricultural and the infection is classified as one of three types8 1?TA6*/?+ #6<*1T#/6 2$A& of human cases3 #6=A4AT#/6 A6T=,AB 2rare3 GA+T,/#6T*+T#6A4 A6T=,AB 2very rare)3

4A!/,AT/,5 #67#1AT#/6+8 6onhemolytic 2sheep blood agar3 6on-motile Gel hydrolysis 1atalase 9

,% cereus

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?nli(e !. anthracis, !. cereus is a motile bacterium which can cause toxin-mediated food poisoning. #t is (nown to inhabit many (inds of food including stew, cereal, and mil(. -ost recently, however, it has been found in fried rice. The two toxins released by the bacterium lead to vomiting and diarrhea, symptoms similar to those of +taphylococcus food poisoning. !ecause toxin production usually ta(es place after the infected foods are coo(ed, proper cold storage of food is recommended immediately after preparation. 4A!/,AT/,5 #67#1AT#/6+8 =emolytic 2sheep blood agar3 -otile Gel hydrolysis 9 Glucose, maltose, C salicin fermentative 1atalase 9 $IST*RI!

4isteria is a Gram-positive rod which is not capable of forming endospores. Although several species of this bacterium exist, our discussion will focus only on the two species of human pathogenic significance8 4. monocytogenes and 4. ivanovii. #n particular, 4. monocytogenes has been implicated in several food poisoning epidemics. This normal inhabitant of the gastrointestinal tract and of animal feces led to a D$EF outbrea( in -assachusetts hospital patients. Those infected suffered from vomiting, nausea, and diarrhea. Apparently, the hospital patients contracted the microbe from the infected hospital food and were at high ris( of infection. Those at high ris( include newborns, pregnant women and their fetuses, the elderly, and persons lac(ing a healthy immune system. The bacterium usually causes septicemia and meningitis in patients with suppressed immune function. #t also causes listeriosis which is an inflammation of the brain. Antibiotics are recommended for treatment of infection because most strains of 4isteria are sensitive to ampicillin and gentamicin.
4A!/,AT/,5 #67#1AT#/6+8 1atalase 9 -otile at room temperature Growth at G degrees 1elsius !ile esculin hydrolysis !eta-hemolysis

$!CTO,!CI$$US

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-ost species of this non-spore-forming bacterium ferment glucose into lactose, hence the name 4actobacillus. The most common application of 4actobacillus is industrial, specifically for dairy production. This genus also contains several bacteria that ma(e up part of the natural flora of the human vagina. !ecause of their ability to derive lactic acid from glucose, these bacteria create an acidic environment which inhibits growth of many bacterial species which can lead to urogenital infections. 4actobacillus is generally harmless to humans, rarely inciting harmful infections or diseases. Treatment of this vancomycin-resistant microbe usually consists of high doses of penicillin in combination with gentamicin. 4A!/,AT/,5 #67#1AT#/6+8 1atalase 4actic acid production from glucose Growth on tomato :uice agar *R#SIP*$OT"RI/

*. rhusiopathiae, the only species of this genus, is better (nown as a veterinary pathogen than as a human pathogen. When cultured on blood agar or some other nutrient medium, *rysipelothrix forms notably large colonies. This ubi;uitous microbe has been found in many farm animals such as pigs, horses, and tur(eys. /ccasionally, though, it can infect a human host and cause an inflammatory s(in disease, *rysipeloid. Treatment usually consists of penicillin G, ampicillin, or cephalothin. -ost clinical strains have been found to be resistant to the super-antibiotic, vancomycin.
4A!/,AT/,5 #67#1AT#/6+8 1atalase 6on-motile T+# 8 ='+ 9

COR#+*,!CT*RI! The coryneform group of Gram-positive bacteria includes several genera of non-spore-forming rods which are ubi;uitous in nature. We will consider only two of these genera in our discussion of clinically significant microorganisms8 Actinomyces and 1orynebacterium. The first genus, Actinomyces, will be presented later when we focus on anaerobic Gram-positive bacteria. The second genus, 1orynebacterium, is comprised of facultatively anaerobic bacteria which are normally saprophitic and harmless to humans. An exception is the bacterium 1. diphtheriae which produces the toxin that causes diphtheria, a disease of the upper

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respiratory system in humans. Under the microscope 2best viewed using 4oeffler"s methylene blue dye3, 1. diphtheria can be seen forming colonies which clump up or stic( together. This is a characteristic associated with many higher forms of bacteria. Although other species of 1orynebacterium can inhabit the mucous membrane, 1. diphtheria is uni;ue in its exotoxin formation. Treatment for the disease usually consists of administration of an antitoxin with penicillin.

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4A!/,AT/,5 #67#1AT#/6+8 1atalase 9 6itrate 9 Glucose fermentation 6on-motile TR*!TM*+T

Table 7. - Choice, Mode of Actio , !"ect#$%, a d Do&a'e of A tibiotic A'e t&

A'e t Mode of Actio A tibacte#ial !"ect#$% of Cli ical (%"o#ta ce Do&a'e

)e icilli *

+acte#icidal, i te#fe#e& -ith bacte#ial cell -all &. the&i& +acte#icidal, &a%e a& abo3e

!t#e"tococci, ) e$%ococci Clo&t#idia, /ei&&e#iae, Co#. ebacte#ia, )a&te$#ella %$ltocida, Acti o%.ce&, T#e"o e%a, 0i&te#ia 4e%o"hil$& i fl$e 5ae, )#ote$& %i#abili&, !al%o allae, !hi'ellae a d &o%e 6. coli. *#a%-"o&iti3e o#'a i&%& a& -ith )e icilli * 7leb&iella &"., Ae#obacte# &"., )&e$do%o a& ae#$'i o&a, !e##atia, i dole "o&iti3e )#ote$& &"., &o%e Methicilli #e&i&ta t !ta"h.lococci *#a%- e'ati3e a ae#obe& e&"eciall. +acte#iode& f#a'ili&. Al&o effecti3e a'ai &t &e3e#al "#oto5oa.

30 %il $ it& (12da. e3e#. 2-4 ho$#& 8 '% (12da. e3e#. 6 ho$#& 5 %'28'2da. e3e#. 812 ho$#& 2 '% (12da. e3e#. 4 ho$#&

A%"icilli

*e ta%ici

+acte#io&tatic, i hibitio of bacte#ial "#otei &. the&i& +acte#iocidal Cell -all &. the&i& i hibito#&, &table to &ta"h.lococcal beta lacta%a&e& +acte#io&tatic, i hibit& "#otei &. the&i&

Met#o ida5ole Cefo9iti :2 d 'e e#atio ce"halo&"o#i ; Cli da%.ci

!a%e a& abo3e "l$& +acte#oide& f#a'ili&, ot acti3e a'ai &t 12 '% (12da. e3e#. 6 te#obacte# &"". 6 ho$#& *#a%-"o&iti3e a d *#a%- e'ati3e a ae#obe&, *#a%"o&iti3e ae#obic cocci, !t#e"tococc$& faecali&, Clo&t#idia 1200-2700 %' (12da. e3e#. 6-8 ho$#&

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PENICILLINS
*ail (to8a5$, )ha#%.D. *oal& a d Ob<ecti3e&. +. the e d of the lect$#e the &t$de t &ho$ld be able to di&c$&& the follo-i ' abo$t "e icilli a tibiotic&= 1. De&c#ibe thei# %echa i&% of actio a d "ha#%acolo'ic "#o"e#tie&. 2. De&c#ibe thei# &"ect#$% of acti3it.. 3. De&c#ibe thei# %a<o# &ide effect&. 4. Di&c$&& thei# $&e i the cli ical &etti '. >e?$i#ed #eadi '&. The 'oal of the&e #eadi '& i& to #ei fo#ce the cli ical a""licatio of "e icilli &. 0o-e# >e&"i#ato#. T#act ( fectio &, Cha"te# 100, "a'e& 1995-2016. )ha#%acothe#a".=A )atho"h.&iolo'ic A""#oach, 3#d 6ditio . @""e# >e&"i#ato#. T#act ( fectio &, Cha"te# 101, "a'e& 2017-2035. )ha#%acothe#a".=A )atho"h.&iolo'ic A""#oach, 3#d 6ditio .

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DRUG NATURAL PENCILLINS A?$eo$& "e icilli * )e icilli * )e cilli 17 PENICILLINASE-RESISTANT PENICILLINS Methicilli O9acilli /aficlli Diclo9acilli Clo9acilli AMINOPENICILLINS A%"icilli A%o9icilli CARBOXY-PENICILLINS Ca#ce icilli Tica#cilli UREIDO-PENICILLIN

DOSE

ROUTE DOSING INTERVAL

1-4 %illio $ it& (1 250-500 %' )O 250-500 %' )O

4-6 6 6

1-2 '% 1-2 '% 500 %' 1-2 '% 250-500 %' 250-500 %' 250-500 %' 1-2 '% 250-500 %' 250-500 %' 382-764 %' 3 '%

(12(M (12(M )O (1(M )O )O )O (12(M )O )O )O (12(M

4-6 4-6 4-6 4-6 4-6 6 6 4-6 6 8 8 4-6

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Me5locilli )i"e#acilli PENICILLIN/INHIBITOR COMBINATIONS A%"icilli 2&$lbacta% Tica#cilli 2cla3$la ate )i"e#acilli 2ta5obacta% A%o9icilli 2cla3$la ate MONOBACTAM A5t#eo a% CARBAPENEM (%i"e e% Me#o"e e% GLYCOPEPTIDE 1a co%.ci

3 '% 4 '% 3-4 '% 3 '% 3.1 '% 3.75 '% 4.5 '% 250-500 %' 1-2 '% 500 %' 1 '% 1 '%

(12(M (12(M (12(M (1 (1 (1 )O (12(M (12(M (1 (1

4 6 4-6 6 4-6 4-6 4 8 6-8 6 8 12-24

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)6/(C(00(/!
*ail (to8a5$, )ha#%.D. (. +AC7*>O@/D )e icilli & a#e beta-lacta% co%"o$ d& -hich ha3e a 4 %e%be#ed beta-lacta% #i ' that i& f$&ed to a 5-%e%be#ed thia5olidi e #i '. Side chain m di!ica"i n# ! "hi# #"$%c"%$e c n!e$#& '( an im)$ *ed #)ec"$%m ! ac"i*i"+, and -( )ha$mac .ine"ic ad*an"a/e#0 !i9 cla&&e& of "e icilli & a#e o- a3ailable. ((. M6C4A/(!M OA ACT(O/ B )4A>MACO0O*(C )>O)6>T(6! 1. )#e3e t& cell -all &. the&i& b. bi di ' to e 5.%e& called "e icilli bi di ' "#otei & :)+)&;. The&e e 5.%e& a#e e&&e tial fo# the &. the&i& of the bacte#ial cell -all. -0 Bac"e$icida10 3. C ncen"$a"i n-inde)enden" 2ac"e$icida1 acti3it.. (((. M6C4A/(!M! OA +ACT6>(A0 >6!(!TA/C6 TO )6/(C(00(/ (t i& ot $ co%%o fo# %o#e tha o e of the&e #e&i&ta ce %echa i&% to be o"e#ati ' &i%$lta eo$&l.. 1. de#"$%c"i n ! 2e"a-1ac"am $in/ b. 2e"a-1ac"ama#e#, a i tact beta-lacta% #i ' i& e&&e tial fo# a tibacte#ial acti3it.. 2. a1"e$ed a!!ini"+ of "e icilli & fo# thei# "a$/e" #i"e, "he "e icilli bi di ' "#otei &. 3. dec$ea#ed )ene"$a"i n ! an"i2i "ic " "he "a$/e" #i"e, the )+)&. Thi& i& o l. a""licable to '#a%- e'ati3e bacte#ia &i ce '#a%"o&iti3e bacte#ia lac8 a o$te# cell %e%b#a e. (t i& the o$te# cell %e%b#a e that #ed$ce& "e#%eabilit. of d#$' to the ta#'et &ite. (1. MACO> C0A!!(A(CAT(O/! OA )6/(C(00(/! 1. )6/(C(00(/ * :+6/DE0)6/(C(00(/; SPECTRUM OF ACTIVITY. G$am-) #i"i*e ae$ 2ic c cci& S"$e)" c cci )+ /ene# 3G$ %) A #"$e)(, S"$e)" c cc%# a/a1ac"iae 3G$ %) B #"$e)(, *i$idan# #"$e)" c cci, En"e$ c cci0 !ta"h.lococci a#e $&$all. #e&i&ta t.

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Penici11in $e#i#"an" S0 )ne%m niae -ith 3a#iable de'#ee& of #e&i&ta ce :i te#%ediatel. #e&i&ta t, hi'hl. #e&i&ta t; to "e icilli i& beco%i ' a -o#ld-ide "#oble%. P "en"ia1 "he$a)ie# fo# the&e #e&i&ta t i&olate& i cl$de ce! "a4ime, ce!"$ia4 ne, *anc m+cin, imi)enem0 G$am-ne/a"i*e ae$ 2e#= Nei##e$ia menin/i"idi#, )a&te$#ella %$ltocida. Anae$ 2e#& C1 #"$idi%m &"ecie&, A$&obacte#i$% &"ecie&, Acti o%.ce& i&#aelii. O"he$& T$e) nema )a11id%m, 0i&te#ia %o oc.to'e e&. PHARMACOKINETICS: Di&t#ib$te& -ell i to the $#i e, &. o3ial, "le$#al, a d "e#ica#dial fl$id&, ce#eb#al &"i al fl$id :C!A;. E1imina"i n i# )$ima$i1+ *ia "he .idne+# a d do&a'e ad<$&t%e t i& ece&&a#. to %i i%i5e the "ote tial fo# &ei5$#e&. GENERAL CLINICAL USES: @&ef$l fo# #.in and # !" "i##%e in!ec"i n# ca$&ed b. !t#e"toccc$& ".o'e e&, menin/i"i# ca$&ed b. &$&ce"tible /. %e i 'itidi& a d !t#e"tococc$& " e$%o iae, $a1 $ den"a1 in!ec"i n# -hich f#e?$e tl. i 3ol3e a ae#obic &t#e"tococci, a d #+)hi1i# -hich i& ca$&ed b. T#e"o e%a "allid$%. GENERAL SIDE EFFECTS/PRECAUTIONS: A. H+)e$#en#i"i*i"+ $eac"i n# %a ife&ted b. #a&he&, eo&i o"hilia, fe3e#, i te#&titial e"h#iti&. +. Ce t#al e#3o$& &ti%$latio i cl$di ' %.oclo ic t-itchi ' a d #ei5%$e#0 >i&8 facto#& i cl$de hi/h d #e#, )a$"ic%1a$1+ 6hen d #e# a$e n " m di!ied ! $ $ena1 d+#!%nc"i n, lo-e#ed &ei5$#e th#e&hold a& %a. occ$# -ith %e i 'iti&. MISCELLANEOUS: A. P$ 2enecid :$&$al do&e of 500%' fo$# ti%e& dail.; bloc8& #e al t$b$la# t#a &"o#t of "e icilli #e&$lti ' i $&$all. a --! 1d inc$ea#e in )enici11in 21 d 1e*e1#0 @&ef$l i alte# ati3e #e'i%e & fo# &."hili& i co%bi atio -ith a%o9icilli , o# i ci#c$%&ta ce& -he hi'he# blood le3el& of "e icilli a#e de&i#ed. SPECIFIC AGENTS: A. A7%e %# )enici11in G0 Thi& fo#%$latio i& $&$all. $&ed i "atie t& -ho #e?$i#e in"$a*en %# )enici11in ! $ m $e #e*e$e $ c m)1ica"ed in!ec"i n# :e'= %e i 'iti&, " e$%o ia;. 3.4 %e? of 7F acco%"a . each 1 %illio $ it :1M@; of "e icilli * a d h+)e$.a1emia %a. occ$# "a#tic$la#l. -he hi'h do&e& a#e 'i3e to "atie t& -ith #e al d.&f$ ctio .

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+. P$ caine )enici11in G0 Re) #i" $+, in"$am%#c%1a$ fo#%$latio that "#o3ide& "#olo 'ed blood le3el& of "e icilli . Ma. be $&ed fo# t#eat%e t of $ co%"licated " e$%o ia ca$&ed b. "e icilli -&$&ce"tible !t#e"tococc$& " e$%o iae, &."hili&. 8P$ caine $eac"i n8 cha#acte#i5ed b. di55i e&&, "al"itatio &, a$dito#. o# 3i&$al di&t$#ba ce&, fea# of i%"e di ' death. !.%"to%& $&$all. #e&ol3e -ithi 5-10 %i $te&. C. Ben5a"hine )enici11in G0 L n/ ac"in/ in"$am%#c%1a$ fo#%$latio that "#o3ide& lo-, blood le3el& fo# 3-4 -ee8&. @&ed fo# &."hili& :"#i%a#., &eco da#., late t;, #he$%atic fe3e# "#o"h.la9i&, !t#e"tococcal "ha#. 'iti&. D. Penici11in G/Penici11in V90 O#al fo#%& of "e icilli . )e icilli * i& &$&ce"tible to b#ea8do- b. 'a&t#ic acid -hich i& -h. it ha& bee la#'el. #e"laced b. )enici11in V9 6hich i# #"a21e in "he acid en*i$ nmen" ! "he #" mach0 2. )6/(C(00(/A!6->6!(!TA/T )6/(C(00(/! !ide chai %odificatio "#e3e t& de&t#$ctio of beta-lacta% #i ' b. beta-lacta%a&e& "#od$ced b. !ta"h.lococci. Th$&, $ li8e "e icilli *, "e icilli a&e-#e&i&ta t "e icilli & a#e $&ef$l fo# !ta"h.lococcal i fectio &. SPECTRUM OF ACTIVITY. G$am-) #i"i*e ae$ 2ic c cci& Me"hici11in-#%#ce)"i21e S"a)h+1 c cc%# a%$e%# 3MSSA(: 3i#ida & &t#e"tococci, le&& "ote t tha "e icilli a'ai &t !t#e"tococc$& ".o'e e& :*#o$" A &t#e"; a d !t#e"tococc$& " e$%o iae, ot acti3e a'ai &t 6 te#ococci. G$am-ne/a"i*e ae$ 2e#= /ot acti3e. Anae$ 2e#& Co%"a#ed to "e icilli , le&& acti3e o# i acti3e a'ai &t "e icilli -&$&ce"tible a ae#obe&. GENERAL CLINICAL USES: )#i%a#il. $&ed to t#eat i fectio & i 3ol3i ' MSSA #%ch a# 2ac"e$emia a## cia"ed 6i"h& '( ind6e11in/ de*ice#, -( in;ec"i n d$%/ %#e, and <( #.in and # !" "i##%e in!ec"i n#: and end ca$di"i# 6hich ma+ 2e a c m)1ica"i n ! 2ac"e$emia0 !o%eti%e& $&ed i c m2ina"i n 6i"h an amin /1+c #ide :$&$all. 'e ta%ici ; fo# thei# #+ne$/i#"ic e!!ec" a'ai &t S"a)h+1 c cci0 GENERAL SIDE EFFECTS/PRECAUTIONS: A. H+)e$#en#i"i*i"+ $eac"i n# %a ife&ted b. #a&he&, eo&i o"hilia, fe3e#, i te#&titial e"h#iti&.

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SPECIFIC AGENTS: A. Na!ci11in0 (12(M2)O fo#%$latio & . )hlebiti&, e$t#o"e ia. +. Me"hici11in0 (12(M fo#%$latio &. 0e&& co%%o l. $&ed beca$&e of i c#ea&ed #i&8 of in"e$#"i"ia1 ne)h$i"i#, &i' & a d &.%"to%& -hich i cl$de eo&i o"hilia, #a&h, #e al fail$#e, "#otei $#ia, fe3e#. C. O4aci11in0 (12(M2)O. He)a"i"i# occ$#& %o#e f#e?$e tl. tha -ith afcilli . D. Dic1 4aci11in and C1 4aci11in0 )O fo#%$latio &. The&e o#al fo#%$latio & a#e "#efe##ed o3e# o#al fo#%& of afcilli o# o9acilli beca$&e thei# 21 d 1e*e1# a$e hi/he$0 3. AM(/O-)6/(C(00(/! !ide chai %odificatio :additio of a%i o '#o$"; to ba&ic be 5.l"e icilli %olec$le i c#ea&e& &"ect#$% of acti3it. to i cl$de ae#obic '#a%- e'ati3e bacilli. SPECTRUM OF ACTIVITY. G$am-) #i"i*e ae$ 2ic c cci& !a%e acti3it. a& fo# "e icilli * b$t i& %o#e acti3e tha "e icilli a'ai &t 6 te#ococci. 0i8e "e icilli *, !ta"h.lococci a#e $&$all. #e&i&ta t to a%"icilli . G$am-ne/a"i*e ae$ 2e#= Acti3e a'ai &t %o&t 2e"a-1ac"ama#e ne/a"i*e Hem )hi1%# in!1%en5ae, 6&che#ichia coli a d )#ote$& %i#abili&, "a#tic$la#l. if i 3ol3ed -ith co%%$ it.-ac?$i#ed i fectio &, !al%o ella a d !hi'ella &"ecie&. @&$all. ot acti3e a'ai &t ae#obic '#a%- e'ati3e bacte#ia ca$&i ' ho&"ital-ac?$i#ed i fectio &. Anae$ 2e#& !ee "e icilli *. O"he$& 0i&te#ia %o oc.to'e e&. GENERAL CLINICAL USES: @&ed a& e%"i#ic the#a". i %a . co%%$ it.-ac?$i#ed i fectio & i 3ol3i ' the #e&"i#ato#. t#act :e'= b#o chiti&, &i $&iti&, otiti& %edia; -he#e f#e?$e t "atho'e & i cl$de !t#e"tococc$& " e$%o iae, 4e%o"hil$& i fl$e 5ae, $#i a#. t#act i fectio & ca$&ed b. &$&ce"tible 6&che#ichia coli. A hi'h "#e3ale ce of beta-lacta%a&e "#od$ci ' ae#obic '#a%- e'ati3e bacte#ia %a. "#ecl$de the e%"i#ic $&e of a%i o-"e icilli & fo# the&e co%%$ it.-ac?$i#ed i fectio &.

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GENERAL SIDE EFFECTS/PRECAUTIONS: A. H+)e$#en#i"i*i"+ $eac"i n# %a ife&ted b. #a&he&, eo&i o"hilia, fe3e#, i te#&titial e"h#iti&. +. A%"icilli #a&h i& a 'e e#ali5ed e#.the%ato$&, %ac$lo"a"$la# #a&h that occ$#& i "atie t& ta8i ' a%"icilli a d -ho ha3e a co c$##e t 3i#al ill e&& :e'= %o o $cleo&i&, c.to%e'alo3i#$&, 3i#al #e&"i#ato#. t#act i fectio ;. MISCELLANEOUS: 1. )#obe ecid i c#ea&e& blood le3el& :&ee GMi&cella eo$&G &ectio $ de# "e icilli *;. SPECIFIC AGENTS: A. Am)ici11in0 (12(M2)O fo#%$latio &. Mo#e effecti3e tha a%o9icilli a'ai &t !hi'ella. +. Am 4ici11in0 )O fo#%$latio . Mo#e acti3e tha a%"icilli a'ai &t !al%o ella. =a* $ed *e$ am)ici11in 2eca%#e& '( 2e""e$ a2# $)"i n, -( ! d d e# n " in"e$!e$e 6i"h a2# $)"i n, <( 1e## !$e7%en" d #in/ :H8 3& H6 ho$#& fo# a%"icilli ;. 4. CA>+OIE-)6/(C(00(/! !ide chai %odificatio :&$b&tit$tio of a%i o '#o$" -ith a ca#bo9. '#o$" a d othe#&; i c#ea&e& &"ect#$% of acti3it. to i cl$de othe# ae#obic '#a%- e'ati3e bacilli. SPECTRUM OF ACTIVITY. G$am-) #i"i*e ae$ 2ic c cci& Le## ac"i*e "han am)ici11in a/ain#" En"e$ c cci, !t#e"tococc$& " e$%o iae, !t#e"tococc$& ".o'e e&. N " ac"i*e a/ain#" %ethicilli -&$&ce"tible !ta"h.lococc$& a$#e$& 3MSSA(0 G$am-ne/a"i*e ae$ 2e#= Ac"i*e a/ain#" %a . ho&"ital-ac?$i#ed "atho'e & &$ch a& P#e%d m na# ae$%/in #a, 6 te#obacte#iaceae :i dole "o&iti3e )#ote$&, 6 te#obacte#, Mo#'a ella;. Simi1a$ ac"i*i"+ " am)ici11in a/ain#" Hem )hi1%# #)ecie#, E#che$ichia c 1i, P$ "e%# mi$a2i1i#0 Inac"i*e a/ain#" 91e2#ie11a0 Anae$ 2e#& +acte#oide& f#a'ili& :at hi'h co ce t#atio &;. GENERAL CLINICAL USES: @&$all. i c m2ina"i n 6i"h an "he$ an"i2i "ic 3/ene$a11+ an amin /1+c #ide( ! $ ae$ 2ic /$amne/a"i*e in!ec"i n# :e&"eciall. ). ae#$'i o&a;.

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GENERAL SIDE EFFECTS/PRECAUTIONS: A. H+)e$#en#i"i*i"+ $eac"i n# %a ife&ted b. #a&he&, eo&i o"hilia, fe3e#, i te#&titial e"h#iti&. SPECIFIC AGENTS: A. Ca$2enici11in indan+1 # di%m0 )O fo#%$latio . A i da .l e&te# -hich #elea&e& acti3e ca#be icilli afte# b#ea8do- i the li3e#. L 6 21 d 1e*e1# )$ec1%de i"# %#e ! $ in!ec"i n# %"#ide "he %$ina$+ "$ac"0 +. Tica$ci11in0 (12(M fo#%$latio &. !i%ila# &"ect#$% to ca#be icilli e9ce"t that it i& --> "ime# m $e ac"i*e "han ca$2enici11in a/ain#" P#e%d m na# ae$%/in #a0 !ide effect& i cl$de occa&io al bleedi ' d$e to "latelet d.&f$ ctio . Each /$am ! "ica$ci11in i& acco%"a ied b. ?0-me7 ! # di%m0 @#eido"e icilli & ha3e a lo-e# &odi$% load :&ee &ectio o @#eido"e icilli &;. 5. @>6(DO-)6/(C(00(/! A$#the# &ide chai %odificatio & i c#ea&ed the &"ect#$% of acti3it. to i cl$de additio al ae#obic '#a%- e'ati3e bacilli. SPECTRUM OF ACTIVITY. G$am-) #i"i*e ae$ 2ic c cci& M $e ac"i*e "han ca$2 4+-)enici11in# a/ain#" En"e$ c cci, !t#e"tococc$& " e$%o iae, !t#e"tococc$& ".o'e e&. G$am-ne/a"i*e ae$ 2e#= Ac"i*e a/ain#" %a . ho&"ital-ac?$i#ed "atho'e & &$ch a& P#e%d m na# ae$%/in #a 3m $e ac"i*e "han ca$2 4+-)enici11in#(, 6 te#obacte#iaceae :e'= 91e2#ie11a, i dole "o&iti3e )#ote$&, 6 te#obacte#, Mo#'a ella;. Mo#e acti3e tha tica#cilli a'ai &t 4e%o"hil$& i fl$e 5ae. PHARMACOKINETICS: 4a& d #e-de)enden", n n-1inea$ .ine"ic#0 GENERAL CLINICAL USES: !i%ila# to ca#bo9.-"e icilli &. GENERAL SIDE EFFECTS/PRECAUTIONS: A. H+)e$#en#i"i*i"+ $eac"i n# %a ife&ted b. #a&he&, eo&i o"hilia, fe3e#, i te#&titial e"h#iti&. SPECIFIC AGENTS:
A. Me0locillin (Me0linR)% #0 #- formulations. +imilar spectrum of activity to ticarcillin including comparable activity against .seudomonas aeruginosaH invitro may be more active against 1le2siella pneumoniae% *ach gram contains D.EAme; of sodium.

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!. Piperacillin (PipracilR)% #0 #- formulations. #t is 3- old more active than me0locillin against Pseudomonas aeruginosa% *ach gram contains D.$Eme; of sodium. F. .*6#1#44#6 #6=#!#T/, 1/-!#6AT#/6+ #n order to overcome resistance due to beta-lactamase enzymes, various penicillins have been combined with beta-lactamase inhibitors that irreversi2ly inhi2its 2eta-lactamases% ?nfortunately, not all beta-lactamase enzymes can be neutralized by the currently available beta-lactamase inhibitors. These inhi2itors generally do not have any clinically use ul anti2acterial activity% 1urrently available products combine ampicillin, amoxicillin, ticarcillin, or piperacillin with a beta-lactamase inhibitor. The intrinsic anti2acterial activity o the penicillin is an important factor in the e com2inations% ectiveness o the penicillin4inhi2itor

7ifferences !etween #nhibitors. Sul2actam5 4ittle activity against 1lass # beta-lactamases.

Clavulanate5 +trongest inducer of type # chromosomal beta-lactamases. Ta0o2actam5 Wea(est inducer of type # chromosomal beta-lactamasesH most potent inhibitor.

.=A,-A1/>#6*T#1+8 .harmaco(inetics of inhibitors are similar to their respective penicillins. G*6*,A4 14#6#1A4 ?+*+8 As monotherapy for mi&ed aero2ic4anaero2ic in ections caused by susceptible bacteria 2eg8 intraabdominal gynecologic infections, s(in and soft tissue infections such as diabetic ulcers3. <or serious infections or infections in which resistant gram-negative bacteria are suspected a second agent 2eg8 aminoglycoside3 can be added. G*6*,A4 +#7* *<<*1T+ .,*1A?T#/6+8 A. "ypersensitivity reactions manifested by rashes, eosinophilia, fever, interstitial nephritis.

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+.*1#<#1 AG*6T+8 A. !mpicillin4sul2actam (UnasynR)% #0 #- formulations. =as the spectrum of ampicillin plus beta-lactamase producing organisms such as "emophilus in luen0ae6 Mora&ella catarrhalis6 ,acteroides ragilis6 *scherichia coli (although suscepti2ilities to *scherchia coli is varia2le)6 Proteus species6 1le2siella species6 *nterobacter aerogenes, !cineto2acter calcoaceticus6 methicillin-susceptible +taphylococcus aureus (MSS!)% ?seful for infections due to these beta-lactamase producing bacteria 2sinusitis, otitis3H mixed aerobic anaerobic infections, 2ite wounds.
!. !mo&icillin4clavulanate (!ugmentinR)% ./ formulation. +imilar to ampicillin sulbactam with respect to spectrum of activity and clinical usefulness. +ide effects include nausea, vomiting, and diarrhea which can sometimes be minimized if ta(en with meals. 1. Ticarcillin4clavulanate (TimentinR)% #0 #- formulations. =as the spectrum of ticarcillin plus beta-lactamase producing bacteria such as +taphylococcus aureus, *scherichia coli, >lebsiella species, .roteus, =emophilus species, !acteroides fragilis. 1lavulante does not increase the activity of ticarcillin against gram-negative bacteria that produce 1lass D ,ichmond-+y(es beta-lactamases 2eg8 .seudomonas, +erratia, 1itrobacter, *nterobacter3. 7. Piperacillin4ta0o2actam (7osynR)% #0 #- formulations. =as the spectrum of piperacillin plus beta-lactamase producing bacteria such as *scherichia coli, *nterobacter, 1itrobacter, .rovidencia, methicillin-susceptible +taphylococcus aureus, !acteroides fragilis, =emophilus species.

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CEPHALOSPORINS
*ail (to8a5$, )ha#%.D *oal& a d Ob<ecti3e&. +. the e d of the lect$#e the &t$de t &ho$ld be able to di&c$&& the follo-i ' abo$t ce"halo&"o#i a tibiotic&= 1. De&c#ibe thei# %echa i&% of actio a d "ha#%acolo'ic "#o"e#tie&. 2. De&c#ibe thei# &"ect#$% of acti3it.. 3. De&c#ibe thei# %a<o# &ide effect&. 4. Di&c$&& thei# $&e i the cli ical &etti '. >e?$i#ed #eadi '&. The 'oal of thi& #eadi ' i& to #ei fo#ce the cli ical a""licatio of ce"halo&"o#i &. *#a%- e'ati3e !e"&i& a d !e"tic !hoc8. Cha"te# 112, "a'e& 2237-2250. Ce)ha1 #) $in '#" Cefa5oli Ce"halothi Ce"ha"i#i Ce"hale9i Cefad#o9il 1-2'% 1-2'% 0.5-1'% 250-500%' 500%' (12(M (12(M (12(M )O )O 8 4-6 4-6 6 12 .e& .e& .e& .e& .e& D #e R %"e D #in/ In"e$*a1 Rena1

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Ce"h#adi e -nd Cefa%a dole Cef$#o9i%e Cefo9iti Cefoteta Cef%eta5ole Cefaclo# Cef"#o5il Cef"odo9i%e 0o#aca#bef <
$d

250%' J500%'K 1-2'% 0.75-1.5'% 250-500%' 1-2'% 1-2'% 2'% 250-500%' 250-500%' 200-400%' 200-400%' 1-2'% 1-2'% 1-2'% 1-2'% 1-2'% 400%' 200%'

)O )O (12(M (12(M )O (12(M (12(M (1 )O )O )O )O (12(M (12(M (12(M (12(M (12(M )O )O

6 12 4-6 8 12 4-6 12 6-12 8 12-24 12 12 6-8 12-24 8-12 8 12 24 12

.e&

.e& .e& .e& .e& .e& .e& .e& .e& .e& .e& .e& .e&

Cefota9i%e Ceft#ia9o e Cefti5o9i%e Cefta5idi%e Cefo"e#a5o e Cefi9i%e >"h Cefi"i%e

.e&

.e&

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(. +AC7*>O@/D Ce"halo&"o#i & a#e beta-lacta% co%"o$ d& i -hich the beta-lacta% #i ' i& f$&ed to a 6-%e%be#ed dih.d#othia5i e #i ', th$& fo#%i ' the ce"he% $cle$&. Side chain m di!ica"i n# " "he ce)hem n%c1e%# c n!e$# '( an im)$ *ed #)ec"$%m ! an"i2ac"e$ia1 ac"i*i"+, -( )ha$mac .ine"ic ad*an"a/e#, and <( addi"i na1 #ide e!!ec"#0 +a&ed o thei# &"ect#$% of acti3it., ce"halo&"o#i & ca be b#oadl. cate'o#i5ed i to ! %$ /ene$a"i n#0 ((. M6C4A/(!M OA ACT(O/ B )4A>MACO0O*(C )>O)6>T(6! 1. )#e3e t& cell -all &. the&i& b. bi di ' to e 5.%e& called "e icilli bi di ' "#otei & :)+)&;. The&e e 5.%e& a#e e&&e tial fo# the &. the&i& of the bacte#ial cell -all. -0 Bac"e$icida10 3. C ncen"$a"i n-inde)enden" 2ac"e$icida1 acti3it., -ith %a9i%al 8illi ' at 4-5 ti%e& the M(C of the o#'a i&%. 4. Cli icall. &i' ifica t "o&t-a tibiotic effect i& ot ob&e#3ed. *i3e the&e "ha#%acod. a%ic "#o"e#tie& :co ce t#atio -i de"e de t bacte#icidal acti3it. a d lac8 of a "o&t-a tibiotic effect, )"ima1 d #in/ $e/imen# #h %1d 2e de#i/ned " c n"in% %#1+ main"ain d$%/ 1e*e1# a2 *e "he MIC ! )a"h /en#0 (((. !)6CT>@M OA ACT(1(TE ( 'e e#al, '#" /ene$a"i n ce)ha1 #) $in# ha3e 2e""e$ ac"i*i"+ a/ain#" /$am-) #i"i*e 2ac"e$ia a d le&& '#a%- e'ati3e acti3it., -hile <$d /ene$a"i n a/en"#, -ith a fe- e9ce"tio &, ha3e 2e""e$ /$am-ne/a"i*e ac"i*i"+ a d le&& '#a%-"o&iti3e acti3it.. The o l. fo$#th 'e e#atio a'e t ha& both '#a%-"o&iti3e a d '#a%- e'ati3e acti3it.. (1. M6C4A/(!M! OA +ACT6>(A0 >6!(!TA/C6 (t i& ot $ co%%o fo# &e3e#al #e&i&ta ce %echa i&%& to be o"e#ati ' &i%$lta eo$&l.. 1. de#"$%c"i n ! 2e"a-1ac"am $in/ b. 2e"a-1ac"ama#e#, a i tact beta-lacta% #i ' i& e&&e tial fo# a tibacte#ial acti3it. 2. a1"e$ed a!!ini"+ of ce"halo&"o#i & fo# thei# "a$/e" #i"e, the "e icilli bi di ' "#otei & 3. dec$ea#ed )ene"$a"i n ! an"i2i "ic " "he "a$/e" #i"e, the )+)&. Thi& i& o l. a""licable to '#a%- e'ati3e bacte#ia beca$&e '#a%"o&iti3e bacte#ia lac8 a o$te# cell %e%b#a e, a d the#efo#e "e et#atio to the ta#'et &ite i& ot a "#oble%. 1. *6/6>A0 (/AO>MAT(O/ AO> C6)4A0O!)O>(/!

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1. SPECTRUM OF ACTIVITY. PHARMACOKINETICS: *e e#all. di&t#ib$te& -ell i to the l$ ', 8id e., $#i e, &. o3ial, "le$#al, a d "e#ica#dial fl$id&. Pene"$a"i n in" "he ce$e2$a1 #)ina1 !1%id :C!A; of &o%e 3#d 'e e#atio ce"halo&"o#i & 3ce! "a4ime, ce!"$ia4 ne, and ce!"a5idime( i# ade7%a"e " e!!ec"i*e1+ "$ea" 2ac"e$ia1 menin/i"i#0 E1imina"i n i# )$ima$i1+ *ia "he .idne+#, tho$'h a fe- e4ce)"i n# inc1%de ce! )e$a5 ne and ce!"$ia4 ne -hich ha3e &i' ifica t bilia#. eli%i atio . GENERAL CLINICAL USES: Thei# b#oad &"ect#$% of acti3it. a d &afet. "#ofile %a8e the ce"halo&"o#i & o e of the %o&t -idel. "#e&c#ibed cla&& of a ti%ic#obial&. The ea$1ie$ /ene$a"i n ce)ha1 #) $in# a#e co%%o l. $&ed fo# c mm%ni"+-ac7%i$ed in!ec"i n#, -hile the 1a"e$ /ene$a"i n a/en"#, -ith thei# bette# &"ect#$% of acti3it. a'ai &t '#a%- e'ati3e bacte#ia %a8e the% $&ef$l fo# h #)i"a1-ac7%i$ed in!ec"i n# $ c m)1ica"ed c mm%ni"+-ac7%i$ed in!ec"i n#0 GENERAL SIDE EFFECTS/PRECAUTIONS: A. H+)e$#en#i"i*i"+ $eac"i n# %a ife&ted b. #a&he&, eo&i o"hilia, fe3e# :1-3L;, i te#&titial e"h#iti&. *i3e the &t#$ct$#al &i%ila#it. of ce"halo&"o#i & a d "e icilli &, a e&ti%ated '-@A ! )a"ien"# 6i"h )enici11in a11e$/ie# 6i11 a1# 2e h+)e$#en#i"i*e " ce)ha1 #) $in#0 Ce)ha1 #) $in# #h %1d 2e a* ided in )a"ien"# 6i"h immedia"e a11e$/ic $eac"i n# " )enici11in# :e'= a a"h.la9i&, b#o cho&"a&%, h."ote &io , etc.;. Ce"halo&"o#i & %a. be "$ied 6i"h ca%"i n in )a"ien"# 6i"h de1a+ed $ mi1d $eac"i n# " )enici11in0 +. Th$ m2 )h1e2i"i# :1-5L;. 1(. A(>!T *6/6>AT(O/ C6)4A0O!)O>(/! SPECTRUM OF ACTIVITY. G$am-) #i"i*e ae$ 2ic c cci& Ve$+ ac"i*e a/ain#" S"$e)" c cci )+ /ene# 3G$ %) A #"$e)(, S"$e)" c cc%# a/a1ac"iae 3G$ %) B #"$e)(, *i$idan# #"$e)" c cci0 Methicilli -#e&i&ta t !ta"h.lococci, 6 te#ococci, "e icilli -#e&i&ta t !t#e"tococc$& " e$%o iae a#e #e&i&ta t. G$am-ne/a"i*e ae$ 2e#= Co%%o l. acti3e a'ai &t 6&che#ichia coli, )#ote$& %i#abili&, a d 7leb&iella " e$%o iae, tho$'h &$&ce"tibilitie& %a. 3a#.. ( ade?$ate acti3it. a'ai &t Mo#a9ella cata##hali& a d 4e%o"hil$& i fl$e 5ae. Anae$ 2e#& Acti3e a'ai &t %o&t "e icilli -&$&ce"tible a ae#obe& fo$ d i the o#al ca3it., e9ce"t tho&e belo 'i ' to the +acte#oide& f#a'ili& '#o$".

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GENERAL CLINICAL USES. Unc m)1ica"ed, c mm%ni"+-ac7%i$ed in!ec"i n# of the &8i a d &oft ti&&$e a d $#i a#. t#act. @&ef$l fo# #e&"i#ato#. t#act i fectio & ca$&ed b. "e cilli -&e &iti3e !t#e"tococc$& " e$%o iae b$t ot fo# 4e%o"hil$& i fl$e 5ae a d Mo#a9ella cata##hali&. Mhile effecti3e fo# the&e i fectio &, othe# le&& e9"e &i3e alte# ati3e& &ho$ld be $&ed -he a""#o"#iate beca$&e of thei# efficac. a d a##o-e# &"ect#$% of acti3it. :e'= "e icilli &, t#i%etho"#i%2&$lfa%etho9a5ole;. )a#e te#al '#" /ene$a"i n a'e t& a#e $&ed fo# #%$/ica1 6 %nd )$ )h+1a4i#0 SPECIFIC AGENTS: A. Ce!a5 1in 3Ance! , 9e!5 1, Ce)ha1 "hin 39e!1in , Van"a/e, Ce)h)i$in 3Ce!ad+1(0 (12(M fo#%$latio &. !"ect#$% of ce"halothi a d cefa5oli a#e &i%ila# e9ce"t that cefa5oli i& &li'htl. %o#e acti3e a'ai &t 6&che#ichia coli a d 7leb&iella &"ecie&. The 1 n/e$ ha1!-1i!e ! ce!a5 1in allo-& le&& f#e?$e t do&i '. +. Ce)ha1e4in 39e!1e4, 9e!"a2, Bi ce!(, Ce)h$adine 3An#) $, Ve1 #e!(, Ce!ad$ 4i1 3D%$ice!, U1"$ace!(0 )O fo#%$latio &. 0e&& f#e?$e t do&i ' -ith cefad#o9il. 1(. !6CO/D *6/6>AT(O/ C6)4A0O!)O>(/! The#e a#e - /$ %)# 6i"hin "he -nd /ene$a"i n a/en"# that diffe# i thei#= 1; &"ect#$% of acti3it. a d 2; ad3e#&e #eactio "#ofile. The&e '#o$"& a#e the 8"$%e8 #ec nd /ene$a"i n ce)ha1 #) $in# :cefa%a dole, cef$#o9i%e; a d the ce)ham+cin# :cefo9iti , cefoteta , cef%eta5ole;. SPECTRUM OF ACTIVITY. G$am-) #i"i*e ae$ 2ic c cci& In /ene$a1, t#$e 2 d 'e e#atio a/en"# a$e co%"a#able to 1&t 'e e#atio a'e t& a'ai &t o e te#ococcal &t#e"tococci: a$e 1e## ac"i*e in*i"$ , 2%" #"i11 ha*e ade7%a"e ac"i*i"+ a/ain#" MSSA0 Co%"a#ed to the 1&t 'e e#atio a'e t&, the ce)ham+cin# a#e 1e## ac"i*e a/ain#" /$am-) #i"i*e c cci. +oth '#o$"& of ce"halo&"o#i & a#e i acti3e a'ai &t %ethicilli -#e&i&ta t !ta"h.lococci a d 6 te#ococci. G$am-ne/a"i*e ae$ 2e#0 The 8"$%e8 ce)ha1 #) $in# a#e %o#e acti3e tha 1&t& fo# Hem )hi1%# in!1%en5ae, M $a4e11a ca"a$$ha1i#, /ei&&e#ia %e i 'itidi&, a d &o%e 6 te#obacte#iaceae. The ce)ham+cin# i &o%e i &ta ce& :e'= ce! "e"an( ha3e im)$ *ed ac"i*i"+ a/ain#" En"e$ 2ac"e$iaceae. Anae$ 2e#& Ce"ha%.ci & a#e acti3e a'ai &t %o&t a ae#obe& fo$ d i the %o$th a& -ell a& colo :e'= +acte#oide& &"ecie&, i cl$di ' +acte#oide& f#a'ili&;. GENERAL CLINICAL USES. The 8"$%e8 -nd /ene$a"i n a/en"# a$e %#e!%1 ! $ c mm%ni"+-ac7%i$ed in!ec"i n# of the #e&"i#ato#. t#act :4e%o"hil$& i fl$e 5ae, Mo#a9ella cata##hali&, !t#e"tococc$& " e$%o iae; a d $ co%"licated $#i a#. t#act i fectio & :6&che#ichia coli;. The

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ce)ham+cin /$ %) i& $&ef$l fo# mi4ed ae$ 2ic/anae$ 2ic in!ec"i n# of the &8i a d &oft ti&&$e&, i t#a-abdo%i al, a d '. ecolo'ic i fectio &, a d #%$/ica1 )$ )h+1a4i#0 SIDE EFFECTS/PRECAUTIONS. The ce)ham+cin a'e t& ha3e a &ide chai called the %eth.lthiotet#a5ole :MTT; '#o$" -hich "#edi&"o&e& "atie t& to= 1; h+) )$ "h$ m2inemia and 21eedin/ b. di&t$#bi ' &. the&i& of 3ita%i -8 de"e de t clotti ' facto#&. >i&8 facto#& a#e #e al o# he"atic di&ea&e, "oo# $t#itio , the elde#l., a d ca ce#. 2; alcohol i tole#a ce b. ca$&i ' a di#%1!i$am-1i.e $eac"i n, a* id a1c h 1 )$ d%c"# ! $ #e*e$a1 da+# a!"e$ an"i2i "ic# ha*e #" ))ed0 SPECIFIC AGENTS:
A. Ce amandole (MandolR)% 2#0 #-3 formulations. !etter activity against selected methicillin-susceptible +taphylococcus aureus than cefazolin. -ay not be reliable therapy for =emophilus influenzae. Although not a cephamycin, it contains an +MTT side chain% !. Ce ur&oime (7inace 6 1e uro&)% #0 #- ./ formulations. +omewhat less potent against +taphylococcus aureus, but more potent against +treptococcus pneumoniae and +treptococcus pyogenes than Dst generation cephalosporins. Active against =emophilus influenzae, -oraxella catarrhalis, *scherichia coli, .roteus mirabilis, >lebsiella species. Although cefuroxime has been used for the treatment of bacterial meningitis caused by =. influenzae, it is not recommended because studies show neurologic deficits are more fre;uent in children treated with cefuroxime versus selected Ird generation cephalosporins 2cefotaxime, ceftriaxone3. This finding is related to delayed sterilization of cerebral spinal fluid. 1. Ce onicid (MonocidR)% #0 #- formulation. +imilar to cefamandole and cefuroxime, though less active against gram-positive cocci 2methicillin-susceptible +taphylococcus aureus, Group A strep, +treptococcus pneumoniae3. 4ong half-life allows once daily dosing. 7. Ce o&itin (Me o&inR)% #0 #- formulations. A cephamycin6 which is less active than Dst generation agents against gram-positive bacteria. Active against 6eisseria gonorrhea, but less active than @true@ second generation cephalosporins against =emophilus influenzae. *. Ce otetan (Ce otanR)% #0 #- formulations. A cephamycin with similar activity to cefoxitin. 1ompared to second generation cephalosporins and cefoxitin, has improved activity against *ntero2acteriaceae including *ntero2acter . Also active against

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=emophilus influenzae, 6eisseria gonorrhea, 6eisseria meningitidis. Generally '-G fold less active than cefoxitin against grampositive cocci. <or ,acteroides ragilis6 is compara2le to ce o&itin8 but less active than ce o&itin against non-,acteroides ragilis species within the !acteroides fragilis groupH the clinical significance of which is un(nown. ?sed in surgical wound prophyla&is when activity against ,acteroides ragilis is needed. <. Ce meta0ole (7e a0oneR)% #0 #- formulations. A cephamycin6 similar to cefoxitin and cefotetan. +imilar to cefoxitin and more active than cefotetan against methicillin-susceptible +taphylococcus aureus. '-G fold more active than cefoxitin against *nterobacteriaceae 2eg8 *scherichia coli, >lebsiella sp, .roteus mirabilis3. Also active against =emophilus influenzae and -oraxella catarrhalis. !acteroides fragilis is similar to cefoxitin, against other !acteroides species, is similar or slightly less active than cefoxitin. ?sed in surgical wound prophyla&is when activity against ,acteroides ragilis is needed6 repeat dose would 2e necessary in procedures lasting more than 3 hours%

G. Ce aclor (Ceclor)6 Ce pro0il (Ce 0il)6 $oracar2e ($ora2id)6 Ce podo&ime pro&etil (.antin)% ./ formulations. 1efaclor is more commonly associated with a serum sic(ness li(e illness. 4oracarbef is a new category of compounds called the carbacephems, which are analogues of cephalosporins. $oracar2e is the car2acephem analogue o ce aclor% =. Ce uro&ime a&etil (Ce tinR)% ./ formulation of cefuroxime. #s the oral ester of cefuroxime that is hydrolyzed to cefuroxime during absorption. 0#. T=#,7 G*6*,AT#/6 1*.=A4/+./,#6+ #mproved activity against *nterobacteriaceae associated with hospital-ac9uired in ections8 some agents are also active against .seudomonas aeruginosa which is a fre;uent cause of hospital-ac;uired pneumonia.

+.*1T,?- /< A1T#0#T5. Gram-positive aero2ic cocci5 1efotaxime, ceftriaxone, and ceftizoxime are active against methicillinsusceptible +taphylococcus aureus 2though less than Dst and some 'nd generation agents3, very active against Groups A and ! streptococci, and viridans streptococci. Ce ota&ime and ce tria&one are more active than ce ti0o&ime against Streptococcus pneumoniae6 particularly intermediately-penicillin resistant +treptococcus pneumoniae. 6one are active against methicillin-resistant +taphylococci, *nterococci, and 4isteria monocytogenes.

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Gram-negative aero2es5 0ery active against =emophilus influenzae, -oraxella catarrhalis, 6eisseria meningitidis, and *nterobacteriaceae 2eg8 *scherichia coli, >lebsiella species, .roteus mirabilis, .rovidencia3found in hospital and community-ac;uired infections. +ome *nterobacter species have a tendency to become resistant during cephalosporin therapy, and thus cephalosporins are not the drugs of choice for *nterobacter infections. /nly and ce ta0idime and ce opera0one are active against Pseudomonas aeruginosa, and ce ta0idime is preferred because it is more potent than ce opera0one against gram-negative bacteria. !naero2es5 1efotaxime, ceftriaxone, and ceftizoxime are ade;uate for oral anaerobes.

G*6*,A4 14#6#1A4 ?+*+. :or in ections involving gram-negative 2acteria6 particularly hospital-ac9uired in ections or complicated community-ac;uired infections of the respiratory tract, blood, intra-abdominal, s(in and soft tissue, and urinary tract. !ecause of their activity includes the aerobic gram negative bacteria covered by aminoglycosides, they may be an alternative to aminoglycosides in some patients with renal dysfunction.
The clinical situations re;uiring use of Ird generation cephalosporins are li(ely to be encountered in patients who are hospitalized, have recently received antibiotics, or are immunocompromised.

+.*1#<#1 AG*6T+8 A. Ce ota&ime (Cla oran)6 Ce tria&one (Rocephin)6 Ce ti0o&ime (ce i0o&) % #0 #- formulations. Activity against *nterobacteriaceae 2eg8 *scherchia coli, >lebsiella pneumoniae3 are similar. +one are active against Pseudomonas aeruginosa% /nly ce ota&ime and ce tria&one achieve ade;uate drug levels in the cerebral spinal fluid to constitute reliable empiric therapy for 2acterial meningitis. Ce tria&one is eliminated to a significant degree by the biliary system, and as a result, 2iliary pseudo-lithiasis has been reported as a side effect of this agent.
!. Ce ta0idime (:orta06 Ta0idime6 Ta0ice )6 Ce opera0one (Ce o2id) . #0 #- formulations. +pectrum includes Pseudomonas aeruginosa 2against which ceftazidime is more active3 and *nterobacteriaceae covered by the Ird generation agents in item A above. 7isadvantages of cefoperazone are8 D3 the least active Ird generation agent against *nterobacteriaceae and '3 contains -TT side chain 2see +#7* *<<*1T+ .,*1A?T#/6+ under 'nd generation agents3.

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1. Ce i&ime (Supra&)6 Ce ti2uten (Ceda&) %./ formulations administered once or twice daily. #nactive against methicillinsusceptible +taphylococcus aureus, thus not good choices for s(in and soft tissue infections. Generally very active against gramnegative bacteria causing community-ac;uired infections2=emophilus influenzae, -oraxella catarrhalis3. Ce i&ime is effective as a single dose therapy or uncomplicated +eisseria gonorrhea in ection% While used in otitis media, ce i&ime may not routinely eradicate Streptococcus pneumoniae% 0##. </?,T= G*6*,AT#/6 1*.=A4/+./,#6 =as the excellent activity against *nterobacteriaceae and .seudomonas aeruginosa which is similar to ceftazidime. #n addition, it also has better gram-positive activity than ceftazidime.

+.*1T,?- /< A1T#0#T5. Gram-positive aero2ic cocci5 Active against +treptococcus pneumoniae, and Groups A and ! streptococci. Though active against methicillin-susceptible +taphylococcus aureus, it is less potent than the Dst and 'nd generation agents. Gram-negative aero2es5 +imilar to ceftazidime.
!naero2es5 6ot active against !acteroides fragilis.

G*6*,A4 14#6#1A4 ?+*+. +imilar to Ird generation agents. +.*1#<#1 AG*6T8 A. Ce epime (Ma&ipimeR)% #0 #- formulations.

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AM(/O*0ECO!(D6!
*ail (to8a5$, )ha#%.D *oal& a d Ob<ecti3e&. +. the e d of the lect$#e the &t$de t &ho$ld be able to di&c$&& the follo-i ' abo$t a%i o'l.co&ide a tibiotic&= 1. De&c#ibe thei# %echa i&% of actio a d "ha#%acolo'ic "#o"e#tie&. 2. De&c#ibe thei# &"ect#$% of acti3it.. 3. De&c#ibe thei# %a<o# &ide effect& a d d#$' i te#actio &. 4. Di&c$&& thei# $&e i the cli ical &etti '. (. +AC7*>O@/D A%i o'l.co&ide a tibiotic& ha3e a e&&e tial &i9-%e%be#ed #i ' -ith a%i o-'#o$" &$b&tit$tio &, th$& the a%e a%i oc.clitol. The. ha3e e9celle t acti3it. a'ai &t ae#obic '#a%- e'ati3e bacte#ia f#e?$e tl. &ee i ho&"ital-ac?$i#ed i fectio &. 4o-e3e#, thei# t-o %a<o# to9icitie& a#e ne)h$ " 4ici"+ a d " " 4ici"+0 ((. M6C4A/(!M OA ACT(O/ B )4A>MACO0O*(C )>O)6>T(6! 1. In"e$!e$e# 6i"h 2ac"e$ia1 )$ "ein #+n"he#i# b. bi di ' to the <BS $i2 # ma1 #%2%ni". A o9.'e -de"e de t t#a &"o#t &.&te% i& ece&&a#. fo# a%i o'l.co&ide& to #each thei# ta#'et &ite, the "$an#) $" #+#"em i# inhi2i"ed 2+ di3ale t catio & :CaFF, M'FF;, 1 6 )H, anae$ 2ia#i#, a d h."e#o&%ola#it.. 2. Ra)id1+ 2ac"e$icida1. 3. C ncen"$a"i n-de)enden" 2ac"e$icida1 acti3it., -hich %ea & that the #ate a d e9te t of bacte#ial 8illi ' i c#ea&e& a& d#$' co ce t#atio & i c#ea&e. 4. P #"-an"i2i "ic e!!ec" :ie;= co ti $ed 8illi ' of bacte#ia de&"ite a tibiotic le3el& belo- the M(C of the o#'a i&%.

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The&e "ha#%acod. a%ic "#o"e#tie& :c ncen"$a"i n-de)enden" .i11in/ and ) #"-an"i2i "ic e!!ec" i& the #atio ale fo# o ce dail. do&i ' of a%i o'l.co&ide&. (((. )4A>MACO7(/6T(C! 1. Ab&o#"tio . P $ $a1 a2# $)"i n0 In"$am%#c%1a$ a2# $)"i n i# / d. )ea8 blood le3el& a#e achie3ed -ithi 0.5-1.5 ho$#&.

2. Di&t#ib$tio . @#i e, 8id e., e dol.%"h, a d "e#il.%"h of the i e# ea#. >ea&o able co ce t#atio & a#e achie3ed i bo e, &. o3ial fl$id, a d "e#ito eal fl$id. )e et#atio i to the ce t#al e#3o$& &.&te% i& "oo#, th$& altho$'h co t#o3e#&ial, i t#athecal o# i t#a3e t#ic$la# ad%i i&t#atio i& &o%eti%e& t#ied. 0o- co ce t#atio & achie3ed i b#o chial &ec#etio &. 3. 6li%i atio . G1 me$%1a$ !i1"$a"i n b. the 8id e.& acco$ t& fo# al%o&t all :99L; of the eli%i atio . A%i o'l.co&ide& a#e #e%o3ed b. "e#ito eal a d he%odial.&i&. A""#o"#iate #efe#e ce& &ho$ld ca be co &$lted fo# &"ecific do&a'e #ed$ctio & fo# 3a#io$& de'#ee& of #e al d.&f$ ctio . DO!6 1. Co 3e tio al. The 'oal of co 3e tio al do&i ' of a%i o'l.co&ide& i& to achie3e "ea8 d#$' le3el& bet-ee 4-10%c'2%l a d t#o$'h co ce t#atio & le&& tha 2.0%c'2%l. 4i'he# le3el& a#e $&ed fo# &e#io$& i fectio & o# i fectio & ca$&ed b. #e&i&ta t bacte#ia, -hile lo-e# le3el& -e#e 'e e#all. $&ed fo# le&& &e#io$& i fectio &, i fectio & at &ite& -he#e a%i o'l.co&ide& a#e hi'hl. co ce t#ated :e'= $#i a#. t#act; o# -he $&ed i co%bi atio -ith othe# a tibiotic& fo# &. e#'.. D #e& :'e ta%ici , tob#a%.ci , etil%ici ; '--m//./ 31ean 2 d+ 6ei/h"( ho$#& i "atie t& -ith o#%al #e al f$ ctio . A%i8aci = 5-7.5%'28' :lea bod. -ei'ht; H8-12 ho$#& i ad$lt& -ith o#%al #e al f$ ctio . D #a/e ad;%#"men"# a#e ece&&a#. i "atie t& -ith $ena1 d+#!%nc"i n and 6h a$e 2e#e0 2. O ce dail. do&i '. A &i 'le dail. do&e :4-7%'28' of 'e ta%ici , tob#a%.ci ; i& ad%i i&te#ed o ce dail.. !i ce a%i o'l.co&ide& di&"la. co ce t#atio de"e de t bacte#icidal acti3it. a d a "o&t-a tibiotic effect, the&e t#ait& -o$ld theo#eticall. "#o3ide fo# a %o#e

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effecti3e a d le&& to9ic #e'i%e . 1a#io$& o%o'#a%& a#e a3ailable fo# o ce-dail. do&i ' of a%i o'l.co&ide&. The#e i& a lac8 of data o the efficac. a d &afet. of o ce-dail. do&i ' of a%i o'l.co&ide& i ce#tai "atie t "o"$latio & a d ce#tai t."e& of i fectio &. 1. !)6CT>@M OA ACT(1(TE A%i o'l.co&ide& a#e $&ef$l fo# i fectio & ca$&ed b. ae#obic '#a%- e'ati3e bacilli, "a#tic$la#l. the %o#e #e&i&ta t bacte#ia a&&ociated -ith ho&"ital-ac?$i#ed i fectio &. Mhile a%i o'l.co&ide& a#e al&o acti3e a'ai &t ae#obic '#a%- e'ati3e bacilli that ca$&e co%%$ it.-ac?$i#ed i fectio &, thei# to9icitie& a d the a3ailabilit. of othe# le&& to9ic a ti%ic#obial& -o$ld ot %a8e the% the d#$'& of choice fo# the&e i fectio &.

1. Ae$ 2ic /$am-ne/a"i*e 2aci11i0 1e#. acti3e, i cl$di ' 6 te#obacte#iaceae :E#che$ichia c 1i, 91e2#ie11a, P$ "e%#(, P#e%d m na# ae$%/in #a, Aci etobacte#, )#o3ide cia. Mi i%all. acti3e a'ai &t 4e%o"hil$&. 2. G$am-) #i"i*e ae$ 2e#0 Tho$'h acti3e a'ai &t !ta"h.lococci, !t#e"tococci :e'= 6 te#ococci, *#o$" + &t#e"tococci, 3i#ida & &t#e"tococci; a%i o'l.co&ide& a#e ot the "#efe##ed a'e t&. A%i o'l.co&ide& :"a#tic$la#l. 'e ta%ici , &t#e"to%.ci ; %a. be $&ed in c m2ina"i n 6i"h ce11-6a11 ac"i*e d$%/# &$ch a& betalacta%& a d 3a co%.ci fo# #+ne$/+ a/ain#" S"a)h+1 c cci and S"$e)" c cci0 :&ee '#a%-"o&iti3e bacte#ia li&ted abo3e;0 (%"o#ta tl., o l. 1 6 1e*e1# ! amin /1+c #ide :"ea8 le3el& of 3-4%c'2%l a d t#o$'h le3el& le&& tha 1%c'2%l; a#e 'e e#all. #eco%%e ded -he $&ed fo# &. e#'.. 3. Anae$ 2e# a$e n " #%#ce)"i21e beca$&e the. lac8 the ece&&a#. &.&te% that t#a &"o#t& a%i o'l.co&ide& to thei# ta#'et &ite. 4. Othe#. M.cobacte#i$% t$be#c$lo&i& :a%i8aci , &t#e"to%.ci ; a d M.cobacte#i$%-a3i$% i t#acell$la#e :a%i8aci ;. 1(. >6!(!TA/C6 >e&i&ta t ae#obic '#a%- e'ati3e bacilli to a%i o'l.co&ide& a#e "#oble%atic i &o%e a#ea&. C#o&&-#e&i&ta ce bet-ee a%i o'l.co&ide& i& ot al-a.& co%"lete. 1. Mecha i&%& of #e&i&ta ce a. amin /1+c #ide m di!+in/ en5+me# that i acti3ate the a%i o'l.co&ide 1. ade .lt#a &fe#a&e --K ade .latio of a h.d#o9.l '#o$"

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2. acet.lt#a%&fe#a&e --K acet.latio of a a%i o '#o$" 3. "ho&"hot#a &fe#a&e --K "ho&"ho#.latio of a h.d#o9.l '#o$" Ami.acin i# 1e## #%#ce)"i21e " amin /1+c #ide-m di!+in/ en5+me# beca$&e of "#otecti3e &ide chai &, a d the#efo#e %a. &till be $&ef$l -he #e&i&ta ce to 'e ta%ici o# tob#a%.ci de3elo"&. b. alte#ed #ibo&o%e bi di ' &ite& c. alte#ed a%i o'l.co&ide $"ta8e, c#o&& #e&i&ta ce to all a%i o'l.co&ide& occ$#&. !(D6 6AA6CT!2)>6CA@T(O/! 1. Ne)h$ " 4ici"+ i# a ma; $ " 4ici"+ 3?-'BA(0 >i&8 facto#& fo# e"h#oto9icit. i cl$de "#olo 'ed d$#atio of the#a"., i c#ea&ed a'e, "#ee9i&ti ' #e al i &$fficie c., #ece t a%i o'l.co&ide the#a"., co c$##e t $&e of othe# e"h#oto9i & :e'= a%"hote#ici b, 3a co%.ci , othe#&;, 3ol$%e de"letio , li3e# di&ea&e. To9icit. i& d$e to acc%m%1a"i n ! amin /1+c #ide# in )$ 4ima1 "%2%1a$ ce11# ! "he .idne+, a d i& %#%a11+ $e*e$#i21e &i ce "#o9i%al t$b$la# cell& ca #e'e e#ate. !o%e &t$die& ha3e &$''e&ted tha etil%ici a d tob#a%.ci a#e le&& e"h#oto9ic tha 'e ta%ici , ho-e3e#, othe# &t$die& ha3e bee $ able to fi d a diffe#e ce bet-ee a%i o'l.co&ide&. 2. O" " 4ici"+, inc1%din/ *e#"i2%1a$ 3'-<A( and a%di" $+ 3--'>A( i# a ma; $ " 4ici"+ a d i& %#%a11+ i$$e*e$#i21e, a d ca occ$# afte# the e d of t#eat%e t. >i&8 facto#& fo# ototo9icit. i cl$de do&e a d d$#atio of the#a"., #e"eated e9"o&$#e to a%i o'l.co&ide&, loo" di$#etic&, 3a co%.ci , h."o3ole%ia, li3e# d.&f$ ctio , i c#ea&ed a'e, hi'he# blood le3el&, #e al i%"ai#%e t. C1inica1 #+m)" m# of cochlea# to9icit. i cl$de "inni"%#, a d of 3e&tib$la# to9icit., headache, na%#ea, and * mi"in/0 3. Ne%$ m%#c%1a$ 21 c.ade %a. be "#oble%atic "a#tic$la#l. i &it$atio & -he#e e$#o%$&c$la# t#a &%i&&io i& al#ead. co%"#o%i&ed :e'= %.a&the ia '#a3i&, ad%i i&t#atio of D-t$boc$a#e, &$cci .lcholi e; i& e3e#&ed b. i t#a3e o$& calci$% 'l$co ate. (1. D>@* (/T6>ACT(O/! 1. Penici11in#0 Coad%i i&t#atio of a%i o'l.co&ide& -ith "e icilli #e&$lt i inac"i*a"i n ! "he amin /1+c #ide0 Thi& in"e$ac"i n ma+ 2e minimi5ed b. ot d#a-i ' a%i o'l.co&ide blood le3el& i%%ediatel. afte# ad%i i&t#atio of the "e icilli .

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2. He)a$in 4e"a#i -ill al&o dec#ea&e the %ea&$#ed a%i o'l.co&ide blood le3el&. Ma a'e%e t i cl$de& "#o"e# fl$&hi ' of i t#a3e o$& li e& co tai i ' he"a#i befo#e d#a-i ' a%i o'l.co&ide blood le3el&. 1((. C0(/(CA0 @!6! A%i o'l.co&ide& a#e e9celle t a'e t& fo# i fectio & d$e to ae#obic '#a%- e'ati3e bacte#ia, "a#tic$la#l. tho&e a&&ociated -ith ho&"italac?$i#ed i fectio &. The. a#e co%%o l. $&ed i co%bi atio -ith cell--all acti3e a tibiotic& :e'= beta-lacta%&; beca$&e co%bi atio & &$ch a& the&e a#e 'e e#all. &. e#'i&tic a'ai &t ae#obic '#a%- e'ati3e bacilli :e'= )&e$do%o a& ae#$'i o&a, 6 te#obacte#iaceae;. 1. 6%"i#ic the#a". fo# #e$i %# $ 1i!e-"h$ea"enin/ in!ec"i n, $ in!ec"i n "ha" i# )$e#%med " 2e d%e " $e#i#"an" ae$ 2ic /$am-ne/a"i*e 2aci11i0 The&e ci#c$%&ta ce& a#e li8el. to be e co$ te#ed i "atie t& -ho a#e h #)i"a1i5ed )a"ien"#, ha3e #ece tl. bee ho&"itali5ed, ha3e #ece tl. #ecei3ed a tibiotic&, o# a#e i%%$ oco%"#o%i&ed.

!e"tice%ia. ( t#aabdo%i al i fectio &. ( co%bi atio -ith othe# a tibiotic& acti3e a'ai &t a ae#obe&. Ac"i*i"+ ! amin /1+c #ide ma+ 2e 1imi"ed 2+= 1; anae$ 2ic en*i$ nmen" and 1 6 )H i a ab&ce&&, 2; ec#otic ti&&$e that %a. co tai di*a1en" ca"i n# :&ee &ectio o %echa i&% of actio . C m)1ica"ed $#i a#. t#act i fectio &. C m)1ica"ed, &8i a d &oft ti&&$e i fectio & :i co%bi atio -ith othe# a""#o"#iate a tibiotic& :e'=diabetic $lce#;. End ca$di"i#0 Mhe $&ed i co%bi atio -ith a cell--all acti3e d#$' :e'= beta-lacta%, 3a co%.ci ; fo# e doca#diti& d$e to '#a%"o&iti3e cocci :!ta"h.lococci, 6 te#ococci, 1i#ida & &t#e"tococci;, lo- le3el& :"ea8 3-4%c'2%l, a d t#o$'h J1.0 %c'2%l; a#e 'e e#all. #eco%%e ded. O&teo%.eliti&2&e"tic a#th#iti&. 0o-e# #e&"i#ato#. t#act. :e'= " e$%o ia;, altho$'h the lo- "4 of b#o chial &ec#etio & %a. i hibit the acti3it. of a%i o'l.co&ide&.

1(((.!)6C(A(C A*6/T!

D. Streptomycin% #- formulation. +treptomycin may be obtained by calling the pharmaceutical company ,oerig, a division of .fizer #ncorporated. ?ses include part of a combination regimen for Myco2acterium tu2erculosis (T,), in combination with a cell-wall active antibiotic 2eg8 penicillin3 for *nterococcal in ection, tularemia, and brucellosis. +ephroto&icity is less common compared to other aminoglycosides% '. Gentamicin (GaramycinR)% #0 #- formulation. '-G times the bactericidal activity of tobramycin against +erratia marcescens.

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I. To2ramycin (+e2cinR)% #0 #- formulation. Generally '-G times more active than gentamicin against .seudomonas aeruginosa. G. +etilmicin (+etromycinR)% 4ess active against either tobramycin or gentamicin against .seudomonas aeruginosa. #t is not clear if netilmicin is associated with less ototoxicity. A. +eomycin sul ate (Myci radin6 Myciguent)% ./ topical formulations. /ral neomycin 2plus oral erythromycin3 is used for bowel decontamination prior to abdominal surgery. F. Paromomycin ("umatinR)% ./ formulation. ?sed for parasitic infections and 1ryptosporridiosis in =#0 patients.

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CARBAPENEMS
*ail (to8a5$, )ha#%.D *oal& a d Ob<ecti3e&. +. the e d of the lect$#e the &t$de t &ho$ld be able to di&c$&& the follo-i ' abo$t ca#ba"e e% a tibiotic&= 1. De&c#ibe thei# %echa i&% of actio a d "ha#%acolo'ic "#o"e#tie&. 2. De&c#ibe thei# &"ect#$% of acti3it.. 3. De&c#ibe thei# %a<o# &ide effect&. 4. Di&c$&& thei# $&e i the cli ical &etti '. (. +AC7*>O@/D Ca#ba"e e%& diffe# f#o% "e icilli a d ce"halo&"o#i & b. a %eth.le e #e"lace%e t fo# the &$lf$# i the 5-%e%be#ed #i ' &t#$ct$#e. The. a#e 3e#. acti3e a'ai &t '#a%- e'ati3e, '#a%-"o&iti3e, a d a ae#obe&. ((. M6C4A/(!M OA ACT(O/ B )4A>MACO0O*(C )>O)6>T(6! 1. In"e$!e$e# 2ac"e$ia1 ce11 6a11 #+n"he#i# b. bi di ' to "e icilli -bi di ' "#otei :)+)&;, e 5.%e& -hich a#e e&&e tial fo# cell -all &. the&i&. 2. Bac"e$icida1. 3. (t i& o l. a3ailable i co%bi atio -ith ci1a#"a"in -hich inhi2i"# deh+d$ )e)"ida##e-I, a e 5.%e i the b#$&h bo#de# of the 8id e. that de'#ade& i%i"e e%. Th$&, i hibitio )$e*en"# inac"i*a"i n ! imi)enem a d it al&o ha& a ne)h$ -)$ "ec"i*e e!!ec"0 Cila&tati ha& o a tibacte#ial acti3it.. (((. )4A>MACO7(/6T(C!

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1. Ab&o#"tio . P $ $a1 a2# $)"i n0 2. Di&t#ib$tio . @#i e, &"$t$%, &. o3ial fl$id, "le$#al fl$id, bo e. 1a#iable "e et#atio i to the ce#eb#al &"i al fl$id ha& bee doc$%e ted, ho-e3e#, 3#d 'e e#atio ce"halo&"o#i & a#e the d#$'& of choice fo# %e i 'iti& fo# &$&ce"tible "atho'e &. (t& "ote tial to ca$&e &ei5$#e& al&o "#ecl$de& it f#o% bei ' a d#$' of choice fo# %e i 'iti&. 3. 6li%i atio . P$ima$i1+ *ia "he .idne+# b. 'lo%e#$la# filt#atio . A""#o"#iate #efe#e ce& &ho$ld be co &$lted fo# &"ecific do&a'e #ed$ctio & fo# 3a#io$& de'#ee& of #e al d.&f$ ctio . 1. !)6CT>@M OA ACT(1(TE +eca$&e of it& bi di ' to )+)& of both '#a%- e'ati3e a d '#a%-"o&iti3e bacte#ia, a d it& &tabilit. to %a . beta-lacta%a&e&, it ha& a *e$+ 2$ ad #)ec"$%m ! ac"i*i"+0 1. Ae#obic '#a%- e'ati3e bacte#ia. Acti3e a'ai &t 6&che#ichia coli, 7leb&iella, 6 te#obacte#, )&e$do%o a& ae#$'i o&a, /ei&&e#ia %e i 'itidi&. 2. *#a%-"o&iti3e cocci. !t#e"tococc$& " e$%o iae :i cl$di ' "e icilli -#e&i&ta t;, %ethicilli -&$&ce"tible !ta"h.lococc$&, &t#e"tococci. 6 te#ococc$& faecali& a#e %ode#atel. &$&ce"tible. 3. A ae#obe&. 1e#. acti3e, i cl$di ' +acte#oide&, A$&obacte#i$%, a ae#obic '#a%-"o&iti3e cocci. +acte#ia that a#e $e#i#"an" to i%i"e e% a#e me"hici11in-$e#i#"an" S"a)h+1 c cci, C $+ne2ac"e$i%m C9, En"e$ c cc%# !aeci%m, Xan"ham na# ma1" )hi1ia, P#e%d m na# ce)acia0 C#o&&-#e&i&ta ce -ith a%i o'l.co&ide&, cefta5idi%e, "i"e#acilli $&$all. doe& ot occ$#. +eca$&e of i d$ctio of beta-lacta%a&e&, #e&i&ta ce to ce"halo&"o#i & a d e9"a ded &"ect#$% "e icilli & %a. occ$# :a ta'o i&%;. 1(. >6!(!TA/C6 1. Mecha i&%& of #e&i&ta ce a. lo&& of a o$te# %e%b#a e "#otei :D2; -hich i& ece&&a#. fo# i%i"e e% to #each it& )+) ta#'et &ite

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b. de&t#$ctio b. beta-lacta%a&e& 1((. C0(/(CA0 @!6! Ca#ba"e e%& a#e e9celle t choice& fo# i fectio & d$e to #e&i&ta t "atho'e & o# fo# i fectio & -ith %$lti"le o#'a i&%& i 3ol3ed :e'= %i9ed, ae#obic2a ae#obic bacte#ia; fo# -hich %o#e tha 1 a tibiotic i& #e?$i#ed. Ca#ba"e e%& a#e co &ide#ed o e of the d#$'& of choice fo# ho&"italac?$i#ed 6 te#obacte#. The&e &it$atio & a#e li8el. to be e co$ te#ed i "atie t& -ho a#e ho&"itali5ed :o# #ece tl. ho&"itali5ed;, ha3e #ece tl. #ecei3ed a tibiotic&, o# -ho a#e i%%$ oco%"#o%i&ed. 1. ( t#a abdo%i al i fectio &. 2. Ob&tet#ic2'. ecolo'ic i fectio &. 3. >e&"i#ato#. t#act i fectio &. a. 4o&"ital-ac?$i#ed " e$%o ia :i cl$di ' a&"i#atio ;. 4. +acte#e%ia. 5. !e#io$& &8i a d &oft ti&&$e i fectio &. 6. +o e a d <oi t. 7. Co%"licated @T(. Ca#ba"e e%& &ho$ld ot be $&ed fo# i fectio & i -hich a a tibiotic -ith a %o#e a##o- &"ect#$% of acti3it. -o$ld &$ffice. 1(((.!)6C(A(C A*6/T!
D. Imipenem4cilastatin (Prima&inR)% #0 #- formulations. Allergic reactions 2JI&3. 7rug fever, pruritus, rash, urticaria. There is cross-reactivity with penicillins% +eizures 2%.G-D.A&3. ,is( factors include underlying central nervous system disorders 2stro(e, seizures3, renal dysfunction in patients in whom the dose was not modified. 6ausea vomiting 2D&3 particularly with rapid infusions.

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'. Meropenem (MerremR)% #0 formulation. -ay also be administered as bolus 2over A minutes3 or as a DA-I% minute infusion. 1ompared to imipenem, has the potential for fewer seizures when given to children with meningitis.

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GLYCOPEPTIDE
*ail (to8a5$, )ha#%.D *oal& a d Ob<ecti3e&. +. the e d of the lect$#e the &t$de t &ho$ld be able to di&c$&& the follo-i ' abo$t 'l.co"e"tide a tibiotic&= 1. De&c#ibe thei# %echa i&% of actio a d "ha#%acolo'ic "#o"e#tie&. 2. De&c#ibe thei# &"ect#$% of acti3it.. 3. De&c#ibe thei# %a<o# &ide effect& a d d#$' i te#actio &. 4. Di&c$&& thei# $&e i the cli ical &etti '. 5. 7 o- -he it i& a""#o"#iate to $&e the i t#a3e o$& 3e#&$& the o#al "#e"a#atio & of 3a co%.ci . >e?$i#ed #eadi '. The 'oal of thi& #eadi ' i& to #ei fo#ce the cli ical a""licatio of '.loco"e"tide a tibiotic&. /o&oco%ial a d De3ice-#elated ( fectio &, Cha"te# 118, "a'e& 2387-2399. )ha#%acothe#a". )atho"h.&iolo'ic A""#oach, 3#d 6ditio . 6dito#&= Di"i#o CT et al. (. +AC7*>O@/D ( t#od$ced i 1956 fo# the t#eat%e t of "e icilli -#e&i&ta t !ta"h.lococci, 3a co%.ci N& to9icit. a& -ell a& the i t#od$ctio of "e icilli a&e#e&i&ta t 'l.co"e"tide a tibiotic& &oo %ade 3a co%.ci a le&& $&ef$l a'e t. 4o-e3e#, the e%e#'e ce of %ethicilli -#e&i&ta t !ta"h.lococci 'a3e 3a co%.ci a i%"o#ta t #ole i the t#eat%e t of i fectio$& di&ea&e&. ((. M6C4A/(!M OA ACT(O/ B )4A>MACO0O*(C )>O)6>T(6!

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1. ( hibit& cell -all &. the&i& b. bi di ' to the D-ala .l-D-ala i e te#%i $& of cell -all "#ec$#&o# $ it&. The#e i& o co%"etitio bet-ee "e icilli a d 3a co%.ci fo# bi di ' &ite&. 2. Bac"e$icida1. (((. )4A>MACO7(/6T(C! 1. Ab&o#"tio . P $ $a1 a2# $)"i n a d la#'e ?$a titie& a#e fo$ d i &tool. Detectable blood le3el& %a. occ$# i "atie t& -ith &e3e#e i fla%%ato#. bo-el di&ea&e a d #e al i &$fficie c.. 2. Di&t#ib$tio . @#i e, 8id e.. )e et#atio i to the ce#eb#al &"i al fl$id i& e##atic. 3. 6li%i atio . Rena1 c1ea$ance *ia /1 me$%1a$ !i1"$a"i n acco$ t& fo# the %a<o#it. of eli%i atio . A""#o"#iate #efe#e ce& &ho$ld be co &$lted fo# &"ecific do&a'e #ed$ctio & fo# 3a#io$& de'#ee& of #e al d.&f$ ctio . 1. Tho$'h the 3al$e of 3a co%.ci blood le3el& i& co t#o3e#&ial a d bei ' #ee3al$ated, &o%e cli icia & %a. ha3e the follo-i ' 'oal&= "ea8 le3el& of 20-40%c'2%l a d t#o$'h le3el& le&& tha 10%c'2%l ha& t#aditio all. bee &$''e&ted. 4o-e3e#, the#e i& a lac8 of data to &$""o#t the&e the#a"e$tic 'oal&. 1. !)6CT>@M OA ACT(1(TE 1a co%.ci i& acti3e a'ai &t '#a%-"o&iti3e bacte#ia i cl$di ' !ta"h.lococci, !t#e"tococci :e'= 6 te#ococci, *#o$" + &t#e"tococci, !t#e"tococc$& " e$%o iae, "e icilli -#e&i&ta t !t#e"tococc$& " e$%o iae, Co#. ebacte#i$% C7, +acill$& &"ecie&, 0i&te#ia, a d Clo&t#idi$% difficile. 1(. >6!(!TA/C6 @ til the late 1980N&, 3a co%.ci co$ld be co$ ted $"o to be effecti3e fo# i fectio & ca$&ed b. '#a%-"o&iti3e bacte#ia &$ch a& !ta"h.lococci a d !t#e"tococci :e'= 6 te#ococc$&;. 4o-e3e#, *anc m+cin-$e#i#"an" En"e$ c cci i& e%e#'i ' a& a i%"o#ta t 6 $1d6ide )$ 21em a& the#e a#e o #eliable, alte# ati3e a ti%ic#obial the#a"ie& fo# the&e o#'a i&%&. 1. Mecha i&%& of #e&i&ta ce a. alte#ed bi di ' to 3a co%.ci ta#'et &ite

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1((. !(D6 6AA6CT!2)>6CA@T(O/! The ea#lie&t "#e"a#atio & of 3a co%.ci co tai ed i%"$#itie& -hich -e#e a&&ociated -ith &i' ifica t to9icitie& :e'= e"h#oto9icit.;. The "$#ified "#e"a#atio & a3ailable toda. a#e %$ch %o#e tole#able, tho$'h to9icitie& &till e9i&t. 1. ( f$&io #elated #eactio & #efe##ed to a& the G#ed %a &. d#o%eG occ$#& -he 3a co%.ci i& i f$&ed to #a"idl.. !.%"to%& of the 8$ed man #+nd$ me8 a$e "in/1in/ and !1%#hin/ ! "he !ace, nec., and "h $a4, and h+) "en#i n0 The %echa i&% of thi& #eactio i& tho$'ht to be #elea&e of hi&ta%i e. S1 6in/ "he in!%#i n $a"e " *e$ ' h %$ i& tole#ated b. %o&t "atie t&. 2. Ne)h$ " 4ici"+ i# %nc mm n -ith the "$#ified "#e"a#atio & a3ailable toda., ho-e3e#, to9icit. i& e ha ced -he $&ed co co%ita tl. -ith a%i o'l.co&ide&. 3. O" " 4ici"+ ha& bee a&&ociated -ith blood le3el& of 60-100%c'2%l. 4. Ne%"$ )enia 'e e#all. occ$#& d$#i ' lo ' te#% the#a"ie& &$ch a& fo# o&teo%.eliti& o# e doca#diti&. (1. D>@* (/T6>ACT(O/! 1. 4e"a#i ad%i i&te#ed co co%ita tl. -ith 3a co%.ci %a. i acti3ate 3a co%.ci , a d ha& bee a&&ociated -ith the#a"e$tic fail$#e. 1((. C0(/(CA0 @!6! ( t#a3e o$& 3a co%.ci i& 'e e#all. #e&e#3ed fo# &it$atio & -he othe# a tibiotic& that a#e $&$all. $&ed fo# '#a%-"o&iti3e i fectio & ca ot be $&ed :e'= '( 2e"a-1ac"am-$e#i#"an" /$am-) #i"i*e in!ec"i n#, -( a11e$/ie# " 2e"a-1ac"am#;. >e&i&ta t "atho'e & a#e li8el. to be e co$ te#ed i h #)i"a1i5ed )a"ien"# 6i"h in"$a*en %# ca"he"e$#, in;ec"i n d$%/ %#e$#0 T+)e# ! in!ec"i n# inc1%de&

e do3a&c$la#2e doca#diti& &8i a d &oft ti&&$e i fectio & o&teo%.eliti&2&e"tic a#th#iti& lo-e# #e&"i#ato#. t#act :e'= ho&"ital ac?$i#ed " e$%o ia; &e"tice%ia2bacte#e%ia

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2. !"ecific "atho'e &. 1. The#e 2ac"e$ia a$e a1# $e!e$$ed " a# me"hici11in-$e#i#"an" S"a)h+1 c cc%# a%$e%# 3MRSA( and me"hici11in-$e#i#"an" S"a)h+1 c cc%# e)ide$midi# 3MRSE(, $e#)ec"i*e1+0 (f i fectio fail& to #e&"o d to 3a co%.ci alo e, 'e ta%ici , #ifa%"i o# both ha3e bee $&ed to achie3e a &. e#'i&tic bacte#icidal acti3it.. 4o-e3e#, a ta'o i&% %a. occ$# -ith &o%e of the&e co%bi atio &. 2. )e icilli -#e&i&ta t !t#e"tococc$& " e$%o iae #e%ai &$&ce"tible to 3a co%.ci . 3. 6 te#ococci that a#e #e&i&ta t to a%"icilli :o# "e icilli ;. (((.!)6C(A(C A*6/T 1. Vanc m+cin 3Vanc cin, Vanc 1id(0 (1 fo#%$latio . ( t#a3e o$& i f$&io &ho$ld be o3e# at lea&t 1 ho$# to %i i%i5e the #i&8 fo# 8$ed man #+nd$ me08 !ho$ld ot be ad%i i&te#ed 3ia i t#a%$&c$la# i <ectio & a& thi& i& 3e#. i##itati '. 2. Vanc m+cin HCL Ca)#%1e# 3Vanc cin HCL P%1*%1e#(0 )O fo#%$latio , 125%' ca"&$le&. Ao# "&e$do%e%b#a o$& coliti&. +eca$&e of co&t a d the #i&8 of &electi ' o$t fo# 3a co%.ci -#e&i&ta t '#a%-"o&iti3e bacte#ia, o#al %et#o ida5ole i& the d#$' of choice fo# Clo&t#idi$% difficile coliti& i %o&t ci#c$%&ta ce&.

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MONOBACTAM
*ail (to8a5$, )ha#%.D *oal& a d Ob<ecti3e&. +. the e d of the lect$#e the &t$de t &ho$ld be able to di&c$&& the follo-i ' abo$t %o obacta% a tibiotic&= 1. De&c#ibe thei# %echa i&% of actio a d "ha#%acolo'ic "#o"e#tie&. 2. De&c#ibe thei# &"ect#$% of acti3it.. 3. De&c#ibe thei# %a<o# &ide effect&. 4. Di&c$&& thei# $&e i the cli ical &etti '. (. +AC7*>O@/D A5t#eo a% i& a %o oc.clic beta-lacta%. (t& &"ect#$% i& 1imi"ed " %na21e " " 1e$a"e 2e"a-1ac"am#0 n1+ ae$ 2ic-/$am ne/a"i*e 2ac"e$ia0 (t i& f#e?$e tl. %#ed in )a"ien"#

((. M6C4A/(!M OA ACT(O/ B )4A>MACO0O*(C )>O)6>T(6! 1. In"e$!e$e# 2ac"e$ia1 ce11 6a11 #+n"he#i# b. bi di ' to "e icilli -bi di ' "#otei 3 :)+) 3; of ae#obic '#a%- e'ati3e bacilli &$ch a& e te#obacte#iaceae a d )&e$do%o a&. 2. Bac"e$icida1. 3. C ncen"$a"i n-inde)enden" 2ac"e$icida1 acti3it., -hich %ea & that o"ti%al do&i ' #e'i%e & &ho$ld %ai tai a tibiotic le3el& abo3e the M(C of the o#'a i&%. (((. )4A>MACO7(/6T(C! 1. Ab&o#"tio . P $ $a1 a2# $)"i n0 >a"id a d co%"lete ab&o#"tio afte# i t#a%$&c$la# i <ectio . 2. Di&t#ib$tio . @#i e, 8id e., "#o&tate, "e#ica#dial fl$id, "e#ito eal fl$id, &. o3ial fl$id, "le$#al fl$id, bo e, li3e#, l$ ', adi"o&e ti&&$e. )e et#atio

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i to the ce#eb#al &"i al fl$id ha& bee doc$%e ted, ho-e3e#, 3#d 'e e#atio ce"halo&"o#i & a#e the d#$'& of choice fo# %e i 'iti& ca$&ed b. &$&ce"tible "atho'e &. 3. 6li%i atio . P$ima$i1+ *ia "he .idne+# -hich acco$ t& fo# t-o-thi#d& of the eli%i atio of $ cha 'ed d#$'. A""#o"#iate #efe#e ce& &ho$ld be co &$lted fo# &"ecific do&a'e #ed$ctio & fo# 3a#io$& de'#ee& of #e al d.&f$ ctio . 1. !)6CT>@M OA ACT(1(TE Limi"ed " n1+ ae$ 2ic-/$am ne/a"i*e 2ac"e$ia0 Acti3e a'ai &t 4e%o"hil$& i fl$e 5ae, )&e$do%o a& ae#$'i o&a, 6 te#obacte#iaceae :e'= 6&che#ichia coli, 7leb&iella " e$%o iae;, /ei&&e#ia %e i 'itidi&, /ei&&e#ia 'o o##hea. Thi& #)ec"$%m ! ac"i*i"+ i# #imi1a$ " "he <$d /ene$a"i n ce)ha1 #) $in# and "he amin /1+c #ide#0 1(. >6!(!TA/C6 >e&i&ta ce to 6 te#obacte#iaceae a d )&e$do%o a& doe& occ$#, it& f#e?$e c. %a. 3a#. bet-ee i &tit$tio &. 1. Mecha i&%& of #e&i&ta ce a. fail$#e to "e et#ate o$te# %e%b#a e of ae#obic '#a%- e'ati3e bacte#ia b. de&t#$ctio b. beta-lacta%a&e& c. fail$#e to bi d to "e icilli bi di ' "#otei & :)+)&; !(D6 6AA6CT!2)>6CA@T(O/! *e e#all. -ell tole#ated. (& -ea8l. i%%$ o'e ic a d ha& bee $&ed i "atie t& -ith "e icilli alle#'ie& $ able to tole#ated "e icilli & o# ce"halo&"o#i &.

1((. C0(/(CA0 @!6!

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( &etti '& -he the#a". i& di#ected a'ai &t ae#obic '#a%- e'ati3e bacte#ia. (f co3e#a'e fo# '#a%-"o&iti3e bacte#ia a d2o# a ae#obe& i& eeded, the the a""#o"#iate additio al a'e t:&; &ho$ld be $&ed i co%bi atio -ith a5t#eo a%. )atie t& -ho ha3e alle#'ic #eactio & to "e icilli , ce"halo&"o#i &, o# ca#ba"e e%& %a. be t#eated -ith a5t#eo a%. @&e i& &i%ila# to 3#d 'e e#atio ce"halo&"o#i &, %a<o# e9ce"tio & -o$ld be %e i 'iti&. 1. ( t#a-abdo%i al i fectio &. +eca$&e a5t#eo a% lac8& acti3it. a'ai &t a ae#obe&, it %$&t be co%bi ed -ith a ti-a ae#obic d#$'&. 2. Ob&tet#ic2'. ecolo'ic i fectio &. !a%e a& fo# i t#a-abdo%i al i fectio &. 3. >e&"i#ato#. t#act i fectio &. a. 4o&"ital-ac?$i#ed " e$%o ia. 0i8e the 3#d 'e e#atio ce"halo&"o#i &, a5t#eo a% i& acti3e a'ai &t %a . of the ae#obic '#a%e'ati3e bacte#ia that ca$&e the&e " e$%o ia&. (f a&"i#atio " e$%o ia i& &$&"ected, a a'e t &$ch a& cli da%.ci &ho$ld be added. b. Co%%$ it.-ac?$i#ed :" e$%o ia, b#o chiti&;. 0ac8 of acti3it. a'ai &t '#a%-"o&iti3e cocci :e'= !t#e"tococc$& " e$%o iae; -hich a#e %a<o# ca$&e& of the&e i fectio & %a8e& it a "oo# choice fo# e%"i#ic %o othe#a".. 4. +acte#e%ia. 5. !8i a d &oft ti&&$e, i co%bi atio -ith a""#o"#iate a ti%ic#obial&. 6. +o e a d <oi t. 1(((.!)6C(A(C A*6/T! 1. A5"$e nam 3A5ac"amR(0 (12(M fo#%$latio &.

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DUINOLONES
*ail (to8a5$, )ha#%.D *oal& a d Ob<ecti3e&. +. the e d of the lect$#e the &t$de t &ho$ld be able to di&c$&& the follo-i ' abo$t ?$i olo e a tibiotic&= 1. De&c#ibe thei# %echa i&% of actio a d "ha#%acolo'ic "#o"e#tie&. 2. De&c#ibe thei# &"ect#$% of acti3it.. 3. De&c#ibe thei# %a<o# &ide effect& a d d#$' i te#actio &. 4. Di&c$&& thei# $&e i the cli ical &etti '. (. +AC7*>O@/D /alidi9ic acid -a& the fi#&t %e%be# of the ?$i olo e cla&& of a ti%ic#obial& de&c#ibed i 1962. 4o-e3e#, it& li%ited &"ect#$% of acti3it. a d the #a"id de3elo"%e t of #e&i&ta ce li%ited it& $&ef$l e&&. ( the 1980N&, %odificatio of the ?$i olo e #i ' i cl$di ' additio of a fl$o#i e at "o&itio 6 :he ce the a%e !1% $ 7%in 1 ne; led to a'e t& -ith= '( an inc$ea#ed an"i2ac"e$ia1 #)ec"$%m, and -( im)$ *ed )ha$mac .ine"ic )$ )e$"ie#0 The te#%& fl$o#o?$i olo e a d ?$i olo e -ill be $&ed i te#cha 'eabl.. ((. M6C4A/(!M OA ACT(O/ B )4A>MACO0O*(C )>O)6>T(6! 1. ( hibit& bacte#ial D/A &. the&i& b. i te#fe#i ' -ith D/A '.#a&e :bacte#ial to"oi&o%e#a&e ((;, -hich i& a e 5.%e ece&&a#. fo# D/A #e"licatio . 2. Ra)id1+ 2ac"e$icida1. 3. C ncen"$a"i n-de)enden" 2ac"e$icida1 acti3it., -hich %ea & that the e9te t of bacte#ial 8illi ' i c#ea&e& a& d#$' co ce t#atio & i c#ea&e. 4. )o&t-a tibiotic effect i& &ee fo# &o%e ae#obic '#a%-"o&iti3e a d e'ati3e bacte#ia, the cli ical &i' ifica ce of thi& fi di ' i& $ 8 o- .

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(((. )4A>MACO7(/6T(C! 1. Ab&o#"tio . Ee11 a2# $2ed a!"e$ $a1 admini#"$a"i n :50L to K95L;. Ab&o#"tio of ci"#oflo9aci a d oflo9ci #e&$lt i blood le3el& co%"a#able to thei# i t#a3e o$& "#e"a#atio &. Th$&, $a1 d #a/e ! $m%1a"i n# :a d ot the "a#e te#al fo#%$latio &; #h %1d 2e %#ed i! "he )a"ien" i# a21e " "a.e $a1 medica"i n#0 2. Di&t#ib$tio . @#i e, 8id e., "#o&tate ti&&$e, l$ ', bo e, &tool, e$t#o"hil&, %ac#o"ha'e&. *i3e thi& ti&&$e di&t#ib$tio , the fl$o#o?$i olo e& a#e 3e#. $&ef$l fo# the %a a'e%e t of i fectio & i the&e a#ea& of the bod.. 3. 6li%i atio . The .idne+# a#e a i%"o#ta t #o$te of eli%i atio , ho-e3e# the e9te t of eli%i atio b. the 8id e.& 3a#ie& bet-ee a'e t&. A""#o"#iate #efe#e ce& &ho$ld be co &$lted fo# &"ecific do&a'e #ed$ctio & fo# 3a#io$& de'#ee& of #e al d.&f$ ctio . Al$o#o?$i olo e )ha#%aco8i etic& Al$o#o?$i olo e:a; Do&e:b; /o#flo9aci Ci"#oflo9aci Oflo9aci 6 o9aci 0o%eflo9aci 400%' "o H12

A:c;

>e al 6ffect of Aood o O#al Ab&o#"tio

35-70L 27L %a. dec#ea&e:f; 29L ---:'; 70L &li'ht dec#ea&e:h; 44L dec#ea&ed 66L

250-750%' "o H12 70L 200-400%' (1 H12:e; 200-400%' "o H12 200-400%' (1 H12 200-400%' "o H12 400%' "o H24 98L 88L K95L

aO?$i olo e& a3ailable i the @ ited !tate&. bO-he do&a'e #a 'e i& 'i3e , the do&e -ill de"e d i "a#t, o the t."e a d &e3e#it. of i fectio . cObioa3ailabilit.. dO#e al eli%i atio . eOA@C& of the 400%' (1 do&e a d 500%' o#al do&e a#e &i%ila#. A@C& of 200%' (1 do&e a d 250%' o#al do&e a#e &i%ila#. f O #eco%%e ded to ta8e 1 h# befo#e o# 2 h# afte# %eal&. 'O%a. ta8e -itho$t #e'a#d to %eal&, ho-e3e# the %a $fact$#e# #eco%%e d& the ideal ti%e i& 2 h#& afte# %eal&. hO%a $fact$#e# doe& ot #eco%%e d ta8i ' -ith food, b$t &i ce the #ate a d e9te t of ab&o#"tio i& o l. &li'htl. dec#ea&ed, ca $&$all. be ta8e -itho$t #e'a#d to %eal&. 1. !)6CT>@M OA ACT(1(TE

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Al$o#o?$i olo e& a#e $&ef$l fo# i fectio & ca$&ed b. '#a%- e'ati3e bacilli. 4o-e3e# c$##e tl. %a#8eted d#$'& i thi& co$ t. ha3e o l. m de$a"e ac"i*i"+ a/ain#" /$am-) #i"i*e 2ac"e$ia a d a#e the#efo#e ot the d#$'& of choice fo# i fectio & ca$&ed b. the&e bacte#ia. The c$##e tl. a3ailable ?$i olo e& i the @ ited !tate& ha3e n c1inica11+ %#e!%1 anae$ 2ic ac"i*i"+0 1. G$am-) #i"i*e 2ac"e$ia0 Mode#ate acti3it. a'ai &t !t#e"tococci a d !ta"h.lococci i cl$di ' &o%e %ethicilli -#e&i&ta t !ta"h.lococci, altho$'h #e&i&ta ce to %ethicilli -#e&i&ta t !ta"h.lococci i& o- %o#e f#e?$e t to ?$i olo e&. 2. G$am-ne/a"i*e 2aci11i0 69celle t acti3it. a'ai &t "atho'e & &ee i hospita !a"#$i%&' i()&"tio(s &$ch a& the En"e$ 2ac"e$iaceae 3E#che$ichia c 1i, 91e2#ie11a #)ecie#, En"e$ 2ac"e$ #)ecie#;, "o**$(it+!a"#$i%&' %&spi%ato%+ i()&"tio(s :Hem )hi1%# in!1%en5ae and M $a4e11a ca"a$$ha1i#;, ,ast%oi(t&sti(a i()&"tio(s :Sa1m ne11a, Shi/e11a, Cam)+1 2ac"e$, a d 1ib#io &"ecie&; a d s&-$a + t%a(s*itt&' 'is&as&s :Nei##e$ia / n $$hea and Ch1am+dia "$ach ma"i#;. Ci"#oflo9aci i& the %o&t acti3e ?$i olo e a'ai &t P#e%d m na# ae$%/in #a. Othe# diffe#e ce& bet-ee ?$i olo e& fo# &"ecific o#'a i&%& e9i&t a d -ill be di&c$&&ed $ de# the i di3id$al a'e t&. 3. O"he$0 !o%e ?$i olo e& a#e $&ed i co%bi atio -ith othe# a ti%.cobacte#ial d#$'& fo# the t#eat%e t of M+c 2ac"e$i%m "%2e$c%1 #i# a d M+c 2ac"e$i%m-a*i%m-in"$ace11%1a$e0 1(. >6!(!TA/C6 Cli icall. &i' ifica t #e&i&ta ce to Al$o#o?$i olo e& i& a i c#ea&i ' "#oble% -o#ld-ide. O3e#$&e a d e9"o&$#e to ?$i olo e& a#e i%"o#ta t #i&8 facto#& fo# the e%e#'e ce of #e&i&ta ce. P#e%d m na# ae$%/in #a and S"a)h+1 c cci a#e "atho'e & -he#e #e&i&ta ce i& beco%i ' %o#e co%%o "lace. 1. Mecha i&%& of #e&i&ta ce a. alte#atio & i D/A '.#a&e b. dec#ea&ed "e#%eabilit.. !(D6 6AA6CT!2)>6CA@T(O/! 1. Sa!e"+ and e!!icac+ in chi1d$en F'G +ea$# ha& ot bee e&tabli&hed a d a i%al &t$die& ha3e de%o &t#ated de&t#$ctio to ca#tila'e ti&&$e. !"ecific lite#at$#e &ho$ld be co &$lted -he the be efit of $&i ' ?$i olo e& i child#e o$t-ei'h& the #i&8 of $&i ' the&e a'e t&. 2. !ho$ld n " 2e %#ed in )$e/nan" $ n%$#in/ 6 men0 3. Tend n $%)"%$e, "a#tic$la#l. the Achille& te do ha& bee #e"o#ted. H$i olo e& &ho$ld be di&co ti $ed at the fi#&t &i' of "o&&ible te do #$"t$#e :e'= "ai , i fla%%atio ; a d to #ef#ai f#o% e9e#ci&e $ til the dia' o&i& of te di iti& i& e9cl$ded.

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4. ( t#a3e o$& ci"#oflo9aci %a. ca$&e i$$i"a"i n a" "he in!%#i n #i"e if the d#$' i& i f$&ed o3e# le&& tha 60 %i $te& o# a &%all "e#i"he#al 3ei i& $&ed. (1. D>@* (/T6>ACT(O/! 1. Ca"i n-c n"ainin/ c m) %nd#0 Co-ad%i i&t#atio of fl$o#o?$i olo e& -ith ca"i n-c n"ainin/ c m) %nd# :e'= al$%i $%, %a' e&i$%, calci$%, 5i c, i#o , &$c#alfate, the b$ffe# i DD( ; #e&$lt& i the fo#%atio of catio -?$i olo e co%"le9e& -hich a#e "oo#l. ab&o#bed. Co c$##e t ad%i i&t#atio of $t#itio al &$""le%e t& ha3e al&o bee fo$ d to dec#ea&e the ab&o#"tio of ?$i olo e& beca$&e the. %a. co tai the di3ale t catio & 5i c a d i#o . The#a"e$tic fail$#e %a. #e&$lt f#o% thi& #i/ni!ican" d$%/ in"e$ac"i n0 PDD( o# dideo9.i o&i e i& $&ed to t#eat 4(1 i fectio . Ma a'e%e t of ( te#actio = !e"a#ate ad%i i&t#atio of ?$i olo e a d catio -co tai i ' co%"o$ d. @&e alte# ati3e the#a"ie& &$ch a& hi&ta%i e bloc8e#& i &tead of a tacid& -he a""#o"#iate. 2. The )h+11ine/Ca!!eine0 +. i hibiti ' the %ic#o&o%al )450 e 5.%e& i 3ol3ed i the %etaboli&% of theo"h.lli e, i c#ea&ed co ce t#atio & of theo"h.lli e %a. occ$#. The effect o theo"h.lli e %etaboli&% 3a#ie& -ith the ?$i olo e, en 4acin ha*in/ "he /$ea"e#" e!!ec" :40-65L #ed$ctio i theo"h.lli e clea#a ce;, follo-ed b. ci"#oflo9aci :30L #ed$ctio i theo"h.lli e clea#a ce;, a d n $!1 4acin, !1 4acin, 1 me!1 4acin ha*in/ "he 1ea#" e!!ec" :2-11L i c#ea&e i theo"h.lli e le3el&;. Ma a'e%e t of ( te#actio . M ni" $ ! $ c1inica1 #i/n# and #+m)" m# ! "he )h+11ine " 4ici"+ : a$&ea, 3o%iti ', headache, i &o% ia, #e&tle&& e&&; a d mea#%$e "he )h+11ine 1e*e1# in )a"ien"# $ecei*in/ en 4acin $ ci)$ !1 4acin0 /o ad<$&t%e t &ho$ld be ece&&a#. i "atie t& #ecei3i ' o#flo9aci , oflo9aci , o# lo%eflo9aci . 3. N n-#"e$ id# an"i-in!1amma" $+ d$%/# 3NSAID(0 Co c$##e t $&e of the /!A(D fe "#ofe ha& #e&$lted i &ti%$latio of the ce t#al e#3o$& &.&te% :ie= #ei5%$e#;. The %echa i&% of thi& i te#actio %a. be di&"lace%e t of the i hibito#. e$#ot#a &%itte# *A+A f#o% thei# #ece"to#& i the b#ai . Ma a'e%e t of ( te#actio = Ma# "atie t& of the "ote tial fo# &ti%$latio of the ce t#al e#3o$& &.&te%. 4. Ea$!a$in0 (t i& ot clea# if the#e i& a i te#actio bet-ee -a#fa#i :i c#ea&e i "#oth#o%bi ti%e; o# c.clo&"o#i e :i c#ea&e i c.clo&"o#i e le3el&;. Clo&e %o ito#i ' of "#oth#o%bi ti%e a d c.clo&"o#i e le3el& &ho$ld be e%"lo.ed $ til %o#e co cl$&i3e data a#e a3ailable. 1((. C0(/(CA0 @!6!

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Al$o#o?$i olo e& a#e effecti3e a'e t& fo# a 3a#iet. of i fectio &, i cl$di ' tho&e li&ted belo-. 4o-e3e#, beca$&e of the co ce# o3e# #e&i&ta ce -ith i di&c#i%i ate $&e of the&e a'e t&, i 'e e#al, fl$o#o?$i olo e& &ho$ld be #e&e#3ed fo# i fectio & d$e to bacte#ia that a#e #e&i&ta t to othe# le&& e9"e &i3e a ti%ic#obial& o# fo# $&e i "atie t& $ able to tole#ate the&e othe# a ti%ic#obial&. 1. U$ina$+ "$ac" in!ec"i n#0 @ co%"licated, co%"licated $#i a#. t#act i fectio &, "#o&tatiti&. O l. oflo9aci a d ci"#oflo9aci a#e a""#o3ed fo# "#o&tatiti&. 2. Se4%a11+ "$an#mi""ed di#ea#e#0 Nei##e$ia / n $$hea0 &i 'le do&e& of ci"#oflo9aci a d oflo9aci ca be $&ed fo# $ co%"licated $#eth#iti&, ce#3iciti&, o# #ectal i fectio &. >e"o#t& of fl$o#o?$i olo e-#e&i&ta t 'o ococci a#e e%e#'i '. Ch1am+dia "$ach ma"i#0 Oflo9aci i& the o l. a""#o3ed ?$i olo e. Chanc$ id0 Ci"#oflo9aci a""#o3ed. <0 Ga#"$ in"e#"ina10 4. Re#)i$a" $+ "$ac"0 C mm%ni"+-ac7%i$ed :e'= " e$%o ia, b#o chiti&, otiti&;. !ho$ld ot be $&ed alo e a& e%"i#ic the#a". beca$&e of thei# inade7%a"e ac"i*i"+ a/ain#" S"$e)" c cc%# )ne%m niae, o e of the co%%o "atho'e & i the&e i fectio &. H$i olo e& -o$ld be effecti3e alte# ati3e& -he i fectio & a#e ca$&ed b. '#a%- e'ati3e bacte#ia &$ch a& 4e%o"hil$& i fl$e 5ae, a d Mo#a9ella cata##hali& that a#e #e&i&ta t to a'e t& &$ch a& a%o9icilli , t#i%etho"#i%2&$lfa%etho9a5ole. H #)i"a1-ac7%i$ed :e'=" e$%o ia;. 4a3e bee effecti3e fo# '#a%- e'ati3e " e$%o ia. A#)i$a"i n )ne%m nia0 !ho$ld ot be $&ed beca$&e of thei# lac8 of acti3it. a'ai &t a ae#obe&. A"+)ica1 )ne%m nia 3e/& M+c )1a#ma, Ch1am+dia, Le/i ne11a(0 A$#the# &t$die& a#e eeded to dete#%i e the #ole of ?$i olo e& i the&e i fectio &. 5. B ne and C in"0 G$am-) #i"i*e 2ac"e$ia0 Altho$'h data e9i&t& to de%o &t#ate thei# effecti3e e&&, ?$i olo e& a#e ot the d#$'& of choice beca$&e of thei# m de$a"e ac"i*i"+ a/ain#" S"a)h+1 c cci, a d "endenc+ ! $ $e#i#"ance " de*e1 )0 G$am-ne/a"i*e 2ac"e$ia0 Co 3e ie t alte# ati3e fo# lo '-te#%, o$t"atie t the#a"..

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6. S.in and # !" "i##%e0 N " "he d$%/# ! ch ice 2eca%#e ! m de$a"e ac"i*i"+ a/ain#" /$am-) #i"i*e 2ac"e$ia0 Ao# %i9ed i fectio & -ith '#a%-"o&iti3e a d '#a%- e'ati3e bacte#ia, a ?$i olo e ca be co%bi ed -ith a a'e t &$ch a& cli da%.ci . Cli da%.ci i& acti3e a'ai &t '#a%-"o&iti3e bacte#ia a d a ae#obe&. 1(((.!)6C(A(C A*6/T!
D. +or lo&acin (+oro&inR)% Poorly a2sor2ed6 and should not be used for infections outside the urinary tract. '. Cipro lo&acin (CiproR)% -ost potent ;uinolone against Pseudomonas aeruginosa6 a common cause of hospital-ac;uired infections. -ay be used as part of a combination regimen for Myco2acterium-avium-intracellularae in ections in "I. patients% An ophthalmic preparation 21iloxan2,33 for bacterial (eratitis and con:unctivitis is available. I. O lo&acin (:lo&inR)% +imilar spectrum of activity to ciprofloxacin, but is at least G-fold less potent than ciprofloxacin against .seudomonas aeruginosa. /floxacin is the most potent ;uinolone against Chlamydia trachomatis6 a pathogen causing se&ually transmitted diseases% An ophthalmic preparation of ofloxacin has been recently mar(eted. G. *no&acin (Penetre&R)% /verall is less active against gram-negative aerobes than is ciprofloxacin and ofloxacin. Absorption is decreased in an al(aline environment as may occur with simultaneous administration of drugs that lower gastric acidity. =as the most potential to reduce theophylline clearance. A. $ome lo&acin (Ma&a9uinR)% 4ong half-life permits once daily dosing% .ostmar(eting surveillance has found this ;uinolone to be a more fre;uent cause of photosensitivity than was initially suspected.

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MACROLIDES, TETRACYCLINES, AND S L!ONAMIDES

)a$la A. Teich e#, )ha#%.D. G a1# and O2;ec"i*e#& +. the e d of thi& lect$#e, the &t$de t &ho$ld be able to= 1. 2. 3. 4. 5. 6. De&c#ibe the %echa i&% of actio fo# the %a#colide&, tet#ac.cli e& a d &$lfo a%ide&. 0i&t the &"ect#$% of acti3it. fo# the %ac#olide&, tet#ac.cli e&, a d &$lfo a%ide&. 0i&t the "ha#%aco8i etic "a#a%ete#& a d the %a<o# cli ical i dicatio & fo# the %ac#olide&, tet#ac.cli e& a d &$lfo a%ide&. De&c#ibe the %a<o# ad3e#&e effect& a d d#$' i te#actio & fo# the %ac#olide&, tet#ac.cli e& a d &$lfo a%ide&. De&c#ibe the diffe#e ce& bet-ee e#.th#o%.ci a d the e-e# %ac#olide& :ad3a ta'e& a d di&ad3a ta'e&;. De3i&e a #atio al t#eat%e t "la fo# $&e of the %ac#olide&, tet#ac.cli e& a d &$lfo a%ide& ba&ed o the cli ical i dicatio a d "atie t &"ecific cha#acte#i&tic&.

Re7%i$ed Readin/& 4a##i&o N& )#i ci"le& of ( te# al Medici e. 12th 6ditio . 1991.Cha"te# 85. )a'e& 489-492.

MACROLIDES
ERYTHROMYCIN
A0 MECHANISM O= ACTION *e e#all. co &ide#ed 2ac"e$i #"a"ic, ho-e3e# %a. be bacte#icidal $ de# ce#tai ci#c$%&ta ce&. ( hibit& bacte#ial >/A-de"e de t "#otei &. the&i&. Mac#olide& bi d to the 50! &$b$ it of the 70! #ibo&o%e, -hich ca$&e& di&&ociatio of t>/A f#o% the #ibo&o%e i hibit& "#otei &. the&i&. B0 SPECTRUM O= ACTIVITY G$am ) #i"i*e ae$ 2e# - Acti3e a'ai &t st%&pto"o""$s p(&$*o(ia& a d othe# &t#e"tococci, &ta"h.lococci, a d "o%+(&.a"t&%i$* 'iphth&%ia&.

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G$am ne/a"i*e ae$ 2e# - Acti3e a'ai &t L&,io(& a p(&$*ophi a/ N&iss&%ia ,o(o%%ho&a&/ Mo%a-& a "ata%%ha is/ 0o%'&t& a p&%t$ssis. 6 te#obacte#iaceae a#e #e&i&ta t. Anae$ 2e# - 0a"t&%oi'&s )%a,i is a#e $&$all. #e&i&ta t. O"he$ - M+"op as*a p(&$*o(ia&/ "h a*+'ia t%a"ho*atis/p(&$*o(ia&/ T%&po(&*a pa i'$*. C0 PHARMACO9INETICS Ab&o#"tio - 6#.th#o%.ci ba&e i& &$b<ect to de&t#$ctio b. 'a&t#ic acid a d i& "oo#l. &ol$ble i -ate#. /e-e# o#al "#e"a#atio & ha3e acid#e&i&ta t coati ' to "#e3e t d#$' di&&ol$tio $ til d#$' #eache& the &%all bo-el. *e e#all. bette# ab&o#"tio i the fa&ti ' &tate. !e3e#al diffe#e t &alt fo#%& a3ailable to %a8e d#$' %o#e &ol$ble a d acid &table. Di&t#ib$tio - )e et#ate& %o&t ti&&$e& e9ce"t the b#ai a d C!A. 4i'h co ce t#atio & achie3ed i %ac#o"ha'e& a d )M/&. )e#&i&t& i ti&&$e lo 'e# tha &e#$%. Metaboli&%269c#etio - Co ce t#ated b. the li3e#, e9c#eted i bile a d fece&. Do&a'e #ed$ctio D0 CLINICAL USES =OR ERYTHROMYCIN Mo&t co%%o $&e&= 1. C mm%ni"+-ac7%i$ed Pne%m nia# - -he#e at."ical "atho'e & &$ch a& M+"op as*a p(&$*o(ia& a d L&,io(& a p(&$*ophi ia a%& "o**o(. 2. Chla%.dial i fectio & :ie. "h a*+'ia p(&$*o(ia& " e$%o ia o# "h a*+'ia t%a"ho*atis "el3ic i fectio &, e&"eciall. i "#e' a c..; 1. 0o%'&t& a p&%t$ssis Othe# $&e&= 1. !t#e"tococcal i fectio & i "atie t& -ith )C/ alle#'. 2. Mi o# &ta"h.lococcal &8i i fectio & 3. Ca%".lobacte# 'a&t#oe te#iti& 4. !."hili& i "#e' a c. 5. )#o"h.la9i& of bacte#ial e doca#diti& E0 ADVERSE DRUG REACTIONS ot ece&&a#. i "atie t& -ith #e al fail$#e.

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1. GI %)#e" - a$&ea, 3o%iti ', dia##hea 2. Th$ m2 )h1e2i"i# - -ith "a#e te#al ad%i i&t#atio . Ca be dec#ea&ed b. dil$ti ' i 250 %l of fl$id a d &lo-i ' the #ate of i f$&io . 3. H+)e$#en#i"i*i"+ $eac"i n# - fe3e#, &8i #a&h, eo&i o"hilia 4. Ch 1e#"a"ic He)a"i"i# - occ$#& -ith e&tolate "#e"a#atio , %ai l. i ad$lt&. DO NOT USE ESTOLATE IN ADULTS0 5. O" " 4ici"+ - a&&ociated -ith la#'e do&e&, e&"eciall. i the elde#l. o# "atie t& -ith $ de#l.i ' #e al i &$fficie c.. =0 DRUG INTERACTIONS 6#.th#o%.ci i hibit& c.toch#o%e )450 e 5.%e &.&te%, a d ca dec#ea&e the clea#a ce a d i c#ea&e the to9icit. of theo"h.lli e, ca#ba%e5e"i e, c.clo&"o#i e, te#fe adi e, t#ia5ola%, etc. 6#.th#o%.ci ca al&o i c#ea&e the h."o"#oth#o%bi e%ic effect of -a#fa#i . 6#.th#o%.ci %a. i c#ea&e the bioa3ailabilit. of di'o9i -hich %a. i c#ea&e the &e#$% le3el& a d ca$&e to9icit.. G0 DRUG PREPARATIONS AND DOSING O$a1 - !e3e#al o#al "#e"a#atio & a#e a3ailable= ba&e, &tea#ate &alt, eth.l&$cci ate e&te# a d e&tolate fo#%. A3ailable a& ca"&$le& a d fil%-coated tablet&. Do&e i& 250-500 %' "o ?6 ho$#&, 333 %' "o ?8 ho$#& o# 500 %' "o ?12h de"e di ' o the &e3e#it. of ill e&& a d the i dicatio . Pa$en"e$a1 - A3ailable a& lactobio ate o# 'l$ce"tate &alt. @&ed fo# "atie t& -ith &e#io$& i fectio & o# "atie t& $ able to ta8e o#al %edicatio &. Do&e i& 250-1000 %' i3 ?6h. M$&t be 'i3e a& a i t#a3e o$& i f$&io . DO /OT 'i3e (M &eco da#. to "ai $"o i <ectio .

CLARITHROMYCIN 3Bia4in( AND AHITHROMYCIN 3Hi"h$ ma4(

A0 BAC9GROUND Cla#ith#o%.ci i& a 14-%e%be# &t#$ct$#e :%ac#olide;, &i%ila# to e#.th#o%.ci , -hile a5ith#o%.ci i& a 15-%e%be# lacto e #i ' :a5alide;. +oth d#$'& -e#e a""#o3ed fo# $&e i 1991. Co%"a#ed to e#.th#o%.ci , the&e a'e t& ha3e bette# ab&o#"tio , a lo 'e# t122, fe-e# *( &ide effect&, bette# ti&&$e "e et#atio a d a b#oade# &"ect#$% of acti3it.. The di&ad3a ta'e i& the hi'h co&t co%"a#ed to e#.th#o%.ci . B0 SPECTRUM O= ACTIVITY

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G$am ) #i"i*e ae$ 2e# - Cla#ith#o%.ci i& 2-4 ti%e& *o%& acti3e i 3it#o tha e#.th#o%.ci a'ai &t %o&t &t#e"tococci a d &ta"h.lococci. A5ith#o%.ci i& 2-4 ti%e& &ss acti3e a'ai &t the '#a% "o&iti3e& co%"a#ed to e#.th#o%.ci . G$am ne/a"i*e ae$ 2e# - A5ith#o%.ci ha& '#eate# acti3it. tha both e#.th#o%.ci a d cla#ith#o%.ci a'ai &t Mo%a-& a "ata%%ha is a d H&*ophi $s i() $&(2a&. The acti3e %etabolite of cla#ith#o%.ci , 14-h.d#o9.cla#ith#o%.ci , i& &li'htl. %o#e acti3e a'ai &t M. "ata%%ha is a d H. i() $&(2a& tha the "a#e t d#$', a d the co%bi atio of the t-o "#o3ide& additi3e o# &. e#'i&tic acti3it.. O"he$ - +oth a5ith#o%.ci a d cla#ith#o%.ci a#e %o#e acti3e tha e#.th#o%.ci a'ai &t "h a*+'ia spp. a d L&,io(& a p(&$*ophi ia. Cla#ith#o%.ci ha& 'ood acti3it. a'ai &t H& i"o.a"t&% p+ o%i. +oth cla#ith#o%.ci a d a5ith#o%.ci a#e acti3e a'ai &t To-op as*a ,o('ii a d at."ical %.cobacte#ia &$ch a& M+"o.a"t&%i$* a3i$*. C0 PHARMACO9INETICS PHARMACO9INETICS +ioa3ailabilit. :L; Di&t#ib$tio Metaboli&% T122 :ho$#&; CLARITHROMYCIN 55L. Ta8e -ith o# -itho$t food ( ti&&$e& 5-7 ho$#& AHITHROMYCIN 37L. Ta8e o e%"t. &to%ach 69te &i3el. di&t#ib$ted i ti&&$e&. 68 ho$#&. T122 i ti&&$e i& 2-4 da.&. /ot #e?$i#ed

( li3e#, %etabolite& #e all. eli%i ated Mo&t $ %etaboli5ed a d e9c#eted i fece&

Do&a'e Ad<$&t%e t i >A C#Cl J 30 %l2%i

D0 INDICATIONS =OR USE O= CLARITHROMYCIN I AHITHROMYCIN 1. @""e# a d lo-e# #e&"i#ato#. t#act i fectio & :ie. "ha#. 'iti&, &i $&iti&, b#o chiti& a d " e$%o ia; - to co3e# "atho'e & $&$all. &ee i the&e i fectio & &$ch a& S. p(&$*o(ia&/ H. i() $&(2a&/ M. p(&$*o(ia&/ M. "ata%%ha is/ etc. 2. !8i i fectio & - $ co%"licated 3. /o -'o ococcal $#eth#iti& a d ce#3iciti& d$e to Ch a*+'ia t%a"ho*atis :A5i"h$ m+cin n1+(. 4. M.cobacte#i$% A3i$% Co%"le9 i "atie t& -ith A(D! - C1a$i"h$ m+cin i& a""#o3ed fo# t#eat%e t, a d %$&t be $&ed i co%bi atio -ith at lea&t o e othe# d#$'. +oth cla#ith#o%.ci a d a5ith#o%.ci a#e a""#o3ed fo# MAC "#o"h.la9i&. 5. H& i"o.a"t&% p+ o%i - C1a$i"h$ m+cin

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E0 ADVERSE DRUG REACTIONS 1. GI - occ$# le&& f#e?$e tl. tha -ith e#.th#o%.ci . Mo&t co%%o a#e a$&ea, dia##hea, abdo%i al "ai a d ta&te di&t$#ba ce. *( &ide effect& %a. be %o#e co%%o i "atie t& -ith 4(1. 2. He)a" " 4ici"+ - ab o#%alitie& i li3e# f$ ctio te&t& occ$# $ co%%o l.. =0 DRUG INTERACTIONS Cla#ith#o%.ci - %a. i c#ea&e le3el& of theo"h.lli e :b. Q20L; a d ca#ba%e5e"i e. Ma. i c#ea&e the ca#dio3a&c$la# to9icit. of te#fe adi e a d a&te%i5ole. Ma. i c#ea&e &e#$% co ce t#atio & of #ifab$ti . A5ith#o%.ci - doe& /OT a""ea# to i te#act -ith the c.toch#o%e )450 &.&te%, the#eb. allo-i ' othe# d#$'& to be %etaboli5ed -itho$t i hibitio . /o 8 o- d#$' i te#actio -ith theo"h.lli e, ca#ba%e5e"i e o# te#fe adi e. R effect o -a#fa#i . Aood dec#ea&e& the ab&o#"tio &e"a#ate f#o% %eal&. G0 DRUG PREPARATIONS AND DOSING Cla#ith#o%.ci O l. a3ailabe "o a& 250 %' a d 500 %' tablet& Do&e i& 250-500 %' "o ?12 ho$#& de"e di ' o i fectio bei ' t#eated. A5ith#o%.ci A3ailable "o a& 250 %' ca"&$le&, 600 %' tab& a d 1 '#a% o#al &$&"e &io do&e "ac8et. Do&e fo# #e&"i#ato#. t#act i fectio & a d &8i i fectio & i& 500 %' 9 1 do&e :2 ca"&$le&;, follo-ed b. 250 %' "o 9 4 %o#e da.& :Total the#a". O 5 da.&;. Ca be 'i3e a& a &ho#te# t#eat%e t co$#&e d$e to "#olo 'ed ti&&$e half-life. Ao# t#eat%e t of o -'o ococcal $#eth#iti&2ce#3iciti&, 'i3e a& a &i 'le 1 '#a% o#al do&e. H0 COST :Co&t "e# t#eat%e t co$#&e i #etail &etti '; 6#.th#o%.ci :500 ?id; Cla#ith#o%.ci :500 bid; A5ith#o%.ci :250 ?d;

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S'-0-J210 da. co$#&e

S62.29210 da. co$#&e

S39.2925 da. co$#&e

I0 C m)a$i# n Be"6een Ne6e$ Mac$ 1ide# and E$+"h$ m+cin Ad3a ta'e& of Cla#ith#o a d A5ith#o o3e# 6#.th#o%.ci

Dec#ea&e *( &ide effect& ( c#ea&e !"ect#$% of acti3it. Ae-e# d#$' i te#actio & :a5ith#o%.ci ; 0e&& f#e?$e t do&i ' :%a. i c#ea&e co%"lia ce; +ette# ti&&$e "e et#atio

Di&ad3a ta'e& ( c#ea&e CO!TT DIRITHROMYCIN :D. abac; /e- %ac#olide -ith &"ect#$% of acti3it. &i%ila# to that of e#.th#o%.ci . A""#o3ed i Octobe# 1995 fo# o ce-dail. do&i ' :500 %' "o ?d;. Ta8e -ith food. A3ailable a& 250 %' tablet&. /ot #eco%%e ded fo# $&e i fectio & -he#e H. i() $&(2a& i& &$&"ected.

TETRACYCLINES
A0 MECHANISM O= ACTION Tet#ac.cli e& a#e "#i%a#il. 2ac"e$i #"a"ic0 The. e te# the bacte#ia b. diff$&io a d o ce i &ide, bi d #e3e#&ibl. to the 30! #ibo&o%al $ it KK bloc8 additio of a%i o acid& to the '#o-i ' "e"tide chai . B0 SPECTRUM O= ACTIVITY G$am ) #i"i*e ae$ 2e# - Ma . '#a% :F; cocci a#e &$&ce"tible, b$t %a . &t#ai & of staph+ o"o""i/ st%&pto"o""i/ a d p(&$*o"o""i a#e de3elo"i ' #e&i&ta ce. The#efo#e, the tet#ac.cli e& a#e /OT the d#$'& of choice fo# %o&t '#a% "o&iti3e ae#obe&.

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G$am ne/a"i*e ae$ 2e# - )&e$do%o ad& a d %a . 6 te#obacte#iaceae a#e #e&i&ta t. @#i a#. co ce t#atio & a#e ade?$ate fo# co%%$ it.ac?$i#ed E. "o i i fectio &. Anae$ 2e# - ( c#ea&ed i cide ce of 0a"t&%oi'&s )%a,i is #e&i&ta ce to the tet#ac.cli e&. The#efo#e the. a#e ot the d#$'& of choice fo# &$&"ected o# doc$%e ted 0. )%a,i is i fectio &. O"he$ - Acti3e a'ai &t M+"op as*a p(&$*o(ia&/ Ch a*+'ia t%a"ho*atis/ 0o%& ia .$%,'o%)&%i/ a(' Ri"4&ttsia&. C0 CLASSI=ICATION C0A!!(A(CAT(O/ Sho%t A"ti(, :o9.tet#ac.cli e, tet#ac.cli e; I(t&%*&'iat& :de%ecloc.cli e; Lo(, A"ti(, :do9.c.cli e, %i oc.cli e; D0 PHARMACO9INETICS Ab&o#"tio occ$#& "#i%a#il. i the "#o9i%al &%all bo-el. (%"#o3ed -he ta8e i the fa&ti ' &tate :le&& i%"o#ta t fo# do9.c.cli e a d %i oc.cli e;. )ea8 le3el& 1-3 ho$#& "o&t- do&e. Ab&o#"tio i& i%"ai#ed -he ta8e co c$##e tl. -ith othe# di3ale t a d t#i3ale t catio & &$ch a& calci$% a d %a' e&i$% :a tacid&, %il8;. Di&t#ib$tio i to the l$ '&, li3e#, 8id e., &"$t$%. All tet#ac.cli e& a#e co ce t#ated i the li3e# a d e9c#eted i to bile. 0o '-acti ' TC/& ha3e e ha ced li"id &ol$bilit. bette# ti&&$e "e et#atio . 69c#etio - "#i%a#il. 3ia the 8id e.&. T122 "#olo 'ed i #e al fail$#e e9ce"t fo# do9.c.cli e. The TC/& a#e ot #eco%%e ded fo# $&e i #e al fail$#e :e9ce"t do9.c.cli e;. SERUM T'/- GI ABSORPTION 3A( 9 ho$#& 8 ho$#& 12 ho$#& 18 ho$#& 16 ho$#& 58 77 66 93 95

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E0 CLINICAL USES =OR THE TETRACYCLINES D#$'& of Choice Ao#= 1. >ic8ett&ial ( fectio & :>oc8. Mo$ tai &"otted fe3e#, etc;. 2. !e9$all. T#a &%itted Di&ea&e& :!TD&;2 )el3ic ( fla%%ato#. Di&ea&e :)(D; - Ch a*+'ia t%a"ho*atis i& co%%o "atho'e i the&e i fectio & a d tet#ac.cli e i& d#$' of choice. 3. At."ical ) e$%o ia& Ca$&ed b. o#'a i&%& &$ch a& M+"op as*a p(&$*o(ia& a d Ch a*+'ia p(&$*o(ia&. 5. 0.%e Di&ea&e :ea#l.; - ca$&ed b. 0o%%& ia .$%,'o)&%i. Othe# Co%%o @&e&= 1. +#$cello&i& 2. H& i"o.a"t&% p+ o%i 3. Ac e 4. T#a3elle#N& dia##hea =0 ADVERSE E==ECTS 1. Tee"h and B ne - Ma. ca$&e a '#e.-b#o- di&colo#atio of the teeth :-hich i& "e#%a e t; a d e a%el h."o"la&ia. Al&o %a. ca$&e de"#e&&io of &8eletal bo e '#o-th i the h$%a fet$& a d child#e . N " ! $ %#e in )$e/nan" $ 1ac"a"in/ 6 men $ in chi1d$en %nde$ G +ea$# ! a/e0 2. H+)e$#en#i"i*i"+ Reac"i n# - $#tica#ia, %o#billifo#% #a&he& 3. Ph " #en#i"i*i"+ 4. Ga#"$ in"e#"ina1 i$$i"a"i n - /a$&ea, 3o%iti ', dia##hea 5. E# )ha/ea1 U1ce$a"i n - Ca be a3oided b. ta8i ' %edicatio -ith f$ll 'la&& of -ate# a d ot "#io# to bed. 6. Rena1 D+#!%nc"i n - Tet#ac.cli e& a''#a3ate "#e-e9i&ti ' #e al fail$#e b. i hibiti ' "#otei &. the&i&. 7. Ve#"i2%1a$ T 4ici"+ - Co &i&t& of ti it$&, di55i e&&, li'ht-headed e&&. Occ$#& o l. -ith %i oc.cli e. >e3e#&ible afte# d2c of d#$'.

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G0 DRUG INTERACTIONS Aood dec#ea&e& ab&o#"tio of tet#ac.cli e. Calci$%, %a' e&i$%, al$%i $%, i#o - co tai i ' "#od$ct& a d %il8 fo#% co%"le9e& -ith the tet#ac.cli e& a d dec$ea#e a2# $)"i nKK!e"a#ate ad%i i&tatio ti%e b. 2 ho$#&. H0 DRUG PREPARATIONS AND DOSING

DRUG

HOE AVAILABLE

USUAL ADULT DOSE

Tet#ac.cli e 250, 500 %' ca"&2tablet& 250-500 %' "o ?6 ho$#& Do9.c.cli e Mi oc.cli e 50, 100 %' ca"&2tablet& 200 %' 9 1, 100 %' "o2(1 ?12-24 ho$#& (/C - 100, 200 %' 3ial 50, 100 %' ca"&2tablet& 200 %' 9 1, 100 %' "o ?12 ho$#& (/C - 100 %' 3ial

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S L!ONAMIDES
A0 MECHANISM O= ACTION The &$lfo a%ide& -e#e the fi#&t &.&te%ic a tibacte#ial d#$'& $&ed i h$%a &. !$lfo a%ide& a#e "#i%a#il. 2ac"e$i #"a"ic, a d -o#8 b. i te#fe#i ' -ith folic acid &. the&i&. !$lfo a%ide& co%"etiti3el. i hibit i co#"o#atio of )A+A :"a#a-a%i obe 5oic acid; i to dih.d#ofolic acid :a i te#%ediate i the "#oce&& of folate %etaboli&%;KK i hibit fo#%atio of folate -hich i& e&&e tial fo# %ic#oo#'a i&% cell di3i&io . B0 SPECTRUM O= ACTIVITY G$am ) #i"i*e ae$ 2e# - A#e acti3e a'ai &t St%&pto"o""$s p+o,&(&s. G$am ne/a"i*e ae$ 2e# - E. "o i a#e $&$all. &$&ce"tible, e&"eciall. at co ce t#atio & achie3ed i the $#i e. Acti3e a'ai &t &o%e &t#ai & of N&iss&%ia *&(i(,iti'is. O"he$ - Acti3e a'ai &t Ch a*+'ia/ To-op as*a a(' No"a%'ia &"ecie&. C0 CLASSI=ICATION O= SUL=ONAMIDES 1. Sh $" Ac"in/ :&$lfi&o9a5ole, &$lfadia5i e; - &ol$ble i $#i e. 2. In"e$media"e Ac"in/ - !$lfa%etho9a5ole :*a ta ol; 0e&& &ol$ble a d e9c#eted %o#e &lo-l. tha &ho#t acti ' &$lfo a%ide& KK "#o3ide& hi'he# blood le3el&. ( c#ea&ed cha ce of c#.&tall$#ia KK eed to e &$#e 'ood $#i e o$t"$t. 3. L n/ Ac"in/ - /o lo 'e# #eco%%e ded &eco da#. to h."e#&e &iti3it. #eactio &. D0 PHARMACO9INETICS >a"idl. ab&o#bed :&ho#t a d i te#%ediate acti ';, -ell-di&t#ib$ted i bod.. D#$' %etaboli5ed i the li3e# a d e9c#eted #e all. 3ia 'lo%e#$la# filt#atio a d t$b$la# &ec#etio . Do&a'e #ed$ctio ece&&a#. i #e al fail$#e.

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E0 CLINICAL USE O= SUL=ONAMIDES 1. @ co%"licated @T( - "#oble%& -ith i c#ea&i ' #e&i&ta ce. 2. To9o"la&%a 'o dii - &$lfadia5i e $&ed i co%bi atio -ith ".#i%etha%i e. 3. /oca#dia a&te#oide& =0 ADVERSE E==ECTS 1. Hema" 1 /ic - a3oid i "atie t& -ith 'l$co&e 6-"ho&"hate deh.d#o'e a&e deficie c. KKhe%ol.&i&. Ca al&o ca$&e bo e %a##o&$""#e&&io KK le$co"e ia, a e%ia, o# th#o%boc.to"e ia. 2. H+)e$#en#i"i*i"+ $eac"i n# - #a&h, fe3e#, 3a&c$liti&, e#.the%a %$ltifo#%e, !te3e &- Coh &o &. d#o%e. 3. 9e$nic"e$%# - A3oid i eo ate& a d d$#i ' the la&t t#i%e&te# of "#e' a c.. !$lfo a%ide& co%"ete fo# bili#$bi -bi di ' &ite& a d i c#ea&e le3el& of $ co <$'ated bili#$bi . G0 DRUG INTERACTIONS !$lfo a%ide& ca i c#ea&e the acti3it. of -a#fa#i eed to dec#ea&e do&e of o#al a ticoa'$la t&. 4."o'l.ce%ic effect of tolb$ta%ide a d chlo#"#o"a%ide %a. be i c#ea&ed b. &$lfo a%ide&.

TRIMET"O#RIM
A0 MECHANISM O= ACTION ( hibit& the e 5.%e dih.d#ofolate #ed$cta&e, the#eb. i te#fe#i ' -ith the co 3e#&io of dih.d#ofolate to tet#ah.d#ofolate, the "#ec$#&o# of foli ic acid. B0 SPECTRUM O= ACTIVITY !ee TM)2!MI belo-

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C0 PHARMACO9INETICS Mell ab&o#bed f#o% the *( t#act, -idel. di&t#ib$ted i ti&&$e&, "#i%a#il. e9c#eted $ cha 'ed b. the 8id e.& :60-80L;. !e#$% t122 9-11 ho$#& a d "#olo 'ed i #e al fail$#e. Do&a'e ad<$&t%e t #e?$i#ed i #e al fail$#e. D0 CLINICAL USE 1. @ co%"licated @T(& 2. ) e$%oc.&ti& ca#i ii " e$%o ia - i co%bi atio -ith da"&o e. E0 AVAILABILITY 100, 200 %' tablet&.

TRIMET"O#RIM$S L!AMET"O%A&OLE KTMP/SMXL, :+act#i%, !e"t#a;

A0 BAC9GROUND Thi& co%"o$ d i& al&o 8 o- a& c -"$im 4a5 1e0 Thi& co%bi atio i hibit& 2 &e?$e tial &te"& of bacte#ial %etaboli&% :&ee belo-;. 4a& 2 theo#etical ad3a ta'e&= 1. Dec#ea&e& cha ce of de3elo"i ' #e&i&ta ce, a d 2. Ma. be &. e#'i&tic. A3ailable i o#al a d i t#a3e o$& fo#%$latio &. Co%bi atio "#o3ide& ideal blood #atio of 1= 20 fo# o"ti%al &. e#'.. B0 MECHANISM O= ACTION !e?$e tial i hibitio of &. the&i& of folic acid i hibit D/A "#od$ctio . Aolate "#od$ctio i& e&&e tial fo# ea#l. all %ic#oo#'a i&%& beca$&e the. ca ot e9t#act e9o'e o$& folate f#o% thei# diet, -hich i& i co t#a&t to %a%%alia cell&. The co%bi atio "#od$ct TM)2!MI i& 2ac"e$icida1 and #+ne$/i#"ic a'ai &t %a . '#a% "o&iti3e a d '#a% e'ati3e bacte#ia.

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C0 SPECTRUM O= ACTIVITY G$am P #i"i*e C cci - Acti3e a'ai &t Staph+ o"o""$s a$%&$s :i cl$di ' &o%e M>!A;, S. &pi'&%*i'is/ St%&pto"o""$s p(&$*o(ia&/ a d 3i#ida & &t#e"tococci. /ot acti3e a'ai &t &(t&%o"o""i. G$am Ne/a"i*e Ae$ 2e# - Acti3e a'ai &t %o&t E(t&%o.a"t&%ia"&a& i cl$di ' E. "o i/ E(t&%o.a"t&% spp. H&*ophi $s i() $&(2a&/ Mo%a-& a "ata%%ha is/ Sa *o(& a a d Shi,& a spp/ 6a(tho*o(as *a tophi ia. /ot acti3e a'ai &t Ps&$'o*o(as a&%$,i(osa. Anae$ 2e# - /ot acti3e a'ai &t a ae#obe&. O"he$ - List&%ia *o(o"+to,&(&s/ P(&$*o"+stis "a%i(ii a d %o&t No"a%'ia sp&"i&s. D0 PHARMACO9INETICS Ab&o#"tio - Mell ab&o#bed f#o% the *( t#act. Di&t#ib$tio - Di&t#ib$te& i to %o&t ti&&$e&, "e et#ate& C!A :Q40L of &e#$% le3el&;, "le$#al a d "e#ito eal fl$id&. Achie3e& hi'h co ce t#atio & i the "#o&tatic fl$id. 6li%i atio - )#i%a#il. e9c#eted b. the 8id e.&. Mhe C#Cl J 30 %l2%i $te, eed& do&a'e ad<$&t%e t. =0 CLINICAL USES =OR TMP/SMX 3DOSING( 1. U$ina$+ T$ac" In!ec"i n# - Ac$te :1 D! "o ?12 ho$#&; - >ec$##e t 2. Pne%m c+#"i# ca$inii )ne%m nia - t#eat%e t a d "#o"h.la9i& :15 %'28'2da. TM) i do&e& ?6-8 ho$#&. 1 D! "o ?d o# ?M,M,A fo# "#o"h.la9i&;. 3. )#o&tatiti& :1 D! "o ?12 ho$#&; 4. Ac$te e9ace#batio & of ch#o ic b#o chiti& :1 D! "o ?12 ho$#&; 5. !i $&iti&2Otiti& %edia - 'ood fo# a%"icilli -#e&i&ta t &t#ai & of H. i() $&(2a& a d M. "ata%%ha is :1 D! "o ?12 ho$#&;. 6. !al%o ella2!hi'ella 7. /oca#dia i fectio & :10-15 %'28'2da. TM);

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G0 ADVERSE E==ECTS 1. GI - a$&ea, 3o%iti ', dia##hea 2. H+)e$#en#i"i*i"+ $eac"i n# - #a&h %o#e co%%o i A(D! "atie t& :ie. i $" to 50L of "atie t&;. 3. Hema" 1 /ic - a& abo3e. 4. Te$a" /ene#i# and 9e$nic"e$%# - A3oid i "#e' a t o# lactati ' -o%e , o# i fa t& J 2 %o th& of a'e. 5. He)a"i"i# - #a#e. H0 DRUG INTERACTIONS A& %e tio ed abo3e. TM)2!MI %a. i c#ea&e le3el& of "he .toi , %ethot#e9ate. @&e ca$tio$&l. i "atie t& #ecei3i ' othe# bo e %a##o&$""#e&&i3e a'e t&, e&"eciall. i "atie t& -ith 4(1 :e9. ADT;. I0 DRUG PREPARATIONS

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T%2e$c%1 #i#
Tho%a& ). 7a .o8, )ha#%.D. I0 In"$ d%c"i n& T$be#c$lo&i& i& a i fectio ofte of lifelo ' d$#atio , ca$&ed b. th#ee &"ecie& of %.cobacte#ia, M. t$.&%"$ osis, M. .o3is/ a d M. a)%i"a($*. (t ca #e&$lt i di&ea&e i 3i#t$all. e3e#. o#'a &.&te% i the bod., %o&t "#o%i e tl. i the l$ '&. A. 4i&to#.=

)aleo"atho'ic e3ide ce of &"i al T+ e9i&t& i eolithic, "#e-Col$%bia , a d ea#l. 6'."tia #e%ai . 4o-e3e#, t$be#c$lo&i& did ot beco%e a %a<o# "#oble% $ til the c#o-ded li3i ' co ditio & of the ea#l. i d$&t#ial #e3ol$tio c#eated e"ide%iolo'ic co ditio & fa3o#i ' it &"#ead. +efo#e the a3ailabilit. of a ti%ic#obial d#$'&, the co# e#&to e of t#eat%e t -a& #e&t i the o"e ai# i &"eciali5ed t#eat%e t &a ito#ia. -ith the de3elo"%e t of I-#a. tech olo'. it beca%e clea# that de3elo"%e t of ca3itatio -a& the "i3otal e3e t i the "#o'#e&&i3e at$#e of "$l%o a#. di&ea&e, a d %o&t &"ecial the#a"ie& -e#e ai%ed at ca3it. clo&$#e. The %ode# e#a of t$be#c$lo&i& be'a i 1946 -ith the de%o &t#atio of the efficac. of &t#e"to%.ci :!M;. ( 1952 the %o#e effecti3e d#$' i&o ia5id :(/4; beca%e a3ailable, %a8i ' T+ c$#able i the 3a&t %a<o#it. of "atie t&, a d i 1970 #ifa%"i :1970; ca%e to be #eco' i5ed a& the %o&t acti3e a ti-T+ a'e t. The ad3e t of effecti3e che%othe#a". fo# T+ lead to the belief that T+ -o$ld be e#adicated b. the .ea# 2000. 4o-e3e#, "$blic health co%"lace c., alo ' -ith a '#oi ' i%%i'#a t "o"$latio , i c#ea&ed ho%ele&& e&&, a d the '#o-i ' "ect#e of co-i fectio -ith 4(1 a d A(D ha& #e&$lted i a i c#ea&e i @.!. T+ ca&e& &i ce 1985. Of e3e %o#e co ce# i& the #i&i ' i cide ce of %$lti"le d#$' #e&i&ta t ca&e& :MD>; of T+ -hich ha3e had de3a&tati ' i%"act, e"e&ciall. i 4(12A(D! "atie t&. /e- effo#t& de&i' ed at di&co3e#i ' e- a ti-t$be#c$lo&i& the#a"ie& a d e- "#o'#a%& ai%ed at co t#olli ' di&ea&e ha3e offe#ed the "#o%i&e of ho"e i co t#olli ' the /o.1 i fectio$& 8ille# i the -o#ld.

II0 Mic$ 2i 1 /+& The te#% t$.&%" & .a"i $s de&i' ate& th#ee &"ecie& of the fa%il. M.cobacte#iacaea, o#de# Acti o%.cetale&= M. t$.&%"$ osis, M. .o3is, a d M. a)%i"a($*. The. a#e di&ti '$i&hed f#o% %a . othe# %.cobacte#ial &"ecie& of 3a#.i ' "atho'e icit. a d cli ical i%"o#ta ce that &ha#e the &tai i ' cha#acte#i&tic 8 o- a acid-fa&t e&&. At "#e&e t di&ea&e ca$&ed b. M. .o3is a d M. af#ica $% i& #elati3el. #a#e. 4$%a a#e the o l. #e&e3oi# fo# T+. (t i& a ae#obic, o -&"o#e fo#%i ', o -%otile bacill$& -ith a hi'h cell -all co te t of hi'h%olec$la# -ei'ht li"id&. *#o-th i& &lo-, the 'e e#atio ti%e bei ' f#o% 15-20 ho$#& :Co%"a#ed -ith -ell $ de# o e ho$# fo# %o&t co%%o bacte#ial "atho'e &;. The te#% acid-fa&t co%e& f#o% the cha#acte#i&tic #ed &tai &ee $"o a""licatio of the Diehl-/eel&o acid-alcohol &tai :%odified b. 7i .o$ ;.

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III0 E)idemi 1 /+& A. *e e#al A""#o9i%atel. 1.7 billio "eo"le :o e-thi#d; of the -o#ldN& "o"$latio i& i fected -ith T+, leadi ' to 10 %illio e- ca&e&, a d to 3 %illio death& "e# .ea#. Thi& %a8e& T+ the $%be# o e i fectio$& di&ea&e 8ille# i the -o#ld. ( the 19th ce t$#. T+ acco$ ted fo# 30L of all death& i 6$#o"e. The M4O e&ti%ate& that T+ -ill ca$&e at lea&t 30 %illio death& f#o% 1990 to 1999. +. >ece t Mo#bidit. a d Mo#talit. T#e d& i the @.!. ( the @.!. the &tead. decli e i t$be#c$lo&i& %o#bidit. #eached a adi# i 1984, -he 9.4 ca&e& "e# 100,000 -e#e #e"o#ted. +et-ee 1985 a d 1994, a e&ti%ated 63,000 Ge9ce&&G ca&e& of acti3e T+ -e#e #e"o#ted. Thi& i c#ea&e -a& d$e to a co%bi atio of &e3e#al &ocial, eco o%ic, a d hi&to#ical facto#& i cl$di ' $#ba ho%ele&& e&&, (1DA, a d "$blic health e'lect of T+ co t#ol "#o'#a%&, b$t the A(D! e"ide%ic ha& be the %o&t otable co t#ib$to#. T+ i& o- co ce t#ated i %edicall. $ de#&e#3ed "o"$latio &, tthe $#ba "oo#, alcoholic&, (1DA, the ho%ele&&, %i'#a t -o#8e#&, a d "#i&o i %ate&, ofte occ$##i ' i co tact ba&ed %ic#oe"ide%ic&. >acial a d eth ic %i o#itie& a#e the %o&t ha#de&t hit aco$ ti ' fo# t-o-thi#d& of all ca&e&. IV0 PATHOGENESIS O= TUBERCULOSIS A0 OVERVIEE

The 3a&t %a<o#it. of t$be#c$lo&i& ca&e& that de3elo" i thi& co$ t#. a#e ca$&ed b. the o#'a i&% M+"o.a"t&%i$* t$.&%"$ osis :MT+;. O l. #a#el. i& di&ea&e ca$&ed b. M+"o.a"t&%i$* .o3is o# a)%i"a($*. ( fectio -ith MT+ i& ca$&ed al%o&t e9cl$&i3el. ae#o&oli5atio of MT+ d#o"let $clei, that a#e i haled i to the al3eola# &"ace, "a&t the o#%al ho&t defe &e& :e.'. cilia#. e"ithelial cell& of the $""e# e&"i#ato#. t#act;, -he#e the. a#e de"o&ited, "ha'oc.ti5ed b. al3eola# %ac#o"ha'e&, a d #e"licatio be'i &. T l.%"hoc.te& a d thei# a&&ociated c.to8i e& a#e i c#ea&i 'l. #eco' i5ed a& "la.i ' a #ole i the i%%$ olo'. of T+ a d a de"letio of CD4 cell& i& #e&"o &ible fo# the de3a&tati ' co &e?$e ce& of T+24(1 i fectio . Afte# a &ho#t "e#iod of #e"licatio :14-21 da.&;, the o#'a i&% &"#ead& th#o$'h #e'io al l.%"hatic& to the hila# l.%"h ode& a d the th#o$'h the blood&t#ea% to all &ite& i the bod.. Thi& di&&e%i atio i& $&$all. &ile t a d i& acco%"li&hed al%o&t &i%$lta eo$&l. b. the o &et of CD4 di#ected i%%$ e #e&"o &e :e.'. dela.ed h."e#&e &iti3it. to the o#'a i&%;. At the &ite& to -hich it di&&e%i ate&, the o#'a i&% i& $&$all., b$t ot al-a.& 8illed. Co &e?$e tl., o#'a i&%& that ha3e bee do#%a t ca beco%e #eacti3ated. @&$all. the o#i'i al i fectio i& co t#olled a d #e%ai & &$bcli ical. !$b&e?$e tl., the#e a#e "#efe#e tial &ite& at -hich thi& o#'a i&% beco%e& #eacti3ated. Ao# the %o&t "a#t, the&e a#e &ite& of "e#&i&te tl. hi'h o9.'e te &io . Mo&t ca&e& of t$be#c$lo&i& occ$# at lea&t %o th&, a d ofte .ea#&, afte# i itial i fectio a d #e"#e&e t e do'e o$& #eacti3ated t$be#c$lo&i&.

B0 THE ROLE O= CELLULAR IMMUNITY IN CONTROLLING DISEASE The %a<o# ho&t defe &e that co t#ol& MT+ i& the %ac#o"ha'e-l.%"hoc.te &.&te%. (%"ai#%e t of cell$la# i%%$ it. "#edi&"o&e& the ho&t to the de3elo"%e t of cli ical di&ea&e d$e to #eacti3atio of late t i fectio .

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C0 S9IN TEST REACTIVITY )#e&e ce of cell$la# i%%$ it. ca be %ea&$#ed b. &8i #eacti3it. to a i t#ac$ta eo$& :))D; a ti'e :Ma to$9 te&t;. 4i&tolo'icall., a "o&iti3e #eactio i& d$e to i filt#atio b. a la#'e $%be# of %o o $clea# cell&. The&e be'i to acc$%$late 24 ho$#& late# a d $&$all. a#e f$ll. %a ife&t bet-ee 48-72 ho$#& afte# i <ectio of the a ti'e . The %echa i&% of the acc$%$latio of cell& at the &ite a""ea#& to be d$e to i itial att#actio to the a ti'e b. o e o# a fe- %e%o#. cell&, -hich elabo#ate a facto# :%ac#o"ha'e i hibito#. facto#; that att#act $ co%%itted %o o $clea# cell& to the a#ea. Thi& "#e&$%abl. i& the %echa i&% b. -hich the cell& co t#ol the i fectio at the &ite of bacte#ial #e"licatio . 1. C1inica1 S.in Te#"in/ The %o&t co%%o a d %o&t $&ef$l &8i te&t& fo# t$be#c$lo&i& i& i t#ac$ta eo$& i oc$latio of "$#ified "#otei de#i3ati3e :))D; of t$be#c$lo&i&. The %o&t co%%o "#e"a#atio $&ed co tai & :5T@;. 2. P #i"i*e Reac"i n The te&t i& #ead at 48-72 ho$#& afte# bei ' "laced a d i& "o&iti3e de"e di ' o the "atie t "o"$latio a d the &i5e of i d$#atio . ( "$l%o a#. t$be#c$lo&i& 20-25L of "atie t& %a. ha3e a e'ati3e i te#%ediated ))D. 3. B #"e$ E!!ec" A e ha ci ' o# boo&ti ' "he o%e a ha& bee #eco' i5ed -ith &e#ial &8i te&ti '. (t i&, b. defi itio , a i c#ea&e i the t$be#c$li &8i te&t #eactio f#o% le&& tha 10%% to '#eate# tha 10 %% of i d$#atio , it th$& %i%ic& &8i te&t co 3e#&io . Thi& boo&te# effect %a. be &ee -ithi 2 o# 3 -ee8& of the i itial te&t, a d the effect "e#&i&t& fo# 1 .ea# o# lo 'e#. D0 OTHER TECHNIDUES IN THE DIAGNOSIS O= TUBERCULOSIS 1. Acid-!a#" 2aci11i 3A=B( 2+ c%1"%$e :'old &ta da#d; a0 Co# e#&to e of the dia' o&i&, &e3e#al -ee8& :2-4; $ til #e&$lt& 20 /eed &"$t$% o# othe# bod. fl$id o# ti&&$e fo# c$lt$#e. 2. Acid-!a#" #mea$# ! a 2 d+ !1%id )#o3ide& &t#o ' e3ide ce that t$be#c$lo&i& i fectio i& "#e&e t. /e3e#thele&&, it i& ot al-a.& "o&&ible o &%ea#& to di&ti '$i&h &a"#o"h.tic f#o% "atho'e ic %.cobacte#ia. 3. Che#" X-$a+ )#e&e ce of di&ti'$i&hi ' le&io & V0 PULMONARY TUBERCULOSIS A0 )$l%o a#. t$be#c$lo&i& i& the %o&t co%%o t."e of di&ea&e &ee i the o -i%%$ oco%"#o%i&ed "atie t. (t ca oc$# i the follo-i ' fo$# diffe#e t fo#%&= 1. Ca3ita#. "$l%o a#. t$be#c$lo&i& 2. T$be#c$lo&i& " e$%o ia

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3. T$be#c$lo&i& "le$#e&. 4. Milia#. t$be#c$loi&i& VI0 EXTRAPULMONARY TUBERCULOSIS Mo#e co%%o l. &&e a& a "#i%a#. i fectio i a i%%$ oco%"#o%i&ed ho&t. T$be#c$lo&i& %a. occ$# i %a . o#'a & a d $&$all. beco%e& %a ife&t i o e of th#ee -a.&. Ai#&t, e9t#a"$l%o a#. i fectio occ$#& i the %ilia#. "#oce&&, b$t, $&$all., 'e e#ali5ed &i' & a d &.%"to%& of di&ea&e a#e %o#e i%"o#ta t tha the %a ife&tatio & of &.%"to%& o# &i' & of &"ecific o#'a i fectio . Mo#e co%%o l., o#'a i 3ol3e%e t ca occ$# &i%$lta eo$&l. -ith the #eacti3atio "#oce&& i the l$ ' a d th$& be %a ife&t at that ti%e. 6?$all. co%%o i& the occ$##e ce of e9t#a"$l%o a#. t$be#c$lo&i& i the ab&e ce of ob3io$& cli ical di&ea&e i the l$ '. Ao#%& of e9t#a"$l%o a#. di&ea&e i cl$de= 1; %e i 'iti&, 2; "e#ica#diti&, 3; #e al, 4; bo e, 5; l.%"h ode&, 6; &e#o$& &$#face& :"le$#al eff$&io , "e#ica#dial eff$&io &, a d "e#ito iti&;, a d 7; &8i . VII0 ANTITUBERCULOSIS THERAPY& =IRST-LINE DRUGS 1. ISONIAHID 3INH( bacte#icidial Mecha i&% of actio = $ 8 o- b$t tho$'ht to be i hibitio of the bio&. the&i& of %.colic acid&. )e et#ate& #eadil. i to all bod. fl$id& a d cell&, i cl$di ' the C/! :&i%ila# to co ce t#atio & a& i "la&%a;. Metaboli5ed "#i%a#il. b. the li3e#, a& a #e&$lt of e 5.%atic acet.latio a d e 5.%atic h.d#ol.&i&. 4alf-life #a 'e& f#o% 1-3 ho$#& a d de"e de t o -hethe# the "atie t i& a fa&t o# &lo- acet.lato#. Do&e& a#e ot #ed$ced i #e al i%"ai#%e t e9ce"t i ad3a ced #e al fail$#e. 9L of all cli ical i&olate& of T+ #e&i&ta t to (/4 a0 D #a/e :$&$all. o#al, ca be i t#a%$&c$la#;= Dai1+ D #e& Ad$lt& 5 %'28' Ma9i%$% do&e= 300 %' Child#e 10 to 20 %'28' Ma9i%$% do&e= 300 %'

T6ice Eee.1+& Ad$lt& 15 %'28' Ma9i%$% do&e= 900 %' Child#e 20 to 40 %'28' Ma9i%$% do&e= 900 %' 20 Ad*e$#e E!!ec"# 3?0>A incidence(& He)a"i"i#& U1 Ad3e#&e #eactio

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12-15L o# %o#e of "atie t& o (/4 %a. ha3e t#a &a%i a&e ele3atio &. 1L de3elo" f#a 8 he"atiti& -hich ca lead to death i #a#e ca&e&. )atie t& -ith "#e-e9i&it ' li3e# di&ea&e, olde# "atie t&, "o&t-"a#te% a d "#e' a t "atie t& a#e at #i&8 fo# the de3elo"%e t of he"atiti&. (t i& #a#el. &ee i "atie t& $ de# 30 .ea#&, b$t i& #e"o#ted i o3e# 2L of "atie t& o3e# 50 .ea#& of a'e. The#e i& o i c#ea&ed #i&8 of he"atiti& fo# %o&t "atie t& -he i&o ia5id a d #ifa%"i a#e $&ed to'ethe#. Mild he"atic di&ea&e doe& ot "#ecl$de the $&e of (/4 :a d #ifa%"i ;, altho$'h &e#ial %o ito#i ' i& &$''e&ted. 6le3atio & of the !*OT o# !*)T to 3-5 ti%e& o#%al &ho$ld lead to #ea&&e&&%e t of the #e'i%e &, if ba&eli e !*OT o# !*)T i& 6-8 ti%e& o#%al le3el&, (/4 :a d #ifa%"i ; &ho$ld be a3oided. Ne%$ 1 /ica1 T 4ici"+& le&& co%%o (/4 e9e#t& it& e$#oto9ic effect th#o$'h e ha ced eli%i atio of ".#ido9i e a d2o# co%"etiti3e i hibitio -ith ".#ido9i e i it& actio a& a cofacto# i the &. the&i& of &. a"tic e$#ot#a &%itte#&. )e#i"he#al e$#o"athie& :0.2L; %o&t co%%o b$t #a#el., &ei5$#e&, o"tic e$#iti&, e ce"halo"athie&, a d the ha d-&ho$lde# &. d#o%e ca occ$#. Co co%ita t ad%i i&t#atio of ".#ido9i e :10-50 %' dail.;. The #o$ti e "#o"h.lactic $&e of ".#ido9i e -ith i&o ia5id &ho$ld be co &ide#ed i "atie t& "#edi&"o&ed to e$#olo'ic to9icit. beca$&e of "#e' a c., diabete&, $#e%ia, alcoholi&%, %al $t#itio , o# a "#io# &ei5$#e di&o#de#. H+)e$#en#i"i*i"+ Reac"i n#& Ae3e# :1.2L;, #a&h :2L;, a d #he$%atoid &. d#o%e& ca occ$#. )o&iti3e a ti $clea# a tibodie& a d l$"$&-e#.the%ato$& cell "#e"a#atio %. be &ee . c0 D$%/ In"e$ac"i n#& ( hibitio of %etaboli&% of "he .toi , ca#ba%a5e"i e, "#i%ido e a d -a#fa#i . 2. RI=AMPIN bacte#icidal MOA= ( hibit& D/A-de"e de t >/A "ol.%e#a&e of %.cobacte#ia a d othe# %ic#oo#'a i&%&, leadi ' to &$""#e&&io of i itiatio of chai fo#%atio i >/A &. the&i&. The o#al fo#% i& -ell ab&o#bed f#o% the *( t#act i the fa&ti ' &tate. >ifa%"i i& -ell di&t#ib$ted, -ith ade?$ate co ce t#atio & i bod. fl$id& :&e#$%, $#i e, &ali3a, "le$#a;, i cl$di ' the C!A. >ifa%"i i& deacet.lated b. the li3e#, a d it& half-life :1.5-5 ho$#&; i& "#olo 'ed i he"atic di&ea&e&. The#e i& o eed to ad<$&t do&e& i #e al fail$#e. 4L of all T+ cli ical i&olate& #e&i&ta t to >(A a0 D #a/e :$&$all. o#al, ca be i t#a3e o$&;= Dai1+ D #e& Ad$lt& 10 %'28' Ma9i%$% do&e= 600 %' Child#e 10 to 20 %'28' Ma9i%$% do&e= 600 %' T6ice Eee.1+&

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Ad$lt& 10 %'28' Ma9i%$% do&e= 600 %' Child#e 10 to 20 %'28' Ma9i%$% do&e= 600 %' 20 Ad*e$#e E!!ec"# 3 F>A(& He)a" " 4ici"+& 20-30L of "atie t& -ho #ecei3e a co%bi atio of (/42>(A -ill e9"e#ie ce a %ild2%ode#ate #i&e i t#a &a%i a &e&. Imm%n 1 /ica1 Reac"i n#& Alle#'ic a d2o# h."e#&e &iti3it. #eactio & &$ch a& d#$' fe3e#, &8i #a&he&, a d eo&i o"hilia a#e $ co%%o . A !1%1i.e #+nd$ me -ith fe3e#, %.al'ia, a d headache ca occ$#. Occ$#& %o#e co%%o -ith i##e'$la# ad%i i&t#atio 3s #o$ti e i te#%itte t t$be#c$lo&i& #e'i%e &. Red- $an/e, Di#c 1 $a"i n of the $#i e, &ali3a, &-eat, a d tea#&, a d "atie t& &ho$ld be fo#e-a# ed of thi& to "#e3e t $ ece&&a#. a 9iet., &oft co tact le &e& %a. beco%e "e#%a e tl. di&colo#ed Ga#"$ in"e#"ina1& 6"i'a&t#ic di&t#e&&, a$&ea a d 3o%iti ' :1.5L;, abdo%i al c#a%"&, dia##hea ha3e occa&io all. #e?$i#ed di&co ti $atio of the d#$'. c0 D$%/ In"e$ac"i n#& >ifa%"i i& a "ote t i d$ce# of he"atic d#$' %etaboli5i ' e 5.%e&. (t ca alte# the %etaboli&% of ADT, "#otea&e i hibito#&, co t#ace"ti3e&, o#al a ticoa'$la t&. 3. PYRAHINAMIDE 3PHA( :bacte#icidal; MOA= !"lit i to a%%o ia a d ".#a5i oic acid. (t i& -ell ab&o#bed o#all. a d "e et#ate& the C/! -he the %e i 'e& a#e i fla%ed. he %a<o# #o$te of e9c#etio i& #e al :'lo%e#$la# filt#atio ;, b$t the d#$' i& al&o h.d#ol.5ed a d the h.d#o9.lated. 6L of all T+ cli ical i&olate& #e&i&ta t to )DA a0 D #a/e :o#al;= Dail. Do&e= Ad$lt& 15 to 30 %'28' Ma9i%$% do&e= 2.0 *% Child#e 15 to 30 %'28' Ma9i%$% do&e= 2.0 *% T-ice Mee8l.= Ad$lt& 50 to 70 %'28' Child#e 50 to 70 %'28'

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20 Ad*e$#e E!!ec"#& He)a" " 4ici"+& $ co%%o !e#ial li3e# f$ ctio te&t& &ho$ld be %o ito#ed o l. i hi'h-#i&8 "atie t& o# d$#i ' lo '-te#% the#a".. )DA doe& ot &i' ifica tl. i c#ea&e the #i&8 of he"atoto9icit. -he $&ed at a do&a'e of 15 to 30 %'28'2da. -he added to a #e'i%e of (/4 a d #ifa%"i d$#i ' the i itial 2 %o th& of the#a".. H+)e$%$icemia& @ co%%o ( te#fe#e& -ith the e9c#etio of $#ate b. dec#ea&i ' it& t$b$la# &ec#etio . Na%#ea, * mi"in/ 4. ETHAMBUTOL :bacte#icidal; MOA= ( hibit the i co#"o#atio of %.colic acid i to the %.cobacte#ial cell -all. Abo$t 75-80L of a o#al do&e i& ab&o#bed f#o% the *( t#act. )e et#ate& ti&&$e -ell e9ce"t the C/! :e3e -he the %e i 'e& a#e i fla%ed;. Abo$t 80L of the do&e i& e9c#eted $ cha 'ed i the $#i e, a d 20L "a&&e& $ cha 'ed i the fece&, 8 to 15L i& e9c#eted i the $#i e i the fo#% of 3a#io$& %etabolite&. 6li%i atio half-life i& 3-4 ho$#&. Do&e& %$&t be #ed$ced i #e al fail$#e. 2-3L of all T+ cli ical i&olate& #e&i&ta t to 6M+ a0 D #a/e :o#al;= Dai1+ D #e& Ad$lt& 15 to 25 %'28' Ma9i%$% do&e= 2.5 *% Child#e 15 to 25 %'28' Ma9i%$% do&e= 2.5 *% T6ice Eee.1+& Ad$lt& 50 %'28' Child#e 50 %'28' 20 Ad*e$#e E!!ec"# 3 F-A a" '? m//.//da+ d #e(& Re"$ 2%12a$ Ne%$i"i# 3B0GA(& !.%"to%& i cl$de bl$##ed 3i&io , ce t#al &coto%ata a d #ed-'#ee colo# bli d e&&. Do&e-#elated co%"licatio = J1L of "atie t& #ecei3i ' 15 %'28'2da., 5L of "atie t& #ecei3i ' 25 %'28'2da., a d 15L of "atie t& #ecei3i ' 50 %'28'2da.. The i te &it. of the 3i&$al diffic$lt. i& #elated to d$#atio of the#a". afte# the dec#ea&e i 3i&$al ac$it. fi#&t beco%e& a""a#e t, a d it %a. be $ ilate#al o# bilate#al. Te&t& of 3i&$al ac$it. a d #ed-'#ee di&c#i%i atio "#io# to the &ta#t of the#a". a d "e#iodicall. a#e #eco%%e ded. >eco3e#. $&$all. occ$#& -he etha%b$tol i& -ithd#a- . Ra#h, =e*e$, A$"ha1/ia#, GI i$$i"a"i n&

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5. STREPTOMYCIN :bacte#icidal; MOA= ( hibitio of %>/A #ibo&o%al &$b$ it &. the&i& (t "#o3ide& o l. fai# ti&&$e "e et#atio i to the C/!. >e all. e9c#eted a d do&a'e ad<$&t%e t eeded i #e al fail$#e. 6L of all T+ cli ical i&olate& #e&i&ta t to !M a0 D #a/e :i t#a%$&c$la#;= Dai1+ D #e& Ad$lt& 15 %'28' Ma9i%$% do&e= 1.0 *% K60 .ea#& old 10 %'28'2da. Ma9i%$% do&e 750 %' Child#e 20 to 40 %'28' Ma9i%$% do&e= 1.0 *% T6ice Eee.1+& Ad$lt& 25 to 30 %'28' Child#e 25 to 30 %'28' 20 Ad*e$#e E!!ec"# 3G0-A(& Ve#"i2%1a$ T 4ici"+& Do&e-#elated, "atie t& a#e #i&8 a#e tho&e -ith i%"ai#ed #e al f$ ctio , elde#l. "atie t&, a d tho&e #ecei3i ' "#olo 'ed co$#&e& of the#a".. Ne)h$ " 4ici"+& @ coo%o le&& tha othe# a%i o'l.co&ide a tibiotic& Ne%$ m%#c%1a$ B1 c.ade& #a#e H+)e$#en#i"i*i"+& #a&h :2L; a d fe3e# :1.4L; VIII0 ANTITUBERCULOSIS THERAPY& SECOND-LINE DRUGS 6thio a%ide, fl$o#o?$i olo e& :ci"#oflo9aci , oflo9aci ;, ca"#eo%.ci , 8a a%.ci , a%i8aci , "a#a-a%i o&alic.lic acid :)A!; a d c.clo&e#i e a#e all $&ef$l d#$'& $ de# a""#o"#iate ci#c$%&ta ce&. !o%e of the&e a#e "a#tic$la#l. $&ef$l i #e&i&ta t fo#%& of t$be#c$lo&i&. The&e a'e t& a#e al&o $&ed i t#eati ' %$lti"le-d#$' #e&i&ta t MT+ i fectio &. IX0 PREVENTIVE THERAPY (& co &ide#ed i "atie t& -ith a "o&iti3e ))D b$t -itho$t acti3e di&ea&e that -o$ld #e?$i#e %$lti-d#$' the#a".. (/4 i& the o l. ca#ef$ll. &t$died d#$' "#o3ed to be effecti3e fo# "#o"h.la9i&. The "o&iti3e &8i te&t -itho$t acti3e di&ea&e i& i te#"#eted to %ea that a fe- do#%a t,

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b$t 3iable, bacilli a#e "#e&e t -ith the "ote tial fo# acti3e i fectio . The#e a#e ce#tai &etti '& i -hich the #i&8 fo# acti3e di&ea&e i& &i' ifica t= >ece t ))D co 3e#te#& :J 1 .ea#;, child#e a d adole&ce t& -ith "o&iti3e &8i te&t&, i%%$ olo'icall. i%"ai#ed ho&t&. A0 INDICATIONS Ce#tai '#o$"& -ithi the i fected "o"$latio a#e at '#eate# #i&8 tha othe#& a d &ho$ld #ecei3e hi'h "#io#it. fo# "#e3e ti3e the#a".. ( the @ ited !tate&, "e#&o & -ith a "o&iti3e #eactio to a ))D :i %illi%ete#& of i d$#atio , 'i3e i "a#e the&e&; a d a . of the follo-i ' 6 #i&8 facto#& &ho$ld be co &ide#ed ca didate& fo# "#e3e ti3e the#a"., #e'a#dle&& of a'e, if the. ha3e ot "#e3io$&l. bee t#eated= 1. )e#&o & -ith 4(1 i fectio :K5%%; a d "e#&o & -ith #i&8 facto#& fo# 4(1 i fectio -ho&e 4(1 i fectio &tat$& i& $ 8 o- b$t -ho a#e &$&"ected of ha3i ' 4(1 i fectio . 2. Clo&e co tact& of "e#&o & -ith e-l. dia' o&ed i fectio$& t$be#c$lo&i& :K 5%%;. ( additio , t$be#c$li - e'ati3e : J 5%%; child#e a d adole&ce t& -ho ha3e bee clo&e co tact& of i fectio$& "e#&o & -ithi the "a&t 3 %o th& a#e ca didate& fo# "#e3e ti3e the#a". $ til a #e"eat ))D i& do e 12 -ee8& afte# co tact -ith the i fectio$& &o$#ce. 3. >ece t co 3e#te#&, a& i dicated b. a ))D :K10%% i c#ea&e -ithi a 2-.ea# "e#iod fo# tho&e J 35 .ea#& old, K15%% i c#ea&e fo# tho&e K35 .ea#& of a'e;. 4. )e#&o & -ith ab o#%al che&t 9-#a. that &ho- fib#otic le&io & li8el. to #e"#e&e t old healed t$be#c$lo&i& :K5%%;. 5. ( t#a3e o$& d#$' ab$&e#& 8 o- to be 4(1-&e#o e'ati3e :K10%%;. 6. )e#&o & -ith %edical co ditio & that ha3e bee #e"o#ted to i c#ea&e the #i&8 of t$be#c$lo&i& :K10%%;= a. &ilico&i& b. 'a&t#ecto%. c. <e<$ oileal b."a&& d. -ei'ht of 10L o# %o#e belo- ideal bod. -ei'ht e. ch#o ic #e al fail$#e f. diabete& %ellit$& '. co ditio & #e?$i#i ' "#olo 'ed hi'h-do&e co#tico&te#oid the#a". a d othe# i%%$ o&$""#e&&i3e the#a". h. &o%e he%atolo'ic di&o#de#& :e.'., le$8e%ia a d l.%"ho%a&; (. othe# %ali' a cie& ( additio , i the ab&e ce of a . of the abo3e #i&8 facto#&, "e#&o & J 35 .ea#& of a'e i the follo-i ' hi'h-i cide ce '#o$"& a#e a""#o"#iate ca didate& fo# "#e3e ti3e the#a". if thei# #eactio to ))D i& K10%%= 1. Ao#ei' -bo# "e#&o & f#o% hi'h-"#e3ale ce co$ t#ie& 2. Medicall. $ de#&e#3ed lo--i co%e "o"$latio &, i cl$di ' hi'h-#i&8 #acial o# eth ic %i o#it., e&"eciall. blac8&, 4i&"a ic&, a d /ati3e A%e#ica & 3. >e&ide t& of facilitie& fo# lo '-te#% ca#e :e.'., co##ectio al i &tit$tio &, $#&i ' ho%e&, a d %e tal i &tit$tio &;.

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B0 PREVENTIVE THERAPY 1. Ad$lt&= (&o ia5id 300 %'2da. 2. Child#e = (&o ia5id 10 %'28'2da., %a9i%$% of 300 %'2da. 3. D$#atio = Ao# at lea&t 6 %o th& a d 3a#ie& f#o% 6 to 12 %o th&, "e#&o & -ith 4(1 i fectio a d "e#&o -ith &table ab o#%al che&t 9#a. co &i&te t -ith "a&t t$be#c$lo&i& &ho$ld #ecei3e 12 %o th& of the#a".. To e &$#e that "e#&o & i hi'h-#i&8 '#o$"& co%"l. -ith the#a"., health-ca#e "e#&o el &ho$ld, if ece&&a#., di#ectl. ob&e#3e the the#a".. (&o ia5id ca be 'i3e t-ice -ee8l. i a do&e of 15 %'28' :$" to 900 %'; -he the#a". %$&t be di#ectl. ob&e#3ed a d #e&o$#ce& a#e i ade?$ate fo# dail. the#a".. C0 MONITORING O= THERAPY 1. Mo thl. i te#3al& fo# &.%"to%& o# &i' & co &i&te t -ith acti3e di&ea&e a d li3e# da%a'e o# ad3e#&e effect. 2. )atie t& le&& tha 35 .ea#& of a'e, t#a &a%i a&e %o ito#i ' ot e&&e tial. 3. )atie t& '#eate# tha 35 .ea#& of a'e, t#a &a%i a&e %o ito#i ' #eco%%e ded :e.'., ba&eli e, 1, 3, 6, 9 %o th&;. (f te&t& e9ceed 3 to 5 ti%e&the $""e# li%it of o#%al, di&co ti $atio of (/4 &ho$ld be &t#o 'l. co &ide#ed. X0 CHEMOTHERAPEUTIC REGIMENS - PULMONARY TUBERCULOSIS The 'oal& of a tit$be#c$lo$& the#a". i cl$de #ed$ci ' the d$#atio of the#a". -hile #etai i ' effecti3e e&&, "#e3e ti ' #ela"&e, o3e#co%i ' d#$' #e&i&ta ce, %i i%i5i ' to9icit., a d %a9i%i5i ' "atie t adhe#e ce. A0 NUMBER O= AGENTS ( $ t#eated "o"$latio & of MT+, the#e a#e &%all $%be#& of t$be#cle bacilli #e&i&ta t to o e effecti3e a'e t. Theo#eticall., the li8elihood that a #e&i&ta t bacte#i$% i& "#e&e t i a le&io i c#ea&e& -ith a i c#ea&i ' load :hi'he# tite#; of o#'a i&%&. Mo#e tha o e a tit$be#c$lo$& a'e t i& $&ed i t#eati ' t$be#c$lo&i& i a atte%"t to dec#ea&e the #i&8 of the de3elo"%e t o# &electi '-o$t of #e&i&ta t o#'a i&%&. The#efo#e, i the #e'i%e & belo-, 4 a'e t& a#e i itiall. $&ed fo# the fi#&t 8 -ee8& of the#a".. The co ti $atio "ha&e of the#a". ofte i 3ol3e& t-o bacte#icidal a'e t& :i&o ia5id a d #ifa%"i ; -he #e&i&ta ce i& ot a "#oble%. ( co%%$ itie& -he#e the#e i& a i itial #ate of (/4 #e&i&ta ce of le&& tha 4L, th#ee d#$'& %a. be $&ed a& i itial the#a".. '0 = %$-d$%/ $e/imen# a0 Ini"ia1 - m n"h# ! "he$a)+0 (/4, >(A, )DA, a d 6M+ o# !M a#e $&ed fo# "$l%o a#. a d e9t#a"$l%o a#. t$be#c$lo&i&. 20 Mhe d#$' &$&ce"tibilit. #e&$lt& a#e a3ailable :e.'., 4 to 8 -ee8& late#;, the #e'i%e &ho$ld be alte#ed a& a""#o"#iate. -0 Th$ee d$%/#, i&o ia5id, #ifa%"i , a d ".#a5i a%ide a#e $&ed, 6hen $e#i#"ance $a"e# " INH a$e 1e## "han >A.

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<0 Addi"i n ! d$%/# " an e4i#"in/ $e/imen0 Mhe e3e# a tit$be#c$lo$& d#$'& a#e to be added to a #e'i%e , a& -he the#e i& co ce# abo$t a i ade?$ate #e&"o &e o# #e&i&ta t %.cobacte#ia, at lea&t t-o e- bacte#icidal d#$'& to -hich he "atie t ha& ot bee e9"o&ed &ho$ld be added. The additio of o l. o e d#$' to a #e'i%e to -hich #e&i&ta ce ha& occ$##ed %a. #e&$lt i #e&i&ta ce to the e- d#$' a& -ell. B0 REGIMEN OPTIONS =OR THE INITIAL TREATMENT O= TUBERCULOSIS IN PATIENTS WITHOUT HIV IN=ECTION 1. O)"i n '& Dail. the#a". ( itial the#".= (/4, >(A, )DA, :a d 6M+ o# !M; dail. fo# 8 -ee8& Co ti $altio )ha&e= (/4 a d >(A dail. fo# 16 -ee8& 2. O)"i n -& Th#ice -ee8l. ( itial the#".= (/4, >(A, )DA, :a d 6M+ o# !M; 39 da. fo# 8 -ee8& Co ti $altio )ha&e= (/4 a d >(A 39 -ee8 fo# 16 -ee8& 3. O)"i n <& De 3e# #e'i%e :&ee do&e& abo3e; ( itial the#".= (/4, >(A, )DA, :a d 6M+ o# !M; dail. fo# 2 -ee8& follo-ed b. the &a%e d#$'& 29 -ee8 fo# a othe# 6 -ee8& Co ti $altio )ha&e= (/4 a d >(A 29 -ee8 fo# 16 -ee8& TUBERCULOSIS IN PATIENTS WITH HIV IN=ECTION O"tio & 1, 2, o# 3 ca be $&ed, b$t t#eat%e t #e'i%e & &ho$ld co ti $e fo# a total of 9 %o th& a d at lea&t 6 %o th& be.o d c$lt$#e co 3e#&io . Thi& lo 'e# d$#atio of the#a". i& al&o #eco%%e ded to "atie t& -ith othe# facto#& that co%"#o%i&e a "atie tN& i%%$ e &.&te%. GENERAL PRINCIPLE Mhe the #e&$lt& of d#$' &$&ce"tibilit. te&t& beco%e a3ailable, #e'i%e & &ho$ld be &"ecificall. defi ed o the ba&i& of tho&e #e&$lt&. Ao# e9a%"le, "atie t& -ho&e t$be#c$lo&i& o#'a i&%& a#e &$&ce"tible to i&o ia5id a d #ifa%"i &ho$ld #ecei3e a #e'i%e of i&o ia5id a d #ifa%"i fo# a f$ll 6 %o th&, &$""le%e ted -ith ".#a5i a%ide d$#i ' the fi#&t 2 %o th&. C0 EVALUATION O= RESPONSE TO TREATMENT 1. Pa"ien"# 6i"h P #i"i*e P$e"$ea"men" S)%"%m D%$in/ "he$a)+& (& be&t e3al$ated b. #e"eated :at lea&t %o thl. i te#3al&; $ til th#ee &"eci%e & of &"$t$% &%ea#& a d c$lt$#e& a#e e'ati3e. At a %i i%$%, a &"$t$% &%ea# a d c$lt$#e &ho$ld be obtai ed afte# 2 o# 3 %o th& of t#eat%e t. Mo#e tha 90L of "atie t& -ho had "o&iti3e &"$t$% befo#e t#eat%e t &ho$ld ha3e co 3e#ted to e'ati3e. )atie t& -ho&e &"$t$% o lo 'e# co tai MT+afte# 3 %o th& of t#eat%e t &ho$ld ha3e at lea&t o e f$#the# &"$t$% &%ea# a d c$lt$#e "e#fo#%ed at co%"letio of the#a".. Che&t 9-#a. at co%"letio of t#eat%e t "#o3ide& a ba&eli e fo# co%"a#i&o -ith f$t$#e fil%&.

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)atie t& -ho&e &"$t$% -ho&e &"$t$% ha& ot co 3e#ted b. 3 %o th& of t#eat%e t &ho$ld be ca#ef$ll. e3al$ated. D#$' &$&ce"tibilit. te&t &ho$ld be "e#fo#%ed a d &e#io$& co &ide#atio &ho$ld be 'i3e to ad%i i&te#i ' t#eat%e t $ de# di#ect ob&e#3atio &. 63al$atio & &ho$ld be "e#fo#%ed at lea&t at %o thl. i te#3al& the#eafte# $ til &"$t$% co 3e#&io occ$#&. A!"e$ "he$a)+ 3M m n"h# ! "$ea"men"(& )atie t& &ho$ld ha3e a follo--$" e3al$atio 6 a d 12 %o th& afte# co%"letio of the#a".. 2. Pa"ien"# 6i"h Ne/a"i*e P$e"$ea"men" S)%"%m& ( all "atie t& ha3e 9-#a. ab o#%alitie& co &i&te t -ith t$be#c$lo&i&, 3i'o#o$& effo#t& &ho$ld be %ade to e&tabli&h a dia' o&i&. (f o dia' o&i& ca be e&tabli&hed, "#e&$%"ti3e t#eat%e t fo# t$be#c$lo&i& %a. be i dicated. The %a<o# i dicato#& of #e&"o &e to the#a". a#e the 9-#a. a d cli ical e3al$atio . Aail$#e of the 9-#a. to i%"#o3e afte# 3 %o th& of che%othe#a". i& &t#o 'l. &$''e&ti3e that the ab o#%alit. i& the #e&$lt of eithe# "#e3io$& t$be#c$lo&i& o# a othe# "#oce&&. (f the t$be#c$li #eactio i& &i' ifica t, (/4 b. it&elf &ho$ld be co ti $ed fo# a total of 1 .ea# o# (/4 a d #ifa%"i ca be co ti $ed fo# a total of 6 %o th&.

3. Pa"ien"# EITHOUT D$%/ S%#ce)"i2i1i"+ Te#"#& Mhe #e&$lt& of d#$' &$&ce"tibilit. te&t& a#e ot a3ailable, eithe# d$e to a fail$#e to "e#fo#% the te&t& o# a fail$#e of the te&t to .ield defi iti3e #e&$lt&, the deci&io to %odif. the#a". &ho$ld be ba&ed o the "#obabilit. of d#$' #e&i&ta ce. Mhe#e the "#e3ale ce of d#$' #e&i&ta ce i& &$fficie tl. &$b&ta tial to <$&tif. &ta#ti ' all "atie t& o the fo$#-d#$' #e'i%e :e.'., a "#e3ale ce of i&o ia5id #e&i&ta ce V4L;, ".#a5i a%ide &ho$ld be di&co ti $ed at 8 -ee8&, b$th etha%b$tol o# &t#e"to%.ci &ho$ld be co ti $ed :alo ' -ith i&o ia5id a d #ifa%"i fo# a total of 6 %o th&. E0 PATIENTS EHOSE TREATMENT HAS =AILED $ EHO HAVE RELAPSED T$ea"men" =ai1%$e& 1. !"$t$% "o&iti3e afte# 5-6 %o th&. 2. >ea&&e&& !$&ce"tibilit. a. Add 2 e- cidal d#$'& that the "atie t ha& ot bee "#e3io$&l. e9"o&ed to b. Ad%i i&t#atio $ de# &$"e#3i&io , c. Add o# delete a'e t& a& dete#%i ed b. &e &iti3itie&. T$ea"men" Re1a)#e& 1. @&$all. d$e to o#'a i&%& -hich ha3e ot bee co%"letel. e#adicated b. 2. the co ti $atio a#% of a che%othe#a"e$tic #e'i%e , 3. )e#fo#% &e &iti3it.

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4. ( &tit$te "#e3io$& #e'i%e , cha 'e a& abo3e if #e&$lt& of c$lt$#e& a d &e &iti3itie& &ho- #e&i&ta ce 5. Ad%i i&t#atio $ de# &$"e#3i&io . =0 SPECIAL CONSIDERATIONS IN TREATMENT 1. E4"$a)%1m na$+ T%2e$c%1 #i# 9 %o th& #e'i%e a d ad<$ cti3e the#a". 2. P$e/nanc+ and Lac"a"i n a. Co fi#% the dia' o&i&, b. A 9-%o th #e'i%e i& #eco%%e ded. ( itial #e'i%e &ho$ld co &i&t of i&o ia5id, #ifa%"i , a d etha%b$tol. ).#a5i a%ide i& ot #eco%%e ded fo# $&e d$#i ' "#e' a c. beca$&e it& te#ato'e ic "ote tial i& $ defi ed. 4o-e3e#, if #e&i&ta ce to othe# d#$'& i& li8el. a d &$&ce"tibilit. to ".#a5i a%ide al&o i& li8el., the $&e of ".#a5i a%ide &ho$ld be co &ide#ed a d the #i&8& a d be efit& of the d#$' ca#ef$ll. -ie'hed. !t#e"to%.ci ha& doc$%e ted ha#%f$l effect& o the fet$& :co 'e ital deaf e&&; a d &ho$ld ot be $&ed. c. !%all co ce t#atio & of a tit$be#c$lo$& d#$'& i b#ea&t %il8 do ot "#od$ce to9icit. i the $#&i ' e-bo# . 3. M%1"id$%/-Re#i#"ance a. )atie t& i co%%$ itie& i -hich the#e i& e3e a &%all #i&8 : K2L; of &i 'le-d#$' #e&i&ta ce &ho$ld be t#eated -ith i&o ia5id, #ifa%"i , ".#a5i a%ide, a d etha%b$tol $ til the #e&$lt& of d#$' &$&ce"tibilit. te&ti ' a#e a3ailable. b. )#o3e M$ltid#$'->e&i&ta t MT+= A t$be#c$lo&i& %&t%&at*&(t #e'i%e &ho$ld al-a.& i cl$de at lea&t fo$# b$t "o&&ibl. a& %a . a& &i9 o# &e3e d#$'&. The $%be# of d#$'& $&ed 3a#ie& de"e di ' o the e9te t of di&ea&e a d the "ote c. of the a3ailable a'e t&. c. )ote tial #e'i%e & fo# "atie t& -ith t$be#c$lo&i& -ith 3a#io$& "atte# & of d#$' #e&i&ta ce %$&t be i di3id$ali5ed to %a9i%i5e efficac. a d %i i%i5e to9icit.. !ee the attached table.

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4. POTENTIAL REGIMENS =OR PATIENTS EITH TUBERCULOSIS EITH VARIOUS PATTERNS O= DRUG RESISTANCE :!o$#ce= N E(, 7 M&' 1993, 329=784-791;

RESISTANCE

SUGGESTED REGIMEN >ifa%"i ).#a5i a%ide 6tha%b$tol A%i8aci P >ifa%"i ).#a5i a%ide Oflo9aci o# Ci"#oflo9aci A%i8aci P ).#a5i a%ide 6tha%b$tol Oflo9aci o# Ci"#oflo9aci A%i8aci P ).#a5i a%ide Oflo9aci o# Ci"#oflo9aci A%i8aci P )l$& 2X 6tha%b$tol Oflo9aci o# Ci"#oflo9aci A%i8aci P )l$& 2X

DURATION O= THERAPY 6 to 9 %o th&

COMMENTS A tici"ate 100L #e"o &e #ate a d le&& tha 5L #ela"&e #ate

(&o ia5id a d &t#e"to%.ci

(&o ia5id a d etha%b$tol :W &t#e"to%.ci ;

6 to 12 %o th&

6fficac. &ho$ld be co%"a#able to abo3e #e'i%e

(&o ia5id a d #ifa%"i :W &t#e"to%.ci ;

18 to 24 %o th&

Co &ide# &$#'e#.

(&o ia5id, #ifa%"i a d etha%b$tol :W &t#e"to%.ci ;

24 %o th& afte# co 3e#&io

Co &ide# &$#'e#.

(&o ia5id, #ifa%"i a d ".#a5i a%ide :W &t#e"to%.ci ;

24 %o th& afte# co 3e#&io

Co &ide# &$#'e#.

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(&o ia5id, #ifa%"i , Oflo9aci o# ".#a5i a%ide, a d Ci"#oflo9aci 24 %o th& afte# !$#'e#., if "o&&ible etha%b$tol A%i8aci P co 3e#&io :W &t#e"to%.ci ; )l$& 3X N I! "he$e i# $e#i#"ance " ami.acin, .anam+cin, and #"$e)" m+cin, ca)$e m+cin i# a / d a1"e$na"i*e0 In;ec"a21e a/en"# a$e %#%a11+ c n"in%ed ! $ ! %$ " #i4 m n"h# i! " 4ici"+ d e# n " in"e$*ene0 A11 "he in;ec"a21e d$%/# a$e /i*en dai1+ 3 $ "6ice $ "h$ice 6ee.1+( and ma+ 2e admini#"e$ed in"$a*en %#1+ $ in"$am%#c%1a$1+0 O P "en"ia1 a/en"# !$ m 6hich " ch #e& e"hi namide, c+c1 #e$ine, $ amin #a1ic+c1ic acid0

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H%man Imm%n de!icienc+ Vi$%# 3HIV( And Ac7%i$ed Imm%ne De!icienc+ S+nd$ me 3AIDS(
Cenn+ C 1 m2 , Pha$m0D0 Can%a$+ 'JJ@

G a1# and O2;ec"i*e#&

+. the e d of thi& lect$#e the &t$de t &ho$ld be able to= 1. De&c#ibe the co$#&e of 4(1 i fectio . 2. Defi e A(D! $&i ' &"ecific CDC c#ite#ia. 3. Di&c$&& the diffe#e t %ethod& of 4(1 te&ti '. 4. (de tif. the 3a#io$& #i&8 facto#& a&&ociated -ith 4(1 i fectio . 5. Di&c$&& the co%"licatio & of 4(1 di&ea&e. 6. @ de#&ta d the life-c.cle of 4(1 a d the "ote tial ta#'et &ite& fo# d#$' acti3it.. 7. Di&c$&& ea#l. i te#3e tio %ethod&. 8. 0i&t labo#ato#. te&t& $&ed to dete#%i e the &ta'e of 4(1 di&ea&e. 9. (de tif. ad3e#&e d#$' effect& a d d#$' i te#actio & fo# c$##e tl. a""#o3ed a ti#et#o3i#al a'e t&. 10. De&i' a #atio al the#a"e$tic "la ba&ed o &ta'e of di&ea&e a d "atie t hi&to#..

Re7%i$ed Readin/&
App i&' Th&%ap&$ti"s: Th& C i(i"a Us& o) D%$,s. !i9th 6ditio , 1995 Cha"te# 68. 4$%a (%%$ odeficie c. 1i#$& :4(1; ( fectio . )a'e& 68-1 - 68-48 Pharmacotherapy: A Pathophysiologic Approach. 3rd Edition, 1996 Chapter 117. Principles and Management of the Acquired mmunodeficienc! "!ndrome. Pages #3$3%#3&6. Carpenter CC', (ischl MA, )ammer "M, )irsch M", 'aco*sen +M, et al. Antiretro,iral -herap! for ) . nfection in 1996/ 0ecommendations of an nternational Panel. 'AMA 19961#76/126%1$2

(.

Bac./$ %nd

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( 1981, A(D! -a& fi#&t #e"o#ted i "#e3io$&l. health. .o$ ' 'a. %e . (t -a& ?$ic8l. #eco' i5ed that thi& di&ea&e -a& ca"able of i fecti ' othe# hi'h #i&8 '#o$" at #ate& %$ch fa&te# tha a .o e co$ld ha3e i%a'i ed. A& of Octobe# 31, 1995, a total of 501,310 ca&e& of A(D! ha3e bee #e"o#ted to the CDC of the&e, 62L ha3e #e&$lted i death. /ea#l. half of the&e ca&e& ha3e bee #e"o#ted &i ce 1993. De&"ite the&e de3a&tati ' $%be#& &i' ifica t ad3a ce& ha3e bee %ade o3e# the "a&t t-o decade& leadi ' to a bette# $ de#&ta di ' of the i%%$ o"atholo'., e"ide%iolo'. a d cli ical %a ife&tatio & of thi& di&ea&e. 4$%a i%%$ odeficie c. 3i#$& :4(1; -a& ide tified a& the ca$&e of A(D! i 1983. The di&ea&e i& cha#acte#i5ed b. the effect of the #et#o3i#$& attac8i ' the ho&t& cell$la# i%%$ it. #e&$lti ' i a i%%$ oco%"#o%i&ed ho&t a d $lti%atel. fatal co%"licatio &. ((. E)idemi 1 /+ and T$end# C%m%1a"i*e Ca#e# ! AIDS n 199$ the 3nited "tates reached $44,444 A +" cases since the start of the epidemic. 5f the cumulati,e cases 146 7ere reported during 19&1%19&7, 216 during 19&&%199# and 296 during 1993 to 5cto*er 199$. C'an(in( Rates Determined by )ender, Race and Ris* !actor -he proportion of A +" cases among females increased from &6 of all reported cases to 1&6 during the period of 1993 to 199$. -he proportion of A +" cases among 7hites decreased from 646 to 236, ho7e,er, the proportion of *lac8s and )ispanics increased from #$6 to 3&6 and from 126 to 1&6 respecti,el!. -he proportion of cases increased from 176 to #76 among persons 7ho reported in9ection%drug use. (or cases attri*uted to heterose:ual transmission the proportion increased from 36 to 146 and cases among men 7ho ha,e se: 7ith men decreased from 626 to 2$6

+orld "ealt' Or(ani,ation An estimated 1& million adults and 1.$ million children ha,e *een infected 7ith ) . resulting in 2.$ million A +" cases 7orld7ide. MMER N *em2e$ ->, 'JJ?/V 10>>/N 0>M

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(((.

The HIV Li!e C+c1e o A#ee 3i#$& e te#& the blood d$#i ' i fectio o 1i#$& e 3elo"e 'l.co"#otei :'"12; attache& to CD4 #ece"to#&, "#i%a#il. fo$ d o the hel"e# T cell&, b$t al&o #eco' i5ed o %ac#o"ha'e&, + cell& a d b#ai cell& o The 3i#$& &hed& it& e 3elo"e a d e te#& the ati3e cell o The i e# co#e i& #e%o3ed #e&$lti ' i #elea&e of 3i#al >/A o +. -a. of the #et#o3i#al #e3e#&e t#a &c#i"ta&e 3i#al D/A &. the&i& i& i itiated o The "#o3i#al D/A e te#& the $clea# c.to"la&% a d i& i te'#ated i to the ati3e cellN& D/A o >et#o3i#al &. the&i& i& be'$ , di#ected b. the cellN& i fected D/A o /e- 3i#$& co#e& a#e a&&e%bled o 6 3elo"e& e clo&e the 3i#$& co#e 3ia b$ddi ' o The co%"lete 3i#$& i& e9t#$ded i to the blood&t#ea%

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Pa"h /ene#i# ) . can infect a ,ariet! of cells. )o7e,er, the helper - cells ha,e *een most 7idel! recogni;ed as the main target of attac8. -he C+2 positi,e - l!mphoc!tes are progressi,el! depleted *! ) . infection. -hese cells are a 8e! component to the part of the immune s!stem that is primaril! responsi*le for controlling in,asion *! intracellular pathogens. As a patients C+2 falls the li8elihood of de,eloping an opportunistic infection is increased. ) . ma! also attach itself to the C+2 receptors of monoc!tes and macrophages, the effect of monoc!te%macrophage infection is not 7ell understood. 5nce in the macrophage ) . remains undetected and ma! replicate freel!. -hus, the macrophage ma! ser,e as a reser,oir for ) .. Macrophages ma! also *e responsi*le for introducing ) . to the *rain potentiall! causing A +"%related dementia. ) . ma! also infect *one marro7 cells resulting in a panc!topenia that is often seen in A +" patients.

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IV0
A.

M de# ! T$an#mi##i n Se4%a1 C n"ac" 1. 4o%o&e9$al, bi&e9$al a d hete#o&e9$al 2. %$lti"le &e9$al "a#t e#&, #ece"ti3e a al i te#co$#&e, "#e&e ce of $lce#& ha3e bee &$''e&ted a& #i&8 facto#& 3. a""#o"#iate $&e of late9 co do%& i& K 90L "#otecti3e

B1 d $ B1 d P$ d%c" E4) #%$e ( <ectio D#$' @&e= &ha#i ' of i fected eedle& +lood T#a &f$&io &= i cide ce ha& bee dec#ea&ed -ith the i%"le%e tatio of blood "#od$ct &c#ee i '. 4ealth Ca#e )#o3ide#&= i ad3e#te t eedle &tic8 o# e9"o&$#e d$#i ' hi'h #i&8 "#oced$#e&, i cide ce i& e9t#e%el. lo-, the be efit of "o&t-e9"o&$#e ADT the#a". ha& e3e# bee "#o3e , o ethele&& thi& i& o e o -a""#o3ed ADT i dicatio . C. Ma"e$na1-In!an" T$an#mi##i n& %a. occ$# i $te#o, d$#i ' deli3e#., o# th#o$'h b#ea&t feedi ' - a""#o9i%atel. 123 of i fa t& bo# to $ t#eated 4(1 :F; %othe#& a#e i fected -ith 4(1. ADT ha& #ece tl. bee &ho- to dec#ea&e the #ate of t#a &%i&&io f#o% 25.5L to 8.3L. Thi& ha& lead to the i dicatio of ADT d$#i ' "#e' a c..
B.

1. 2. 3.

De!ini"i n# and C1a##i!ica"i n ! HIV In!ec"i n

4(1 ( fectio - defi ed a& &e#oco 3e#&io doc$%e ted b. the "#e&e ce of 4(1 a tibodie& :60(!A, Me&te# +lot Te&t;. Ca al&o be dete#%i ed b. the "#e&e ce of "24 a ti'e o# b. 3i#al c$lt$#e. E. A(D! - CDC Ca&e Defi itio
D.

-./0 % patients 7ith opportunistic infections 7ithout e,idence of an immunodeficient state or patients < 64 !ears old diagnosed 7ith =aposi>s "arcoma. ?prior to a,aila*ilit! of ) . testing@ -./1$-./2 % de,elopment of serologic testing -./3 % C+C defined a classification s!stem -./4 % C+C e:panded its definition of A +" to include other A +" related conditions such as ) . encephalopath! and 7asting s!ndrome

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-..0 % C+C re,ises the classification s!stem and e:pands the case definition for A +" to include other A +" related conditions such as pulmonar! tu*erculosis, in,asi,e cer,ical cancer and recurrent *acterial pneumonia ?# episodesA!ear@. n addition, the definition of A +" 7as e:panded to include all ) . infected persons 7ho ha,e less than #44 C+2B -%l!mphoc!tesAml or a C+2B -%l!mphoc!te percent of total l!mphoc!tes less than 126.
F.

Cla&&ificatio Acco#di ' to A(D! !$#3eilla ce Ca&e Defi itio =1993

Cli ical Cate'o#ie& CD4 cell cate'o#ie& A As!mptomatic, or PCD or PCD or acute ) . infection 1;K5002c$ %% :'#eate# tha o# e?$al to 29L; 2;200-4992c$ %% :14-28L; 3;J2002c$ %% :J14L; A1 A2 - A3 + CP

"!mptomaticEE ?Fot A A +" indicator condition or C@ ?19&7@ +1 +2 - +3 - C1 - C2 - C3 -

EAll patients in categories A3, G3, and C 1%3 are reported as A +", *ased on the A +"%indicator conditions and Aor a C+2 cell count <#44Amm3. A +" indicator conditions include three ne7 entries/ recurrent *acterial pneumonia, in,asi,e cer,ical cancer, and pulmonar! tu*erculosis. EE "!mptomatic conditions not included in Categor! C that are a@ attri*uted to ) . infection or indicati,e of a defect in cell%mediated immunit!, or *@ considered to ha,e a clinical course or management that is complicated *! ) . infection. E:amples of G conditions include *ut are not limited to *acillar! angiomatosis1 thrush1 ,ul,o,aginal candidasis that is persistent, frequent, or poorl! responsi,e to therap!1 cer,ical d!splasia ?moderate or se,ere@1 cer,ical carcinoma in situ1 constitutional s!mptoms such as fe,er ?3&.$ C@ or diarrhea H 1 month1 oral hair! leu8opla8ia1 )erpes ;oster in,ol,ing t7o episodes or H1 dermatome1 -P1 listeriosis1 P + ?especiall! if complicated *! a tu*o%o,arian a*scess@1 and peripheral neuropath!.

((.

Se$ 1 /ic Te#"in//S"a/in/ ! Di#ea#e - HIV An"i2 d+ A##a+#

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1.

En5+me-Lin.ed Imm%n # $2en" A##a+ 3ELISA( Measures serum anti%) .%1 anti*odies. -his test is 7idel! used *ecause it is ine:pensi,e, rapid and 7ell suited for large num*ers of samples. )o7e,er, it has the potential to produce false positi,e reactions due to nonspecific *inding of anti*odies present in samples from su*9ects e:posed to other infections or ,accines. f positi,e, this test must *e follo7ed *! a confirmator! test.

2.

Ee#"e$n B1 " -his test has *ecome the principle method of confirming ) .%1 infection. -he Iestern Glot also measures anti%) .%1 anti*odies and is capa*le of identif!ing specific ) .%1 antigens that are present. -his test is reser,ed as a confirmator! test *ecause it is slo7, la*or intensi,e and costl!.

B.

C.

Te#"# Tha" Mea#%$e HIV Vi$%# $ Vi$a1 C m) nen"# 1. Vi$a1 C%1"%$e - c$lt$#e& a#e ca"able of %ea&$#i ' the #elati3e a%o$ t of 3i#$& -ithi the cell& o# the %o$ t of f#ee 3i#$& i the "la&%a. Altho$'h c$lt$#e& a#e a di#ect %ethod of %ea&$#i ' 3i#al load the. a#e e9t#e%el. e9"e &i3e, labo# i te &i3e a d ot .et $&ed -idel. i "#actice. 2. Vi$a1 1 ad= P 1+me$a#e Chain Reac"i n 3PCR( :>oche; - thi& tech i?$e ca a%"lif. ta#'et D/A e9i&ti ' i 3e#. &%all a%o$ t& th#o$'h a &e#ie& of bi a#. #e"licati3e c.cle&. Thi& "#oced$#e ca al&o be a""lied to >/A. )C> i& e9t#e%el. &e &iti3e -hich "o&e& both a &t#e 'th a d a -ea8 e&&. )C> ca be $&ed ea#l. to detect di&ea&e e3e befo#e a &e#olo'ic #e&"o &e a d it ca al&o be $&ed &$cce&&f$ll. to ?$a titate 4(1 a& a #elati3e %ea&$#e of 3i#al load. A othe# %ethod fo# %ea&$#i ' 3i#al load i& B$anched DNA :Chi#o ;. The&e tech i?$e& diffe# i &e &iti3it., th$&, %ea&$#e%e t& a#e ot i te#cha 'eable. The&e te&t& a#e e9"e &i3e a d ti%el., ho-e3e#, the. a#e #a"idl. 'ai i ' -ide $&e b. cli icia & i dete#%i i ' di&ea&e "#o'#e&&io a d the#a"e$tic efficac. o# fail$#e. 3. )-> An"i/en - thi& a&&a. %ea&$#e& the a%o$ t of f#ee 3i#al "#otei :"24; "#e&e t i the "la&%a. Thi& "#otei %a. be i the "la&%a at all &ta'e&, b$t it i& %o&t "#e3ale t d$#i ' the ti%e of i itial &e#oco 3e#&io a d a'ai late# i the co$#&e of %o#e ad3a ced di&ea&e. Thi& te&t i& -idel. $&ed i cli ical "#actice, ho-e3e#, beca$&e it i& a i di#ect -a. of %ea&$#i ' 3i#al load it ha& 3e#. little 3al$e i dete#%i i ' "#o'#e&&io of di&ea&e o# efficac. of a ti#et#o3i#al a'e t&. S%$$ /a"e Ma$.e$# CD1 "urrogate mar8ers are 7idel! used in practice to determine the stage and progression of disease.

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-he CD1 count is the most commonl! used mar8er in clinical practice. -he C+2 is 7idel! used as an indicator for therapeutic inter,entions including initiation of antiretro,iral therap! and proph!la:is of opportunistic infections ?e.g. PCP, MAC@. -he C+2 can ,ar! 7idel! from time to time and can *e affected *! time of da! or the presence of an acute infection. Although, still 7idel! used this mar8er is quic8l! losing its ,alue in clinical practice. Another mar8er is the CD15 ?< $46@ 7hich tends to ,ar! less. n addition the CD16CD/ ratio ?normal H1@ is decreased 7ith disease progression. A2# 1%"e CD> c %n" P total M+C X L l.%"hoc.te X CD4 L

Corresponding C+2 counts to C+6/ CD> ce11 c %n" ACD> K 500 K 29L 200-500 14-28L J 200 J14L Vi$a1 L ad Thi& i& the be&t %a#8e# fo# "#edicti ' di&ea&e "#o'#e&&io . A co &e &$& "a el #eco%%e d& $&i ' 3i#al load i all "atie t& to '$ide i itiatio of the#a"., cha 'e& i the#a". a d d#$' #e&i&ta ce. (. C1inica1 C %$#e ! HIV In!ec"i n ) . infection is a progressi,e disease. -!picall! the patients progress from acute infection to an as!mptomatic stage through a progressi,e l!mphadenopath! and finall! to full *lo7n A +". -he time course ,aries 7idel! from patient to patient, *ut the a,erage life%e:pectanc! from time of serocon,ersion is estimated to *e 14 !ears.

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AA

S"a/e# ! HIV Di#ea#e 1i#al t#a &%i&&io Ac$te #et#o3i#al &. d#o%e !e#oco 3e#&io Cli ical late t "e#iod -ith o# -itho$t "e#&i&te t 'e e#ali5ed l.%"hade o"ath. :)*0; 6a#l. &.%"to%atic 4(1 i fectio :A(D!->elated Co%"le9; A(D! a& defi ed b. the CDC

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193339060.doc.DOC

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AA

C $$e1a"i n ! HIV C m)1ica"i n# 6i"h CD> Ce11 C %n"

CD> ce11 c %n"N In!ec"i n# K5002%%3 Ac$te #et#o3i#al &. d#o%e Ca didal 3a'i iti& N n-in!ec"i n#NN )e#&i&te t 'e e#ali5ed 0.%"hade o"ath.:)*0; *$illai -+a##e &. d#o%e )ol.%.o&iti& A&e"tic %e i 'iti& Ce#3ical i t#ae"ithelial /eo"la&ia Ce#3ical ca ce# 7a"o&i &a#co%a +-cell l.%"ho%a A e%ia Mo o e$#iti& %$lti"le9 (dio"athic Th#o%boc.to"e ic )$#"$#a Ma&ti ' )e#i"he#al e$#o"ath. 4(1-a&&ociated De%e tia C/! l.%"ho%a Ca#dio%.o"ath.

200-5002%%3

) e$%ococcal a d othe# +acte#ial " e$%o ia )$l%o a#. T+ 4e#"e& 5o&te# Th#$&h Ca didal e&o"ha'iti& C#."to&"o#idio&i&, !elf-li%ited

J2002%%3

J502%%3

P."a%i(ii " e$%o ia Di&&e%i ated2ch#o ic 4e#"e& &i%"le9 To9o"la&%o&i& C#."tococco&i& Di&&e%i ated hi&to"la&%o&i& A d coccidioido%.co&i& C#."to&"o#idio&i&, ch#o ic Mic#o&"o#idio&i& Milia#.2e9t#a"$l%o a#. T+ Di&&e%i ated CM1 Di&&e%i ated M. a3i$* co%"le9

E Most complications occur 7ith increased frequenc! at lo7er C+2 counts1 l!mphomas ma! occur at an! C+2 counts, *ut are most frequent 7ith counts <#44Amm3. EE "ome conditions listed as JFon%infectionsJ are pro*a*l! associated 7ith transmissi*le micro*es/ l!mphomas, cer,ical cancer, C F and =aposi sarcoma.

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((.

Mana/emen" ! HIV Di#ea#e Earl! detection of ) . is essential in order to decrease the rate of transmission. t is also critical to identif! potentiall! pre,enta*le conditions such as tu*erculosis, pneumococcal pneumonia, s!philis, etc. Additionall!, earl! initiation of antiretro,iral therap! ma! impro,e qualit! of life and sur,i,al.

AA

Ea$1+ In"e$*en"i n 1. Di#ea#e de"ec"i n& ))D &8i te&t &e#olo'ic te&ti ' fo# othe# di&ea&e& :e.'. To9o"la&%o&i&, !."hili&, 4e"atiti&; "a" &%ea# 2. Ba#e1ine La2 $a" $+ Te#"# Ca hel" dete#%i e he%atolo'ic, #e al a d he"atic &tat$&. "a#tic$la#l. $&ef$l "#io# to i &tit$ti ' the#a". a d to detect $ de#l.i ' di&ea&e& o# co%"licatio & of 4(1. C+C che%i&t#ie& *-6-)D le3el CD42CD4L 1i#al load 3. Imm%ni5a"i n# (%%$ i5atio i& a 3e#. i%"o#ta t "a#t of ea#l. %a a'e%e t i 4(1-i fected "atie t&. ( 'e e#al, &.%"to%atic "atie t& ha3e a &$bo"ti%al #e&"o &e to 3acci e&. The#efo#e, all 3acci e& &ho$ld be 'i3e a& ea#l. i the co$#&e of 4(1 a& "o&&ible. Ao# the %o&t "a#t, 4(1-i fected "atie t& &ho$ld ot #ecei3e li3e 3i#$& o# li3e bacte#ia 3acci e&. Influenza: a $al 3acci atio i& #eco%%e ded Pneumococcal: co &ide# #e3acci atio e3e#. 6 .ea#& Haemophilus B Influenza: @&e i& co t#o3e#&ial Hepatitis B: #eco%%e ded i "atie t& -ith o e3ide ce of e9"o&$#e Tetanus-Diphtheria: #eco%%e ded e3e#. 10 .ea#& MMR: ca be co &ide#ed :li3e 3i#$& 3acci e;
B.

A))$ ache# ! $ An"i$e"$ *i$a1 The$a)+

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 M n "he$a)+= o lo 'e# #eco%%e ded d$e to "oo# efficac. a d #a"id de3elo"%e t of #e&i&ta ce. C m2ina"i n The$a)+ :t-o 3& th#ee a'e t& 3& fo$#;= co%bi atio the#a". i& &ta da#d of ca#e. The deci&io o -hethe# to $&e 2, 3 o# 4 d#$'& de"e d& o &ta'e of di&ea&e :3i#al load, CD4;, d#$' tole#a ce, "#io# a ti#et#o3i#al $&e, co co%ita t d#$'&, co%"lia ce a d i &$#a ce. The O"ti%al co%bi atio 3a#ie& f#o% "atie t to "atie t. A1"e$na"in/ Re/imen# Se7%en"ia1 The$a)+
AA

P "en"ia1 Si"e# ! Ac"i n#

AA

P "en"ia1 Bene!i"# ! An"i$e"$ *i$a1 The$a)+

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AA

AA

M ni" $in/ Vi$a1 L ad= obtai 2 ba&eli e %ea&$#e%e t& at lea&t 2 -ee8& a"a#t, the at 1 %o th afte# &ta#t o# cha 'e of the#a".. A cha 'e of at lea&e 0.5 lo' :3 fold; i& co &ide#ed &i' ifica t. A ideal 3i#al load i& J 5000 co"ie&2%l. )atie t& -ith 3i#al load& B*6 100,000 co"ie&2%l ha3e a "oo# "#o' o&i&. CD>/CD>A= obtai 1 ba&eli e #eadi ' -ith 3i#al load, the #e"eat e3e#. 3 %o th& o# ha d i ha d -ith 3i#al load&. O)) $"%ni#"ic In!ec"i n# O"he$ HIV C m)1ica"i n# :ie. -a&ti ' &. d#o%e, 7a"o&i& &a#co%a, 0.%"ho%a; AA An"i$e"$ *i$a1 A/en"# 1. Re*e$#e T$an#c$i)"a#e Inhi2i" $#& Nucleoside Analogue:

"#olo ' &$#3i3al &lo- di&ea&e "#o'#e&&io i%"#o3e ?$alit. of life a d f$ ctio al &tat$& #ed$ce i cide ce a d &e3e#it. o""o#t$ i&tic di&ea&e& P "en"ia1 P$ 21em# 6i"h An"i$e"$ *i$a1 The$a)+ #e&i&ta ce to9icitie& co&t d#$'-i te#actio &

AA

HIDOVUDINE 3AHT, Re"$ *i$( 100%' ca"&$le& INDICATIONS: A +", as!mptomatic ) . 7ith C+2 < $44, C+2 H $44 contro,ersial. "hould no longer *e used as monotherap!. Cood com*inations include/ AK-A3-C, AK-Add , AK-A+2-, AK-A++C, AK-AFe,irapine plus or minus a protease inhi*itor. Non-Approved Indications: pre,ent maternal transmission, post%e:posure proph!la:is, A +" dementia and ) .%0elated throm*oc!topenia. Dose6 #44mg - + ?minimum effecti,e dose/ 344mgAda!@ or 344mg G + Absor7tion% 646 *ioa,aila*ilit!

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Distribution% 32%3&6 plasma protein *inding 7idel! distri*uted penetrates C"( Elimination8Metabolism% 7$6 hepatic meta*olism and #$6 renal elimination1 "erum half%life is appro:imatel! 1.1 hour in normal renal function1 ntracellular half%life is 3 hours Renal Disease% dose should *e ad9usted for patients 7ith se,ere renal d!sfunction ?CrCl < 14mlAmin@ to half dose. "pecific guidelines are not a,aila*le. Ad9erse Dru( Reactions6 1. 2. !$b<ecti3e= *( i tole#a ce, i &o% ia, %.al'ia&,%alai&e a d headache&. *( i tole#a ce %a. i%"#o3e b. ad%i i&t#atio -ith food. )atie t& co%"lai of the&e &ide-effect& i the fi#&t 1-4 -ee8& of the#a". a d %o&t i%"#o3e -ith co ti $ed t#eat%e t. 4e%atolo'ic To9icit.= i& both di&ea&e &ta'e a d do&e-de"e de t. Anemia occ$#& i 29L of A(D! "atie t& a d o l. i 2L of a&.%"to%atic 4(1 "atie t&. Ne%"$ )enia occ$#& i 37L of A(D! "atie t& a d i o l. 1L of a&.%"to%atic 4(1 "atie t&. Ma a'e%e t i cl$de& #ed$ci ' the do&e of ADT, di&co ti $i ' ADT a d &$b&tit$ti ' -ith othe# a'e t o# t#eat%e t -ith e"o'e o# e$"o'e . The latte# i& e9t#e%el. co&tl. a d &ho$ld o l. be co &ide#ed -he the fi#&t t-o o"tio & a#e ot acce"table. Mac#oc.to&i&= occ$#& i %o&t "atie t& -ithi the fi#&t fo$# -ee8& of the#a". a d ca be $&ed a& a i dicato# of co%"lia ce. Othe#&= %.o"ath., %.o&iti&, ail bed "i'%e tatio , he"atiti& :i c#ea&e& i t#a &a%i a&e le3el&;, #a&h, fe3e#

3. 4.

AA

DIDANOSINE 3DDI, Vide4( 25%', 50%', 100%' Tablet&, 167%', 250%', 375%' b$ffe#ed "o-de#

"ac8et& INDICATIONS: originall! indicated for patients 7ith ad,anced ) . infection intolerant of AK- and for patients not responding to AK-. More recent data suggests that ++ ma! *e considered as potential first%line therap! or earlier post AK- therap!. Cood com*inations

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include/ AK-A++ , ++ AFe,irapine, ++ A+2- plus or minus protease inhi*itor. Although not recommended ++ ma! *e considered as monotherap! in patients 7ho do not tolerate an! other antiretro,irals. Dose/ *ased on *od! 7eight K 608' 200%' +(D fo# "atie t&:TEO 100%' Tab&; J 608' 125%' +(D fo# "atie t&:ONE each 100 B 25%';
P

M%#" "a.e TEO "a21e"# in $de$ " /e" "he !%11 2ene!i" ! "he 2%!!e$ #+#"em needed ! $ a2# $)"i n0 On em)"+ #" mach0 Absor7tion% 246 *ioa,aila*le in the ta*let form and 346 in the po7der form. ++ is acid la*ile so that oral preparations contain *uffer to promote a*sorption. Distribution% ,aria*le ,olume of distri*ution, #46 of plasma concentrations detected in C"( Elimination% 0enal clearance accounts for appro:imatel! 366 of the administered dose, ho7e,er, the e:act fate of the meta*oli;ed ++ is un8no7n. -he plasma half%life is appro:imatel! 1.$ hours and the intracellular half%life has *een reported in the range of 1# to #2 hours. Renal or "e7atic failure% appear to *e associated 7ith higher to:icit! and dose reductions should *e considered, ho7e,er, there are no guidelines a,aila*le. Ad9erse Dru( Reactions/ 1. )e#i"he#al e$#o"athie&= -ith "ai a d2o# "a#e&the&ia& i e9t#e%itie& #elated to c$%$lati3e do&e occ$#& i 5-12L of "atie t&. Ma. be #e3e#&ible i %o&t ca&e& "#o3ided DD( i& di&co ti $ed "#o%"tl.. (f DD( i& co ti $ed de&"ite &.%"to%& of e$#o"ath. the "atie t& %a. e9"e#ie ce "e#&i&te t, debilitati ' "ai . 2. )a c#eatiti&= ha& bee #elated to total c$%$lati3e do&e, "#ee9i&ti ' "a c#eatic di&ea&e, alcoholi&%, ad3a ced &ta'e 4(1 di&ea&e a d co c$##e t %edicatio & that ca$&e "a c#eatiti&. (t ha& bee #e"o#ted i

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5-9L of "atie t& a d i& fatal i 6L of tho&e -ith "a c#eatiti&. Co &ide# #ed$ci ' do&e o# di&co ti $i ' the#a". if &e#$% a%.la&e i& K 1.5-2I $""e# li%it of o#%al. 3. *a&t#oi te&ti al= : a$&ea, 3o%iti ', dia##hea; %a. be #elated to b$ffe# &.&te% a d ta&te. 4. Othe#= #a&h, he"atiti&, h."e#$#ice%ia HALCITABINE 3DDC, Hi*id( B0<@?m/, B0@?m/ INDICATIONS: originall! appro,ed for use in com*ination 7ith AK- onl!. Com*inations of AK-A++CAProtease inhi*itor are effecti,e. 5ther ++C com*inations ha,e not *e studied. Dose/ 4.7$mg - + Absor7tion% &$6 *ioa,aila*le Distribution% <26 protein *inding. C"( penetration is appro:imatel! #46 of serum le,els. Elimination % mostl! e:creted unchanged, cleared predominantl! *! the 8idne!. )alf% life is 1%# hours. Ad9erse Dru( Reactions/ ++C is associated 7ith peripheral neuropathies, oral ulcerations, anore:ia, nausea, ,omiting, headache, fe,er, rash and fatigue. Pancreatitis and ototo:icit! ha,e also *een reported.
AA

STAVUDINE 3D>T, He$i"( 15%', 20%', 30%', 40%' INDICATIONS: nitiall! appro,ed for patients 7ho are intolerant of other nucleoside analogues as last line therap!. Ma! *e considered as monotherap! for in patients 7ho do not tolerate other antiretro,iral agents. Cood com*inations include/ AK-Ad2-, dd Ad2-, 3-CAd2- plus or minus protease inhi*itors. Caution 7ith dd due to o,erlapping side% effects. Dose/ Gased on *od! 7eight

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K60 8' 40%' +(D J60 8' 30%' +(D Ad*e$#e D$%/ Reac"i n#& D4T i& %o#e co%%o l. a&&ociated -ith "e#i"he#al e$#o"athie&. (t i& othe#-i&e -ell tole#ated. )a c#eatiti& ha& bee #e"o#ted.
AA

LAMIVUDINE 3<TC, E)i*i$( 150%' Appro,ed in 199$ for use in com*ination 7ith AK-. Iidel! used in com*ination 7ith AKor d2- plus or minus a protease inhi*itor +ose/ 1$4mg G + No(!N$" &osi'&s:

AA

NEVIRAPINE 3Vi$am%ne( a""#o3ed i A$'$&t 1996 +ose/ #44mg dail! : # 7ee8s1 then #44mg G + pharmaco8inetics/ rapidl! a*sor*ed and meta*oli;ed *! the li,er. interactions/ interacts 7ith drugs meta*oli;ed *! C!tochrome P%2$4 ?potent inducer@ side%effects/ rash?346@, nausea, diarrhea, increased D(-s, fe,er indications/ "hould ne,er *e used alone due to rapid de,elopment of resistance. Com*ination 7ith # nucleoside analogs appears to 7or8 *est ?ie. AK-A++C@. Concomitant use :it' 7rotease in'ibitors currently not recommended due to decreased le,els of protease inhi*itors leading to su*%therapeutic le,els.

AA

DELAVIRDINE :i 3e&ti'atio al; 2. P$ "ea#e Inhi2i" $#

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) . protease is an en;!me required for the clea,age of ,iral pol!protein precursors into indi,idual functional proteins found in infectious ) .. Protease inhi*itors *ind to the protease acti,it! site and inhi*it the acti,it! of this en;!me. -his pre,ents clea,age of these pol!proteins and produces immature noninfectious ,iral particles. -hese agents ha,e recentl! *een sho7n to *e the most potent antiretro,iral agents a,aila*le. )o7e,er, the! are associated 7ith numerous pro*lems. -hese agents must al7a!s *e used in com*ination ? 3% drug com*ination appears to *e most effecti,e@ due to rapid de,elopment of resistance. -herapeutic serum le,els must *e maintained in order to dela! drug resistance, thus, full compliance is e:tremel! important. -hese agents are all meta*oli;ed *! the c!tochrome p%2$4 s!stem and are associated 7ith numerous significant drug interactions. Cross%resistance is common among these agents. Castrointestinal side%effects are common. (inall!, these agents are e:tremel! e:pensi,e.
AA

SADUINAVIR 3In*i$a#e-R che(

dose/ 644mg - + 7ith meals side$effects/ nausea, diarrhea, headaches dru($interactions/ 0ifampin and rifa*utin significantl! decrease A3C of saquina,ir1 8etocona;ole increases A3C and Cma: of saquina,ir.
AA

INDINAVIR 3C$i4i*an-Me$c.( dose/ &44mg - + on empt! stomach side$effects/ h!per*iliru*inemia, nephrolithiasis, C dru($interactions/ ndina,ir and didanosine should *e administered at least one hour apart on an empt! stomach *ecause the gastric *uffering propert! ma! interfere 7ith the a*sorption of indina,ir. 0ifa*utin dose should *e decreased 7hen used concurrentl! and indina,ir dose should *e decreased 7hen used concurrentl! 7ith 8etocona;ole. Co% administration of rifampin and indina,ir should *e a,oided if possi*le. ndina,ir ma! compete 7ith meta*olism of terfenadine, astemi;ole, cisapride, tria;olam, and mida;olam and create potential for serious andAor life%threatening e,ents. ndina,ir should not *e administered concurrentl! 7ith an! of these agents.

AA

RITONAVIR 3A22 ""(

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dose/ 644mg G + ?dose escalation recommended@ side$effects/ nausea, diarrhea, circumoral paresthesias dru($interactions/ 0itona,ir has a ,er! high affinit! for se,eral c!tochrome P%2$4 en;!mes and is meta*oli;ed *! the same en;!me s!stem, there are significant drug interactions 7ith this agent. -he follo7ing drugs should not *e coadministered 7ith ritona,ir/ amiodarone, astemi;ole, *epridil, *upropion, cisapride, clo;apine, encainide, flecainide, meperidine, piro:icam, propafenone, propo:!phene, quinidine, rifa*utin, terfenadine, alpra;olam, clora;epate, dia;epam, esta;olam, flura;epam, mida;olam, tria;olam, ;olpidem.

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OPPORTUNISTIC IN=ECTIONS IN HIV-IN=ECTED PATIENTS PART I

;enny Colombo, #'arm<D<, #M#R =10, ;anuary -..4

G a1# and O2;ec"i*e#&

+. the e d of thi& lect$#e the &t$de t &ho$ld be able to= 1. (de tif. A(D!-Defi i ' (ll e&&e& a& defi ed b. the Ce te# fo# Di&ea&e Co t#ol :CDC;. 2. De&c#ibe the cli ical "#e&e tatio of P(&$*o"+stis "a%i(ii " e$%o ia, Di&&e%i ated M+"o.a"t&%i$* a3i$* Co%"le9, C#."tococcal %e i 'iti& a d To9o"la&%o&i&. 3. De3i&e a the#a"e$tic "la fo# each of the follo-i ' o""o#t$ i&tic i fectio &= )C), MAC, To9o"la&%o&i&, Ca didia&i& a d C#."tococc$&. 4. >eco' i5e ad3e#&e effect& a d d#$' i te#actio & of a'e t& $&ed fo# the t#eat%e t a d "#e3e tio of o""o#t$ i&tic i fectio &

Se1ec"ed $eadin/#&
App i&' Th&%ap&$ti"s: Th& C i(i"a Us& o) D%$,s. !ith 6ditio , 1995 Cha"te# 68. 4$%a (%%$ odeficie c. 1i#$& :4(1; ( fectio . )a'e& 68-1 - 68-48 Pharmacotherapy: A Pathophysiologic Approach. 3rd Edition, 1996 Chapter 117 Principles and Management of the acquired immunodeficienc! s!ndrome. Pages #3$3 #3&6. Dane )C, Daughon GE, (alloon ', =o,acs 'A, +a,e! 0-, et al. 0ecent Ad,ances in the Management of A +"% 0elated 5pportunistic nfections. Ann ntern Med. 199211#4/92$%9$$ Callant 'E, Moore 0+ and Chaisson 0E. Proph!la:is for 5pportunistic nfections in Patients 7ith ) . nfection. Ann ntern Med. 199211#4/93#%922 (. INTRODUCTION "erious opportunistic infections occur most often in the late stages of ) . disease. -he ris8 of de,eloping certain opportunistic infections has *een closel! associated to the C+2 count. -he ,ast ma9orit! of deaths in ) .%infected patients are due to an opportunistic infection. -he high incidence of occurrence and

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mortalit! associated 7ith these infections has lead to recent research regarding the pre,ention and treatment of these infections in a desperate attempt to impro,e mortalit! and impro,e qualit! of life. )o7e,er, the relati,el! high occurrence of drug to:icities and drug interactions hampers our a*ilit! to effecti,el! and safel! manage opportunistic infections. ((. AIDS DE=INING ILLNESSES o Ca didia&i& of b#o chi, t#achea, o# l$ '& o Ca didia&i&, e&o"ha'eal o Ce#3ical ca ce#, i 3a&i3eP o Coccidioido%.co&i&, di&&e%i ated o# e9t#a"$l%o a#. o C#."tococco&i&, e9t#a"$l%o a#. o C#."to&"o#idio&i&, ch#o ic i te&ti al :K1 %o thN& d$#atio ; o C.to%e'alo3i#$& di&ea&e :othe# that li3e#, &"lee , o# ode&; o C.to%e'alo3i#$& #eti iti& :-ith lo&& of 3i&io ; o 6 ce"halo"ath., 4(1-#elated o 4e#"e& &i%"le9= ch#o ic $lce#:&; :K1 %o thN& d$#atio ;, o# b#o chial " e$%o iti&, o# e9o"ha'iti& o 4i&to"la&%o&i&, di&&e%i ated o# e9t#a"$l%o a#. o (&o&"o#ia&i&, ch#o ic i te&ti al :K1 %o thN& d$#atio ; o 7a"o&iN& &a#co%a o 0.%"ho%a, +$#8ittN& :o# e?$i3ale t te#%; o 0.%"ho%a, i%%$ abla&tic :o# e?$i3ale t te#%; o 0.%"ho%a, "#i%a#., of b#ai o M.cobacte#i$% a3i$% co%"le9 o# M. 8a &a&ii, di&&e%i ated o# e9t#a"$l%o a#. o M..cobacte#i$% t$be#c$lo&i&, a . &ite :"$l%o a#.P o# e9t#a"$l%o a#.; o M.cobacte#i$%, othe# &"ecie& o# $ ide tified &"ecie&, di&&e%i ated e9t#a"$l%o a#. o ) e$%oc.&ti& ca#i ii " e$%o ia o ) e$%o ia, #ec$##e tP o )#o'#e&&i3e %$ltifocal le$8oe ce"halo"ath. o !al%o ella &e"tice%ia, #ec$##e t o To9o"la&%o&i& of b#ai o Ma&ti ' &. d#o%e d$e to 4(1 MANAGEMENT O= SPECI=IC OPPORTUNISTIC IN=ECTIONS

(((.

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A.

Pneumocystis carinii "ince the recognition of A +", Pneumocystis carinii pneumonia ?PCP@ has *een the most frequent A +"%defining diagnosis in the 3nited "tates. )o7e,er, the relati,e frequenc! of PCP is decreasing presuma*l! as a result of proph!la:is and anti,iral therap!. -he lung is the most important target organ of Pneumocystis carinii. Although rare, other sites of infection ha,e *een reported including s8in, li,er, 8idne!, l!mph nodes, CF", spleen and heart. 1. C1inica1 Mani!e#"a"i n# fe3e#, co$'h, -ei'ht lo&&, a d %alai&e i &idio$& a d "#olo 'ed o &et :-ee8& to %o th&; 0ab&= dec#ea&ed )O2, ele3ated 0D4 CI>= bilate#al i te#&titial i filt#ate& :%a. be o#%al i ea#l. &ta'e&; Dia/n #i#

2.

di#ect dia' o&i&= ca o l. be %ade b. ide tificatio of the o#'a i&% i the &"$t$% i d$ced &"$t$% - "o&iti3e i 60-70L b#o choal3eola# la3a'e :+A0; - dia' o&tic i 95-99L of ca&e& t#a &b#o chial bio"&. - &e &iti3it. a""#oache& 97L o"e l$ ' bio"&. - 99L &e &iti3e. Thi& %ethod i& #e&e#3ed a& a la&t #e&o#t. i di#ect dia' o&i&= ca be %ade o the ba&i& of cli ical "#e&e tatio , che&t 9-#a., a d a#te#ial blood 'a&. di&ea&e &e3e#it. ca be dete#%i ed b. )O2= Mild= )O2 K 70%%h' Mode#ate2!e3e#e )O2 J 70%%h'

3.

=ac" $# A## cia"ed 6i"h P $ P$ /n #i#

&e3e#e h."o9e%ia "#olo 'ed &.%"to%& e9te &i3e #adio'#a"hic i 3ol3e%e t eed fo# %echa ical 3e tilatio

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4.

T$ea"men" All 4(1:F; "atie t& -ith co fi#%ed )C) &ho$ld be t#eated. Choice of the#a". -ill de"e d o &e3e#it. of di&ea&e a d abilit. to tole#ate ce#tai %edicatio . The o"ti%al d$#atio of the#a". i& $ clea#, b$t 14-21 da.& i& 'e e#all. #eco%%e ded. !IRST C"OICE TM#8SM& is the drug of choice for the treatment of PCP, ho7e,er, greater than $46 of the ) .%infected population is intolerant to -MPA"MK. Dose6 1$%#4mgA8gAda! ?*ased on -MP component@ .PG for moderate to se,ere disease ?P5# < 74mmhg@ or P5 for mild disease ?P5# H 74mmhg@ di,ided into 3 to 2 doses. Ad9erse reactions occur in o,er 646 of A +" patients. -he! include rash, fe,er, leu8openia, anemia, throm*oc!topenia, nausea, ,omiting, ele,ated serum creatinine, ele,ated li,er function tests. Most side%effects are dose dependent. ALTERNATI>E C"OICES -hese choices ha,e *een sho7n to *e effecti,e in the treatment of PCP, *ut recent data suggests that none is *e as effecti,e as -MPA"MK. #entamidine is the second most 7idel! used therap! for PCP. Dose6 2mgA8gAda! gi,en *! slo7 intra,enous infusion o,er 64%94 minutes. ntramuscular in9ections are possi*le *ut are associated 7ith sterile a*scesses. -here is no oral form. Ad9erse reactions also occur frequentl! in this patient population, in fact, man! clinicians a,oid this drug due to the high incidence of serious to:icities. )!potension and throm*ophle*itis can occur during infusion. Acute side%effects include nephroto:icit!, h!pogl!cemia, fe,er, leu8openia, pancreatitis. -he d!sgl!cemias can occur da!s to 7ee8s after therap! and insulin%dependent dia*etes ma! de,elop months after therap!.

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Clindamycin ? #rima@uine can *e used as an alternati,e for mild to moderate disease n mild disease *oth drugs can *e gi,en orall! and in moderate disease clindam!cin should *e gi,en intra,enousl!. Dose6 Clindamycin 2$4mg e,er! 6 hours P5 or 644mg .PG e,er! 6 hours #rima@uine 1$%34mg P5 +ail! Ad9erse reactions include diarrhea, rash and anemia. Da7sone ? Trimet'o7rim Dose6 Da7sone 144mg P5 dail! Trimet'o7rim #4mgA8gAda! in 2 di,ided doses Ad9erse reactions include hemol!tic anemia ?patients 7ith C6P+ deficienc!@, leu8openia, rash, nausea, and ,omiting. Ato9a@uone 7as appro,ed in 199# for the treatment of mild to moderate PCP onl!. nitiall!, the drug 7as a,aila*le as a #$4mg ta*let 7ith e:tremel! poor *ioa,aila*ilit! 7hich 7as impro,ed three fold 7hen administered 7ith high fat meals. 0ecentl!, it 7as made a,aila*le as a suspension 7ith impro,ed *ioa,aila*ilit! no longer requiring coadministration of high fat meals. Dose6 "uspension (orm/ 7$4mgA$ml P5 G + Ad9erse reactions include rash, ele,ated D(-s, nausea, ,omiting, diarrhea and headaches. TrimetreAate appro,ed for use in patients 7ith se,ere disease and 7ho are refractor! or intolerant to other therapies. t is inferior to -MPA"MK 7hen used as initial therap!. ts use is limited *! se,ere to:icities and it must *e used 7ith leuco,orin during and for 3 da!s after discontinuation of therap!. Dose6 2$mgAM# . infusion o,er 64%94 minutes dail! Deuco,orin/ #4mgAM# P5 or . q 6 hours

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Ad9erse reactions include se,ere *one marro7 suppression, renal and hepatic impairment, and oral and C ulcerations.

AD; NCTI>E T"ERA#Y Corticosteroids is standard of care for all patients 7ith an initial room air P5# < 74 mmhg."teroids should *e added to therap! 7ithin #2%7# hours of presentation. "teroids added earl! in the course ma! reduce respirator! failure, deterioration of o:!genation and mortalit!. Consensus Re7ort Recommends t'e follo:in( re(imen6 Da.& 1-5 )#ed i&o e 40%' )O +(D Da.& 6-10 )#ed i&o e 40%' )O dail. Da.& 11-21 )#ed i&o e 20%' )O dail. ( "atie t& -ho ca 5. P$ )h+1a4i# ! PCP Primary Prophyla is is indicated for patients 7ho ha,e no prior histor! of PCP *ut ha,e a C+2 count <#44 or C+2 6 <#46, or patients 7ith une:plained fe,er H # 7ee8s or oral thrush. Secondary Prophyla is is indicated for all patients 7ho ha,e had at least one episode of PCP TM#8SM&6 has *een sho7n to *e the most effecti,e agent. t also has the added ad,antage of *eing ine:pensi,e and ha,ing acti,it! against other organisms such as to:oplasmosis and *acteria. Dose6 1 +" ta*let +ail! ?less frequent and lo7er doses ma! also *e effecti,e@ ot ta8e )O "#ed i&o e, "a#e te#al %eth.l"#ed i&olo e %a. be &$b&tit$ted

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Da7sone/ not as effecti,e as -MPA"MK, *ut has similar ad,antages including acti,it! against to:oplasmosis and it is ine:pensi,e. "hould *e considered as the second choice agent for proph!la:is. Dose6 $4%144mg +ail! ?less frequent dosing has also *een studied@ Aerosoli,ed #entamidine/ not as effecti,e as -MPA"MK, *ut is as effecti,e as dapsone. +isad,antages include narro7 spectrum of acti,it!, high cost, potential spreading of -* and potential occupational ha;ard. -his form of proh!la:is should onl! *e considered in patients 7ho do not tolerate -MPA"MK or dapsone. Dose6 344mg ,ia ne*uli;er once e,er! month
B.

Candidia#i# 5ral and esophageal candidiasis occur frequentl! in patients 7ith ) . disease. Esophageal candidiasis can *ecome ,er! se,ere causing a great deal of pain and an ina*ilit! to s7allo7 food, drin8s or medication. -he role of proph!la:is has !et to *e determined. Treatment F!statin suspension 144,444 to 1,$44,444 units Js7ish and s7allo7J e,er! 2%6 hours thi& fo#% of to"ical t#eat%e t ha& ot bee fo$ d to be 3e#. effecti3e i thi& "atie t "o"$latio d$e to i ade?$ate co tact ti%e, "oo# ta&te a d f#e?$e c.. Clot#i%a5ole t#oche 10%' o#all. 5I dail. -he $&ed co##ectl. thi& to"ical t#eat%e t ca be effecti3e, "a#tic$la#l. i %ild ca&e& of th#$&h. )atie t& %$&t be i &t#$cted to di&&ol3e the t#oche i thei# %o$th. Di&ad3a ta'e& i cl$de f#e?$e c. of do&i ' a d ta&te. 7etoco a5ole 200-400%' Dail. ab&o#"tio "#oble%& i "atie t& -ith achlo#h.d#ia

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 d#$' i te#actio & Al$co a5ole 100-200%' o#all. Dail. 9 1 -ee8 #e&i&ta ce ha& bee #e"o#ted tracona;ole "uspension 144mg orall! G + : 1 7ee8 Amphotericin 144mgAml 1ml?s7ish as long as possi*le then s7allo7@ : # 7ee8s. Amphotericin . used in se,ere cases of esophagitis
AA

ryptococcus neoformans menin/i"i# '0 C1inica1 Mani!e#"a"i n# i &idio$& o &et %ild &.%"to%& i cl$de headache, a$&ea, di55i e&&,&o% ole ce &e3e#e &.%"to%& i cl$de %e tal &tat$& cha 'e&, &ei5$#e&, co%a -ith c#a ial e#3e i 3ol3e%e t the#e %a. be facial $%b e&& a d 3i&$al cha 'e& -0 Dia/n #i# 0$%ba# "$ ct$#e fo# e9a%i atio of C!A= dec#ea&ed 'l$co&e, i c#ea&ed "#otei a d M+C& %a. be o#%al i A(D! "atie t& ( dia ( 8 !%ea# of C!A i& F i 80L of "atie t& C$lt$#e& of C!A o# +lood C#."tococcal a ti'e i& "#e&e t i K 90L of ca&e& 3. T$ea"men" Am7'otericin B remains first line of therap!. t has *een associated 7ith decreased mortalit! in the first t7o 7ee8s of therap! due to an earlier micro*iologic response. Ma! *e used alone or in com*ination 7ith $%fluc!tosine, ho7e,er, patients seldom tolerate the $%(C due to se,ere *one marro7 suppression. Most e:perts reccommmend com*ination therap! to start 7ith since this is associated 7ith a faster rate of C"( sterili;ation. 5ptimal duration of acute therap! is & to 14 7ee8s total, follo7ed *! life%long maintenance therap!.

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Dose6 4.2%4.7mgA8gAda! or 1.4mgA8g e,er! other da! . BA% $%(C #$mg%37.$mgA8g four times dail!. -herap! should *e continued for a minimum of t7o 7ee8s. Ad9erse reactions include nephroto:icit!, electrol!te im*alance, anemia, infusion related to:icities and if $%(C is used se,ere *one marro7 suppression and C intolerance. !lucona,ole ma! ha,e a role in the treatment of cr!ptococcal meningitis in A +" patients 7ho are intolerant or refractor! to Amphotericin G. (lucona;ole is recommended for the completion of acute treatment after a # 7ee8 course of ampho G ?for a total of at least & 7ee8s@. Dose6 244mg P5 dail! for & to 14 7ee8s Ad9erse reactions include nausea, ,omiting and hepatoto:icit!

4. Main"enance The$a)+ 50L of all ca&e& #ela"&e i 6 %o th& !lucona,ole -CC$0CCm( daily Am7'otericin B -CCm( I> :ee*ly
B.

Myco!acterium a"ium C m)1e4 3MAC( MAC is the most common m!co*acterial infection in A +" patients. t causes disseminated disease in #$%$46 of patients 7ith A +". t is primaril! seen in patients 7ith ,er! ad,anced disease ?C+2 < 7$@ and it is associated 7ith a high mortalit!. '0 C1inica1 Mani!e#"a"i n# i &idio$& o &et o -&"ecific &.%"to%& i cl$de fe3e#, i'ht &-eat&, dia##hea, abdo%i al "ai , a$&ea, a d 3o%iti ' o -&"ecific &i' & i cl$de, a e%ia, ele3ated al8 "ho&, -ei'ht lo&&, l.%"hade o"ath. a d he"ato&"le o%e'al.. -0 Dia/n #i#

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"o&iti3e blood c$lt$#e ide tificatio f#o% ti&&$e bio"&. :ie. bo e %a##o-, li3e#, l.%"h ode; 3. T$ea"men"

3ntil recentl! no therap! 7as thought to *e effecti,e, ho7e,er, recent studies suggest not onl! the potential of acute therap! to impro,e sur,i,al *ut that there is the potential to pre,ent this disease. An! treatment regimen should include at least t7o drugs and e,er! regimen should include a macrolide as specified *elo7/

Cla#ith#o%.ci 500%'-1000%' +(D o# A5ith#o%.ci 500%' dail. P1%# ne $ m $e ! "he a/en"# 1i#"ed 2e1 6 the follo-i ' t-o ha3e bee &ho- to be %o&t effecti3e Etham*utol 1$mgA8g dail! 0ifa*utin 344mg dail! LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL Ciproflo:acin 7$4mg G + Ami8acin 14%1$mgA8g .A M dail! ?incon,enient 05A, to:ic@ Clofa;amine 144%#44mg dail! ?no longer recommended, e:ceptions ma! include patients 7ith macrolide resistance@ The#a". &ho$ld co ti $e fo# the lifeti%e of the "atie t. The&e a'e t& all ha3e a "ote tial fo# d#$'- d#$' i te#actio & a d ad3e#&e #eactio & that &t$de t& &ho$ld beco%e fa%ilia# -ith. 4. P$ )h+1a4i# 0ecentl!, the C+C re,ised its recommendations to state proph!la:is is recommended in patients 7ith a C+2 count of < 7$.

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Rifabutin 344mgAda! 0ifa*utin is associated 7ith numerous ad,erse effects including neutropenia, rash, C intolerance and discolored urine. t also has similar drug interactions to rifampin. Caution must *e used 7hen prescri*ed 7ith Protease nhi*itors. Clarit'romycin $44mg G + A,it'romycin 1#44mg q 7ee8
C.

T 4 )1a#m #i# 0eacti,ation of prior latent infection 7ith To oplasma gondii is the most common cause of encephalitis in A +" patients. f left untreated, the mortalit! rate approaches 1446. -reatment of acute to:oplasmosis is associated 7ith response rates of 6$ to 946. 3nfortunatel!, greater than $46 of patients treated for this disease e:perience se,ere drug to:icities requiring discontinuation of therap!. Primar! therap! of to:oplasmosis must *e follo7ed *! life%long suppressi,e therap!, since relapse rates 7ithout continued therap! nears 1446. '0 C1inica1 Mani!e#"a"i n %ild o &"ecific= fe3e#, %alai&e, -ea8 e&& %e tal &tat$& cha 'e&, 3i&$al cha 'e&, &ei5$#e&, co%a, he%i"a#e&i& -0 Dia/n #i# CT &ca co &i&te t -ith %$lti"le le&io & a d %ild to %ode#ate ede%a M>( hel"f$l -he CT &ca doe& Nt #e3eal cha 'e& C!A fl$id= o o# fe- M+C&, o#%al 'l$co&e, ele3ated "#otei 3. T$ea"men" =i$#" Line The$a)+& ).#i%etha%i e 100-200%' )O I 1, the 50-75%' )O Dail. "l$& !$lfadia5i e 1-2*% )O e3e#. 6 ho$#& "l$&

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0e$co3o#i :foli ic acid; 5-10%' )O Dail. :$"to %o; ( itial #e&"o &e i& e9"ected i 2-3 -ee8&, ho-e3e#, the#a". -ith f$ll do&e& &ho$ld be co ti $ed fo# 4 to 6 -ee8& afte# #e&ol$tio of &i' & a d &.%"to%&. Alternati9e T'era7y6 ?for patients 7ith "ulfa Allergies@ P!rimethamine ?see a*o,e@ "l$& Cli da%.ci 600%' )O o# (1 e3e#. 6 ho$#& "l$& 0e$co3o#i :&ee abo3e; Efficac! of this regimen has not *een 7ell esta*lished -he use of a;ithrom!cin alone or in com*ination 7ith p!rimethamine has *een studied and data are not con,incing !et. )o7e,er, this com*ination ma! *e considered in patients 7ho do not tolerate clindam!cin. Ad9erse reactions associated 7ith p!rimethamine include dose%dependent throm*oc!topenia, granuloc!topenia and megalo*lastic anemia. "ulfadia;ine has *een associated 7ith rash, neutropenia, nephritis and ele,ated transaminases. 4. S%))$e##i*e The$a)+ ).#i%etha%i F 0e$co3o#i $ ).#i%etha%i F 0e$co3o#i e 25-50%' dail. F !$lfadia5i e 1'% e3e#. 6 ho$#& 5-10%' dail. e 25-50%' dail. F Cli da%.ci 300-600%' e3e#. 6 ho$#& 5-10%' dail.

Primar! proph!la:is studies using dapsoneAp!rimethamine, -MPA"MK or Ato,aquone are ongoing and ma! pro,ide hope for the future.

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OPPORTUNISTIC IN=ECTIONS PART II - VIRAL IN=ECTIONS

;enny Colombo, #'arm<D<, #M#R =10, ;anuary -..4

G a1# and O2;ec"i*e#&

+. the e d of thi& lect$#e the &t$de t &ho$ld be able to= 1. De&c#ibe the cli ical "#e&e tatio of the follo-i ' o""o#t$ i&tic i fectio & i 4(1 :F; "atie t&= *e ital a d a o#ectal 4e#"e&, 1a#icella Do&te#, a d CM1 #eti iti&. 2. Di&c$&& a the#a"e$tic "la fo# the ac$te t#eat%e t,%ai te a ce the#a". a d "#o"h.la9i& fo# the follo-i ' i fectio &= 4e#"e& !i%"le9, 1a#icella Do&te# a d CM1 #eti iti&. 3. Di&c$&& the#a"e$tic alte# ati3e& a d the i dicatio & fo# the&e alte# ati3e& fo# the t#eat%e t of 4e#"e& !i%"le9, 1a#icella Do&te# a d CM1 #eti iti&. 4. >eco' i5e ad3e#&e effect&, co t#ai dicatio & a d d#$' i te#actio & a&&ociated -ith each of the follo-i ' a ti3i#al a'e t&= ac.clo3i#, fa%ciclo3i#, 3alac.clo3i#, 'a ciclo3i#, fo&ca# et a d cidofo3i#.

Se1ec"ed $eadin/#&
App i&' Th&%ap&$ti"s: Th& C i(i"a Us& o) D%$,s. !ith 6ditio , 1995 Cha"te# 68. 4$%a (%%$ odeficie c. 1i#$& :4(1; ( fectio . )a'e& 68-1 - 68-48 Pharmacotherapy: A Pathophysiologic Approach. 3rd Edition, 1996 Chapter 117 Principles and Management of the acquired immunodeficienc! s!ndrome. Pages #3$3 #3&6. Dane )C, Daughon GE, (alloon ', =o,acs 'A, +a,e! 0-, et al. 0ecent Ad,ances in the Management of A +"% 0elated 5pportunistic nfections. Ann ntern Med. 199211#4/92$%9$$ Callant 'E, Moore 0+ and Chaisson 0E. Proph!la:is for 5pportunistic nfections in Patients 7ith ) . nfection. Ann ntern Med. 199211#4/93#%922 (. He$)e# Sim)1e4 Vi$%# )erpes simple: ,irus t!pes 1 and # ?)".%1, )".%#@ can cause disease in *oth normal and immunocompromised patients and are responsi*le for significant mor*idit! in A +" patients. Most adult

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patients 7ith A +" ha,e *een infected 7ith one or *oth )". t!pes at some point prior to the de,elopment of A +". -hus, these patients are not usuall! at ris8 of de,eloping primar! disease. )o7e,er, A +" patients remain at ris8 for significant disease due to reacti,ation of latent ,irus. Ihen latent )". reacti,ates it can cause se,ere recurrent )". disease 7ith prolonged ,iral shedding. -he pre,alence of )". infection in is higher in the A +" population due to the common ris8 factor for transmission of )". and ) .. "erologic studies ha,e re,ealed that up to 776 of ) .%infected patients ha,e *een pre,iousl! infected 7ith )".. A. C1inica1 P$e#en"a"i n &e3e#it. of di&ea&e "#e&e tatio de"e d& o a ato%ical &ite of i fectio , de'#ee of i%%$ o&$""#e&&io a d -hethe# the i fectio i& "#i%a#., i itial o "#i%a#., a d #ec$##e t. "#e&e tatio i& ofte at."ical co%"a#ed to o#%al ho&t& locali5ed %$coc$ta eo$& $lce#ati3e le&io & i& the %o&t f#e?$e t "#e&e tatio &.&te%ic &.%"to%& i cl$de fe3e#, %alai&e, %.al'ia&, headache, l.%"hade o"ath. O$ 1a2ia1& "ai f$l 3e&ic$la# le&io & alo ' the li", to '$e, "ha#. 9, o# b$ccal %$co&a. 0ocal &.%"to%& i cl$de "ai , "ha#. 'iti& a d ce#3ical ade o"ath. Geni"a1 in!ec"i n& &.%"to%& i cl$de "ai , d.&$#ia a d i '$i al ade o"ath. An $ec"a1 in!ec"i n& "e#ia al $lce#atio &, &e3e#e a o#ectal "ai , co &ti"atio , te e&%$&, i%"ote ce, a d e$#o'e ic bladde# a#e t."ical "#e&e ti ' co%"lai t& E# )ha/i"i#& &.%"to%& i cl$de #et#o&te# al "ai a d od. o"ha'ia. the cli ical "ict$#e i& ofte co f$&ed -ith Ca('i'a a d CM1 e&o"ha'iti& Ence)ha1i"i#& occ$#& #a#el. i A(D! b$t i& the %o&t life-th#eate i ' fo#% of 4!1 Dia/n #i# 3i#al c$lt$#e& - i& the G*old !ta da#dG a ti'e detectio b. di#ect fl$o#e&ce t a tibod. :DAA; cli ical &i' & a d &.%"to%& T$ea"men" The "#o%"t ad%i i&t#atio of a ti3i#al the#a". #ed$ce& %o#talit. a d #i&8 of &e#io$& co%"licatio &.

B0

C.

Ac+c1 *i$ - i# "he an"i*i$a1 a/en" ! ch ice ! $ HSV The d#$' %a. be ad%i i&te#ed eithe# )O o# (1. The o"ti%al #o$te of ad%i i&t#atio , do&a'e a d d$#atio de"e d o &ite a d &e3e#it. of i fectio . a. )ha#%acolo'. ab&o#"tio i& &lo- a d i co%"lete di&t#ib$ted i to all ti&&$e&
AA

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b.

c.

e9c#eted #e all. :#e?$i#e& do&e #ed$ctio & i "atie t& -ith #e al d.&f9 ; Ad3e#&e >eactio & (1 ad%i i&t#atio %a. be a&&ociated -ith "hlebiti&, i##itatio at the &ite of i <ectio a d #e al d.&f$ ctio : d$e to c#.&talli5atio i #e al t$b$le&;. )O ha& bee a&&ociated -ith %ild a$&ea a d 3o%iti ', headache& a d #a&h. O3e#all, thi& d#$' i& 3e#. -ell tole#ated Do&i ' >e'i%e &

Mucocutaneous )erpes ?genital, anorectal@ Mild ca&e&= 200%' )O 59 dail. 9 10 da.& !e3e#e ca&e&= 5%'28' (1 ? 8 h#& 9 7 da.& )#o"h.la9i&= 200-400%' )O T(D i dicated i "atie t& -ith #ec$##e t e"i&ode& :K 5 "e# .ea#; : ote= b#ea8th#o$'h i fectio doe& ot ece&&a#il. i%"l. #e&i&ta ce; A A A1"e$na"i*e The$a)+

(amciclo,ir 1#$mg P5 G + : $ +a!s ?indicated for treatment of recurrent episodes onl!@ .alac!clo,ir $44mg P5 G + : $ da!s ?indicated treatment of recurrent infection in immunocompetent patients@

AA

T$ea"men" ! Ac+c1 *i$-Re#i#"an" He$)e# Ac!clo,ir resistant herpes are deficient in th!midine 8inase. +rug of choice/ (oscarnet 24mgA8g . - + : 7 da!s

((.

Va$ice11a-H #"e$ Vi$%# 3VHV( (ortunatel!, primar! .K. infection is usuall! a childhood disease, thus, most adult patients 7ith A +" ha,e *een pre,iousl! infected 7ith .K.. A +" patients, on the other hand, are at greater ris8 than the general

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population for de,eloping recurrent disease. (or A +" patients 7ho ha,e ne,er *een e:posed to .K., primar! infection can *e ,er! serious and life%threatening. A0 C1inica1 P$e#en"a"i n %o&t ofte a #ec$##e t i fectio #adic$la# "ai follo-ed b. locali5ed o# &e'%e ted #a&h co3e#i ' 1-3 de#%ato%e& -ide&"#ead c$ta eo$& o# 3i&ce#al di&&e%i atio %a. occ$# 3i&ce#al di&&e%i atio to the l$ ', li3e# o# C/! ca be life-th#eate i ' T$ea"men" ! VHV

B0

Earl! recognition and treatment ?7ithin 7# hrs@ is essential in pre,enting postherpetic neuralgia and other complications. Man! patients can *e treated 7ith oral agents.
AA

Ac+c1 *i$ - D$%/ ! Ch ice primar! infection/ 14mgA8gA . q & hours : 7 da!s or &44mg P5 $M dail! recurrent infection locali;ed/ treat as a*o,e recurrent disseminated/ 14mgA8g . q & hours : 7 da!s

AA

=amcic1 *i$ ?BBm/ PO TID 4 @ da+# ndicated for primar! or recurrent locali;ed onl!

AA

Va1ac+c1 *i$ '/m PO TID 4 @da+# indicated onl! in immunocompetent patients

AA

T$ea"men" ! ac+c1 *i$-$e#i#"an" *5* (oscarnet 24mgA8g . q & hours

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((.

C+" me/a1 *i$%# 3CMV( nfection 7ith CM. is e:tremel! common in patients 7ith ad,anced A +". t can result in se,eral clinical illnesses, including retinitis, pneumonia, colitis, esophagitis and encephalitis. 0etinitis occurs most often ?in up to 246 of A +" patients@ 7hile gastrointestinal infection occurs less frequentl! ?$%146@. .iremia 7ill e,entuall! de,elop in the ma9orit! of patients, *ut not all patients 7ill de,elop clinical disease as a result of positi,e *lood or urine cultures. -herefore, detection of disease should *e made *! tissue *iops! or histologic e,idence of damage caused *! the ,irus. A. Ch $i $e"ini"i# Thi& i& the %o&t co%%o &ite of CM1 i fectio i A(D! "atie t&. (t Ca "#e&e t a& a $ ilate#al o# a bilate#al i fectio cha#acte#i5ed he%o##ha'ic le&io &. Thi& di&ea&e ca "#o'#e&& #a"idl. a d ca$&e "a#tial o# total bli d e&&. >ela"&e afte# i itial the#a". i& 3e#. co%%o #e?$i#i ' life-lo ' %ai te a ce the#a".. T$ea"men" T#eat%e t of CM1 #eti iti& i& "#i%a#il. li%ited to t-o d#$'&, altho$'h #ece tl., a thi#d d#$' -a& a""#o3ed. T#eat%e t of ac$te i fectio %$&t be ad%i i&te#ed (1 :i d$ctio ;. Mai te a ce the#a". i& life-lo ' a d ca be ad%i i&te#ed i a 3a#iet. of -a.& i cl$di ' (1, )O, i t#a3it#eal a d oc$la# i%"la t&. T$ea"men" i# n " a c%$e i" n1+ #%))$e##e# "he *i$%#0 AA *a ciclo3i# a. )ha#%acolo'. ab&o#"tio i& "oo# di&t#ib$ted -idel. :3a#iable di&t#ib$tio to the e.e; eli%i ated #e all. :#e?$i#e& do&a'e ad<$&t%e t&; b. Ad3e#&e effect& %.elo&$""#e&&io - e$t#o"e ia occ$#& i 25-40L of "atie t& ofte #e?$i#i ' do&e ad<$&t%e t&, di&co ti $atio :&-itch to othe# a'e t; o# co co%ita t t#eat%e t -ith *C!A. Co &ide# di&co ti $i ' othe# %.elo&$""#e&&i3e d#$'& :i.e. ADT, TM)2!MD; if allo-able. othe#& i cl$de= li3e# f$ ctio ab o#%alitie&, fe3e#, a$&ea, &ei5$#e& c. Do&i ' >e'i%e & ( d$ctio The#a".= 5%'28' (1 ? 12 9 14-21 da.& o# $ til cli ical i%"#o3e%e t Mai te a ce The#a".= :life-lo ';

+.

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(1= 5%'28' ? da. = Thi& #o$te "#o3ide& &.&te%ic "#otectio . Di&ad3a ta'e& i cl$de &.te%ic to9icitie&, li e &e"&i&, dail. i f$&io &, ce t#al li e. )O= 1000 %' T(D -ith food :o#al *C1 i& a&&ociated -ith a #i&8 of a %o#e #a"id #ate of "#o'#e&&io to #eti iti&; Ad3a ta'e& i cl$de &.&te%ic "#otectio a d o eed fo# ce t#al li e. ntra,itreal in9ections/ #44%1644mcg q 7ee8 ?higher conc. at site of infection, ma! *e associated 7ith ris8 of opthalmitis and other ocular complications, offers no s!stemic protection@ 5cular implants/ 1mcgAhr replace q 6 months ?associated 7ith the longest time to progression of disease1 ho7e,er it offers no s!stemic protection and the other e!e remains at ris8. Also, associated 7ith surgical complications and infections. d.
AA

>e&i&ta ce to 'a ciclo3i# ha& bee #e"o#ted. ( the&e ca&e& fo&ca# et %$&t be $&ed.

Ao&ca# et a. )ha#%acolo'. "oo#l. ab&o#bed : ot a3ailable a& o#al a'e t; -idel. di&t#ib$ted #e all. eli%i ated b. Ad3e#&e effect& #e al i &$fficie c. i& the %o&t &e#io$& &ide-effect :ade?$ate h.d#atio i& #e?$i#ed a d do&a'e ad<$&t%e t& acco#di ' to c#cl; othe#& i cl$de= a$&ea, headache, t#e%o#, "hlebiti&, h."o8ale%ia, h."o%a' e&e%ia, h."ocalce%ia a d h."o"ho&"hate%ia. c. Do&i ' >e'i%e & ( d$ctio The#a".= 60%'28' (1)+ ? 8h#& o# 90%'28' ? 12 h#& 14-21 da.& Mai te a ce The#a".= :life-lo ';

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90-120%'28' (1)+ ? da. i t#a3it#eal i <ectio &= 1200-2400 %c' ? -ee8 Mo ito# &e#$% c#eati i e a d elect#ol.te& ca#ef$ll.. Ad<$&t do&e& ba&ed o #e al f$ ctio a d ad<$&t do&e acco#di 'l.. Di&co ti $e othe# e"h#to9ic d#$'& if "o&&ible. >e"lace elect#ol.te& a''#e&&i3el. i o#de# to a3oid co%"licatio & :i.e. &ei5$#e&;.

d.

Co%bi atio 'a ciclo3i# a d fo&ca# et -his com*ination should *e reser,ed for patients 7ith refractor! disease. Ihen compared to either ganciclo,ir alone or foscarnet alone the com*ination 7as significantl! superior in dela!ing disease progression and there 7ere no differences in side%effects. )o7e,er, there 7as a noticea*le decrease in qualit! of life due to the numerous and duration of infusions +ose/ Canciclo,ir $mgA8g dail! .PG B foscarnet 94mgA8g dail! .PG

e.

Cidofo3i# :a""#o3ed i 6296; -his is the ne7est of the CM. agents and although it offers an alternati,e for patients 7ho can>t tolerate ganciclo,ir or foscarnet it should *e reser,ed as a third line agent. Cidofo,ir offers the ad,antage of e,er! other 7ee8 dosing, ho7e,er, it is e:tremel! nephroto:ic and must *e used 7ith caution in all patients particularl! those 7ith pre% e:isting renal d!sfunction or on concomitant nephroto:ic drugs. n order to a,oid or minimi;e nephroto:icit! the patients must *e adequatel! h!drated prior to each dose. Additionall!, patients must ta8e pro*enecid prior to and after each dose of cidofo,ir. ( d$ctio the#a".= 5%'28' i f$&ed o3e# 1 ho$# -ee8l. 9 2 -ee8& "l$& "#obe ecid 2'% 3 h#& "#io# to i f$&io a d 1'% at 2 a d 8 h#& afte# i f$&io

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Mai te a ce the#a".= 5%'28' i f$&ed o3e# 1 ho$# e3e#. 2 -ee8& "l$& "#obe ecid a& de&c#ibed abo3e. !e#$% c#eati i e %$&t be %o ito#ed clo&el. a d the d#$' &ho$ld be do&e ad<$&ted o# di&co ti $ed. Ca%"i n& Pa"ien"# 6h a$e 2ein/ #6i"hced !$ m ! #ca$ne" $e7%i$e an ade7%a"e 6a#h %" )e$i d )$i $ " #"a$"in/ cid ! *i$0 !0 P$ )h+1a4i# Proph!la:is of CM. retinitis is contro,ersial. -7o ma9or place*o controlled trials ha,e sho7n contradicting results. Although, oral ganciclo,ir 7as recentl! appro,ed for this indication in patients 7ith C+2 < $4 most e:perts hesitate to use it due the contro,ersial data and the e:tremel! high cost.

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EMERGING PATHOGENS
!$&a 0. )e dla d, )ha#%.D. GOALS AND OBCECTIVES +. the e d of thi& lect$#e the &t$de t &ho$ld be able to= 1. (de tif. &o%e of the "atho'e & that ha3e e%e#'ed i #ece t .ea#& a d the "#oble%& that the. "o&e. INTRODUCTION 6%e#'i ' i fectio$& di&ea&e& a#e di&ea&e& of i fectio$& o#i'i i -hich the i cide ce i h$%a & ha& eithe# i c#ea&ed -ithi the la&t t-o decade& o# th#eate & to i c#ea&e i the ea# f$t$#e. A e%e#'i ' "atho'e i& 'e e#all. di3ided i to 3 cate'o#ie&. (t ca be a %ic#oo#'a i&% that i& totall. e- :e.'., h$%a i%%$ odeficie c. 3i#$&;, o e that -a& "#e3io$&l. 8 o- b$t o l. #ece tl. ide tified a& a "atho'e :e.'., H& i"o.a"t&% p+ o%i;, o# o e that i& old b$t ha& $ de#'o e cha 'e& :e.'., #e&i&ta t %ic#oo#'a i&%&;. ( the "a&t 20 .ea#&, the @.!. "$blic health &.&te% ha& bee co f#o ted -ith a $%be# of "#e3io$&l. $ #eco' i5ed "atho'e &. ( cl$ded i the li&t of the&e i fectio$& di&ea&e& a#e to9ic &hoc8 &. d#o%e, 0e'io ai#e&N di&ea&e, 0.%e di&ea&e, ac?$i#ed i%%$ odeficie c. &. d#o%e :A(D!;, he"atiti& C 3i#$&, a d ha ta3i#$& "$l%o a#. &. d#o%e. Ma . old "atho'e & ha3e beco%e %a<o# cli ical "#oble%& beca$&e of i c#ea&ed 3i#$le ce :e.'., St%&pto"o""$s p+o,&(&s; o# a tibiotic #e&i&ta ce :e.'., "e icilli -#e&i&ta t S. p(&$*o(ia&, %$ltid#$'-#e&i&ta t M+"o.a"t&%i$* t$.&%"$ osis, %ethicilli -#e&i&ta t Staph+ o"o""$s a$%&$s, a d 3a co%.ci -#e&i&ta t E(t&%o"o""$s )a&"i$*;. Ma . di&ea&e& "#e3io$&l. tho$'ht to be $ de# co t#ol, &$ch a& t$be#c$lo&i&, chole#a, .ello- fe3e#, a d de '$e, a#e o- &"#eadi ' to othe# #e'io & of the -o#ld. The ac?$i#ed i%%$ odeficie c. &. d#o%e :A(D!; co ti $e& to "o&e a &e#io$& th#eat th#o$'ho$t the -o#ld. The "#oble%& a&&ociated -ith 4(1 -e#e co3e#ed i "#e3io$& lect$#e& a d -ill ot be i cl$ded i the follo-i ' di&c$&&io . ANTIBIOTIC RESISTANCE The e%e#'e ce of a tibiotic #e&i&ta ce i bacte#ia i& o e of the %o&t &e#io$& "#oble%& faci ' ot o l. the @.!., b$t %o&t othe# co$ t#ie& a& -ell. The follo-i ' i cl$de& &o%e of the #e&i&ta t bacte#ia that a#e c$##e tl. of '#eate&t co ce# =

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St%&pto"o""$s p(&$*o(ia&= Thi& o#'a i&% i& the %o&t co%%o ca$&e of bacte#ial " e$%o ia i ad$lt& a d of otiti& %edia, bacte#e%ia, a d bacte#ial %e i 'iti& i child#e i the @.!. Ao# .ea#& it -a& co &ide#ed to be &$&ce"tible to "e icilli . ( the late 1960N& #e&i&ta t &t#ai & -e#e i&olated i A$&t#alia a d /e- *$i ea. ( 1977 "e icilli -#e&i&ta t a d %$lti#e&i&ta t &t#ai & of S. p(&$*o(ia& e%e#'ed a& a %a<o# o&oco%ial "#oble% i ho&"ital& i !o$th Af#ica. !$b&e?$e tl., #e&i&ta t " e$%ococci -e#e #eco' i5ed -o#ld-ide. Mo&t of the&e &t#ai & -e#e o l. "a#tiall. #e&i&ta t :i te#%ediate &e &iti3it.; to "e icilli , the#efo#e hi'h do&e& of the d#$' -e#e &till effecti3e i t#eati ' %o&t i fectio &. 4o-e3e#, alte# ati3e the#a". -a& ece&&a#. fo# %e i 'iti&. !$&ce"tibilit. "atte# & i the @.!. a#e cha 'i '. ( Dalla&, f#o% 1981-1983 o l. 8.1L of " e$%ococcal i&olate& -e#e i te#%ediatel. "e icilli -#e&i&ta t :M(C 0.1-1.0 $'2%l; a d o e -e#e #e&i&ta t to cefota9i%e. +. 1991-1992, 11.6L -e#e i te#%ediatel. #e&i&ta t to "e icilli a d 8L -e#e #e&i&ta t to cefota9i%e. +. 1993, 18.5L -e#e i te#%ediatel. #e&i&ta t to "e icilli , of -hich 4L -e#e hi'hl. #e&i&ta t :M(C K2.0 $'2%l;, a d 12.9L -e#e #e&i&ta t to cefota9i%e. A e"ide%ic of otiti& %edia i a da. ca#e ce te# i ce t#al 7e t$c8. fo$ d 28L of all S. p(&$*o(ia& i&olate& to be "e icilli -#e&i&ta t, -ith al%o&t half &ho-i ' hi'h le3el #e&i&ta ce. ( additio , 27L -e#e #e&i&ta t to cefota9i%e. A othe# %$ltice te# &t$d. of 1500 S. p(&$*o(ia& i&olate& collected bet-ee 1994 a d 1995 fo$ d that 23.6L of the o#'a i&%& -e#e ot &$&ce"tible to "e icilli . ( te#%ediate #e&i&ta ce -a& &ee i 14.1L, b$t 9.5L bei ' hi'hl. #e&i&ta t. /ot o l. a#e "e icilli -#e&i&ta t " e$%ococci #e&i&ta t to othe# beta-lacta%& b$t the. ca al&o be #e&i&ta t to %ac#olide&, t#i%etho"#i%2&$lfa%etho9a5ole, chlo#a%"he icol, a d tet#ac.cli e. +eca$&e S. p(&$*o(ia& i& &$ch a co%%o "atho'e a d #e&i&ta ce i& &teadil. i c#ea&i ', the#e i& %$ch debate o3e# the choice of e%"i#ic the#a". fo# 3a#io$& i fectio &, e&"eciall. %e i 'iti&. !o%e cli icia & o- #eco%%e d 3a co%.ci fo# e%"i#ic t#eat%e t of %e i 'iti& $ til c$lt$#e a d &e &iti3it. #e&$lt& a#e 8 o- . 4o-e3e#, the#e i& fea# that '#eate# $&e of 3a co%.ci -ill #e&$lt i the de3elo"%e t of 3a co%.ci #e&i&ta ce. Methicilli ->e&i&ta t Staph+ o"o""$s a$%&$s :M>!A;= !ta"h.lococci de3elo"ed #e&i&ta ce to "e icilli &ho#tl. afte# thi& a'e t -a& i t#od$ced i to cli ical "#actice. A ti&ta"h.lococcal "e icilli & :%ethicilli , o9acilli , afcilli , clo9acilli , diclo9acilli ; -e#e de3elo"ed to co$ te# thi& "#oble%. !$b&e?$e tl., &t#ai & e%e#'ed that -e#e #e&i&ta t to the&e d#$'& a d to the ce"halo&"o#i &. The&e -e#e d$bbed M>!A. The i cide ce of M>!A ha& bee i c#ea&i ' &teadil. &i ce the 1980N&. Thi& "atho'e ot o l. ca$&e& o&oco%ial i fectio & i la#'e teachi ' ho&"ital&, b$t i& al&o a "#oble% i %a . o -ho&"itali5ed "atie t& a& -ell. C$##e tl. the o l. a3ailable a'e t fo# t#eati ' i fectio & -ith M>!A i& 3a co%.ci . The de3elo"%e t of 3a co%.ci #e&i&ta t M>!A -o$ld lea3e $& -ith o t#eat%e t fo# thi& 3e#. "atho'e ic %ic#oo#'a i&%. 1a co%.ci -#e&i&ta t Staph+ o"o""$s &pi'&%*i'is ha& bee #e"o#ted i "atie t&. The#e i& t#e%e do$& co ce# that 3a co%.ci -#e&i&ta t &t#ai & of S. &pi'&%*i'is o# e te#ococci -ill t#a &fe# the 'e e& fo# #e&i&ta ce to M>!A.

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1a co%.ci ->e&i&ta t 6 te#ococci :1>6;= The&e o#'a i&%&, "#i%a#il. E(t&%o"o""$s )a&"a is a d E. )a&"i$*, a#e i%"o#ta t o&oco%ial "atho'e &. The e te#ococci a#e the thi#d %o&t co%%o "atho'e a&&ociated -ith blood&t#ea% i fectio & a d the &eco d %o&t co%%o l. i&olated "atho'e o3e#all. The. a#e #elati3el. #e&i&ta t to "e icilli . )atie t& -ith &e3e#e i fectio & fo# -hich bacte#icidal the#a". i& ece&&a#. :e.'., e doca#diti&; #e?$i#e t#eat%e t -ith a co%bi atio of "e icilli o# 3a co%.ci a d a a%i o'l.co&ide. The e%e#'e ce of &e3e#al #e&i&ta t "atte# & ha& e#oded the efficac. of the&e a'e t&. The&e "atte# & a#e :1; hi'h-le3el #e&i&ta ce to 'e ta%ici o# &t#e"to%.ci , the#eb. eli%i ati ' a . &. e#'i&tic acti3it. -ith cell--all acti3e a'e t& to "#o3ide bacte#icidal acti3it., :2; "#od$ctio of a beta-lacta%a&e b. E. )a&"a is, :3; o e 5.%atic "e icilli #e&i&ta ce i E. )a&"i$*, d$e i "a#t to the "#od$ctio of la#'e a%o$ t& of a lo--affi it. )+)5, a d :4; 3a co%.ci #e&i&ta ce i E. )a&"i$* a d E. )a&"a is. The#e i& o t#eat%e t a3ailable fo# "atie t& -ith &e#io$& i fectio & ca$&ed b. &t#ai & #e&i&ta t to "e icilli a d to 3a co%.ci . A ca$&e fo# f$#the# co ce# i& the fact that #e&i&ta ce to 3a co%.ci ca be t#a &fe##ed to othe# o#'a i&%& :S. a$%&$s a d S. p(&$*o(ia&;. *#a%- e'ati3e bacte#ia= Mhile the#e i& t#e%e do$& co ce# -ith the de3elo"%e t of 3a co%.ci #e&i&ta ce fo# *#a%-"o&iti3e o#'a i&%&, the#e i& a e?$al a%o$ t of co ce# -ith #e&i&ta ce de3elo"i ' i %a . *#a%- e'ati3e o#'a i&%&. Ha&*ophi $s i() $&(2a&, N&iss&%ia *&(i(,itis, a d N. ,o(o%%ho&a& all $&ed to be &e &iti3e to "e icilli . T#eat%e t of i fectio & d$e to the&e o#'a i&%& cha 'ed -ith the ac?$i&itio of the 'e e fo# T6M-1 betalacta%a&e "#od$ctio , -hich %ade the#a". -ith "e icilli $ #eliable. The thi#d-'e e#atio ce"halo&"o#i & beca%e the t#eat%e t of choice. The co ce# o- i& that the&e o#'a i&%& -ill ac?$i#e the 'e e fo# T6M-3 o# othe# b#oad-&"ect#$% beta-lacta%a&e, -hich -o$ld %a8e the% #e&i&ta t to the thi#d-'e e#atio ce"halo&"o#i &. Ma . %e%be#& of the 6 te#obacte#iaceae ha3e de3elo"ed #e&i&ta ce to %o&t a'e t& c$##e tl. a3ailable fo# t#eat%e t. /o&oco%ial i fectio & -ith K &.si& a a d E(t&%o.a"t&% ha3e beco%e a &e#io$& "#oble% d$e to the de3elo"%e t of #e&i&ta ce to all a3ailable a tibiotic&. M$lti"le #e&i&ta ce i& co%%o l. #e"o#ted -ith Ps&$'o*o(as a&%$,i(osa. M$lti"le #e&i&ta ce i& al&o &ee -ith the e te#ic "atho'e &, Sa *o(& a a d Shi,& a. Othe#&= Othe# i%"o#ta t "atho'e & ha3e al&o de%o &t#ated i c#ea&i ' #e&i&ta ce. M$lti"le-d#$' #e&i&ta t M+"o.a"t&%i$* t$.&%"$ osis :MD>-T+; i& a &i' ifica t "#oble%. >e&i&ta ce ha& al&o bee #e"o#ted -ith .ea&t&, e&"eciall. i 4(1 "atie t& #ecei3i ' lo '-te#% "#o"h.la9i& -ith fl$co a5ole. )a#a&ite&, &$ch a& %ala#ia, a#e beco%i ' %o#e diffic$lt to t#eat beca$&e of the e%e#'e ce of #e&i&ta ce to a ti"a#a&itic a'e t&. >e&i&ta t 3i#$&e& a#e a othe# a#ea fo# co ce# , e&"eciall. i the 4(1 "o"$latio .

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INCREASED VIRULENCE St%&pto"o""$s p+o,&(&s :'#o$" A beta &t#e"tococc$&;= The +#iti&h tabloid& #ece tl. coi ed the te#% Gfle&h-eati ' bacte#iaG to de&c#ibe i 3a&i3e ec#oti5i ' i fectio & ca$&ed b. '#o$" A beta &t#e"tococci. The i te#e&t -a& ot &o %$ch i the i cide ce of the&e i fectio &, b$t i thei# d#a%atic at$#e. The&e hi'hl. i 3a&i3e '#o$" A &t#e"tococcal i fectio &, -ith o# -itho$t ec#oti5i ' fa&ciiti& a d a&&ociated -ith &hoc8 a d o#'a fail$#e, ha3e bee te#%ed &t#e"tococcal to9ic-&hoc8 &. d#o%e :T!!;. The. ha3e bee #e"o#ted "#edo%i atel. i /o#th A%e#ica a d 6$#o"e. )e#&o & of all a'e& a#e affected, %o&t do ot ha3e "#edi&"o&i ' $ de#l.i ' di&ea&e&. Thi& i& i &ha#" co t#act to "#e3io$& #e"o#t& of '#o$" A &t#e"tococcal bacte#e%ia, i -hich "atie t& -e#e eithe# 3e#. .o$ ' o# old, a d %o&t had $ de#l.i ' co ditio & &$ch a& ca ce#, #e al fail$#e, &e3e#e b$# &, o# -e#e #ecei3i ' i%%$ o&$""#e&&i3e the#a".. The co%"licatio & of c$##e t i fectio & a#e &e3e#e. +acte#e%ia a&&ociated -ith &oft ti&&$e i fectio , &hoc8, ad$lt #e&"i#ato#. di&t#e&& &. d#o%e a d #e al fail$#e a#e co%%o . A""#o9i%atel. 30-70L of "atie t& die i &"ite of a''#e&&i3e %ode# t#eat%e t&. !e3e#al h."othe&i& ha3e bee "o&t$lated to e9"lai the i c#ea&ed 3i#$le ce of thi& o#'a i&%. The %o&t "o"$la# h."othe&i& i& that a bacte#ial "#otei act& a& a G&$"e# a ti'e G -hich i d$ce& the c.to8i e& #e&"o &ible fo# &hoc8 a d ti&&$e i <$#.. ( te#e&ti 'l., i 3it#o te&ti ' of the&e &t#ai & &ho- S. p+o,&(&s to be 3e#. &e &iti3e to "e icilli . 4o-e3e#, &o%e of the %o#e a''#e&&i3e i fectio & -ith '#o$" A &t#e"tococci ha3e ot #e&"o ded -ell to "e icilli the#a".. ( a %o$&e %odel of i fectio , cli da%.ci ha& bee &ho- to be %o#e effecti3e tha "e icilli . Othe# t#eat%e t %ea&$#e& &$ch a& "#o%"t a d a''#e&&i3e e9"lo#atio a d deb#ide%e t of &$&"ected dee"-&eated i fectio a#e %a dato#.. EMERGING PATHOGENS& BACTERIA Es"h&%i"hia "o i 0157=47 E. "o i 0157=47 -a& fi#&t #eco' i5ed a& a ca$&e of h$%a ill e&& i 2 &e"a#ate o$tb#ea8& of he%o##ha'ic coliti& i Michi'a a d O#e'o i 1982. The o#'a i&%& -e#e t#a &%itted b. the &a%e &o$#ce of $ de#coo8ed beef, a d !hi'a-li8e to9i -"#od$ci ' &t#ai & of E. "o i 0157=47 -e#e i&olated f#o% the &tool& of the affected "e#&o &, f#o% &a%"le& of the i%"licated beef b$#'e#&, b$t ot f#o% health. co t#ol&. ( c#ea&ed $%be#& of di&ea&e& #elated to E. "o i 0157=47 ha3e &i ce bee #e"o#ted. Mo&t ca&e& ha3e bee &"o#adic, b$t i &tit$tio al a d co%%$ it.-ide o$tb#ea8& ha3e occ$##ed i $#&i ' ho%e&, &chool&, a d da. ca#e ce te#&, o# ha3e bee #elated to eati ' at fa&t food #e&ta$#a t&, d#i 8i ' $ t#eated %$ ici"al -ate#, o# &-i%%i ' i la8e -ate#. A""#o9i%atel. 0.5-2.4L of all ca&e& of dia##hea, a d 15-36L of all ca&e& of blood. dia##hea o# he%o##ha'ic coliti&, a#e a&&ociated -ith thi& o#'a i&%. ( a 1 .ea# &t$d. i the )$'et !o$ d a#ea of Ma&hi 'to , E. "o i 0157=47 -a& the thi#d %o&t co%%o ca$&e of bacte#ial dia##hea. ( fectio -ith E. "o i 0157=47 "#e&e t& -ith a -ide &"ect#$% of cli ical %a ife&tatio &. The&e i cl$de &e3e#e abdo%i al c#a%"&, little o# o fe3e#, a d -ate#. dia##hea that ofte "#o'#e&&e& to '#o&&l. blood. dia##hea. 69t#ai te&ti al i 3ol3e%e t, i cl$di ' ca#diac a d e$#olo'ic %a ife&tatio &, ha& bee #e"o#ted. E. "o i 0157=47 acco$ t& fo# %o&t

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of ca&e& of he%ol.tic-$#e%ic &. d#o%e. Child#e a d the elde#l. &$ffe# the '#eate&t %o#bidit. a d %o#talit.. /o &"ecific t#eat%e t c$##e tl. e9i&t& fo# E. "o i 0157=47 i fectio othe# tha &$""o#ti3e the#a". a d %a a'e%e t of co%"licatio & &$ch a& a e%ia a d #e al fail$#e. Mo&t of the i&olate& ha3e bee &e &iti3e i 3it#o to %o&t a ti%ic#obial a'e t&. EMERGING PATHOGENS& PARASITES C%+ptospo%i'i$* &"ecie&= C%+ptospo%i'i$* &"ecie& i& o- co &ide#ed to be a i%"o#ta t e te#ic "#oto5oa "atho'e . ( the ea#l. 1980N&, %o&t #e"o#ted i fectio & -e#e i "atie t& -ith A(D!. )atie t& had "#ot#acted, ofte &e3e#e, -ate#. dia##hea a d -a&ti ', a d C%+ptospo%i'i$* -a& co &ide#ed to be "#i%a#il. a o""o#t$ i&tic "atho'e . A la#'e# #ole fo# thi& "a#a&ite i h$%a di&ea&e ha& e%e#'ed -ith a i c#ea&ed a-a#e e&& of the o#'a i&% a d i%"#o3ed %ethod& of dia' o&i&. C%+ptospo%i'i$* &"ecie& i o- co%%o l. ide tified i ca&e& of ac$te, &elf-li%iti ' dia##heal ill e&& i i%%$ oco%"ete t ho&t& i both de3elo"ed a d de3elo"i ' atio &. T#a3ele#& ab#oad ha3e beco%e i fected a d o$tb#ea8& ha3e occ$##ed a%o ' child#e i da.-ca#e ce te#&. Aecal-o#al &"#ead a%o ' h$%a & a d a i%al& a d i 'e&tio of co ta%i ated -ate# a""ea# to be the "#i ci"le %ode& of t#a &%i&&io . The e9act %echa i&% b. -hich thi& "a#a&ite ca$&e& dia##hea i& $ 8 o- . ( A"#il 1993, Mil-a$8eeN& -ate# &$""l. -a& co ta%i ated -ith C%+ptospo%i'i$*, #e&$lti ' i the la#'e&t #eco' i5ed o$tb#ea8 of -ate#bo# e ill e&& i @.!. hi&to#.. Mo#e tha 400,000 "e#&o & had "#olo 'ed dia##hea, -ith a""#o9i%atel. 4,400 ho&"itali5atio & a d 100 death& #e"o#ted. Acco#di ' to the 6)A, %o&t @.!. &$#face -ate# i& co ta%i ated -ith the "a#a&ite. (%%$ oco%"ete t "e#&o & ha3e &elf-li%ited i fectio & -hich %a. #e?$i#e ho&"itali5atio fo# #eh.d#atio a d &.%"to%atic #elief. (%%$ oco%"#o%i&ed "atie t&, -ho #a#el. i%"#o3e &"o ta eo$&l., %a. #e?$i#e additio al the#a".. @ fo#t$ atel., the#e i& o effecti3e t#eat%e t c$##e tl. a3ailable. !t$die& a#e c$##e tl. $ de#-a. e3al$ati ' &e3e#al a'e t&. EMERGING PATHOGENS& VIRUSES 4a ta3i#$&= ( Ma. 1993, a ( dia 4ealth !e#3ice "h.&icia &a- a "#e3io$&l. health. 19-.ea#-old %a#atho #$ e# -ho had bee ill fo# 1 da. -ith fe3e#, %.al'ia, chill&, headache, a d %alai&e. 4i& fia ce, a 21-.ea#-old -o%a had died 5 da.& ea#lie# of ac$te #e&"i#ato#. fail$#e. 4e -a& &e t ho%e -ith &.%"to%atic the#a".. O3e# the e9t 2 da.& he de3elo"ed 3o%iti ' a d dia##hea, the co$'h -ith .ello- &"$t$% a d d.&" ea. 4e -a& ad%itted -ith -o#&e i ' &.%"to%&, &$ffe#ed ca#dio#e&"i#ato#. a##e&t a d died. ( the follo-i ' 2 -ee8 "e#iod, 24 additio al ca&e& -e#e #e"o#ted, -ith 12 death&. ( 3e&ti'ato#& f#o% CDC -e#e b#o$'ht i a d fo$ d the ca$&e of the ill e&& -a& a ha ta3i#$&. @ li8e othe# ha ta3i#$&e&, thi& 3i#$& ca$&ed a &e3e#e "$l%o a#. &. d#o%e -ith '#eate# tha 50L %o#talit.. @&i ' &"ecific i%%$ ofl$o#e&ce t &tai &, i 3e&ti'ato#& f#o% the CDC -e#e able to de%o &t#ate the &a%e 3i#$& f#o% l$ ' ti&&$e f#o% 1975, i dicati ' that the 3i#$& -a& ot e-. The

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3i#$& i& ca##ied b. co%%o dee# %ice. !i ce the di&ea&e -a& fi#&t #e"o#ted, %o#e tha 80 ca&e& ha3e bee detected i %o#e tha a do5e &tate&, #e&$lti ' i %o#e tha 40 death&. The#a". co &i&t& "#i%a#il. of ho&"itali5atio fo# &.%"to%atic ca#e, e&"eciall. fo# the A>D! &. d#o%e -hich 'e e#all. #e?$i#e& %echa ical 3e tilatio . >iba3i#i ca be $&ed, altho$'h it& efficac. i& $ 8 o- . 6bola= O Ma. 6, 1995, the CDC -a& otified of a o$tb#ea8 of 3i#al he%o##ha'ic fe3e# i Dai#e. Te&ti ' of blood &a%"le& co fi#%ed that the o$tb#ea8 -a& ca$&ed b. 6bola 3i#$&. +. Ma. 24, a total of 144 "e#&o & -ith 3i#al he%o##ha'ic fe3e#, i cl$di ' 108 :75L; death&, had bee co fi#%ed. The %edia a'e of ill "atie t& -a& 37 .ea#&. The i c$batio "e#iod fo# thi& 3i#$& #a 'e& f#o% 2-21 da.&. +eca$&e of the lo ' i c$batio "e#iod, the "ote tial e9i&t& fo# i fected "e#&o & to t#a3el f#o% a o$tb#ea8-affected a#ea to the @.!. a d othe# co$ t#ie&. EMERGING PATHOGENS& =UNGI Defi i ' a "a#tic$la# f$ '$& a& a e- o# e%e#'i ' "atho'e i& &o%e-hat &$b<ecti3e. A$ 'al i fectio & a#e ot G#e"o#tableG di&ea&e&, &o o databa&e e9i&t& i the @.!. -hich co%"a#e& &"ecific i&olatio & f#o% .ea# to .ea#. Ca&e #e"o#t& i the lite#at$#e a#e the "#i%a#. %ea & i -hich e%e#'i ' f$ 'al "atho'e & a#e ide tified. De&"ite "#oble%& i #e"o#ti ', &e3e#al f$ 'i a""ea# to be e%e#'i ' a& i%"o#ta t "atho'e &. ( cl$ded a%o ' &o%e of the %o#e co%%o i&olate& a#e Ma ass&2ia, Rho'oto%$ a, Ha(s&($ a, a d T%i"hospo%o( &"ecie&. NONIN=ECTIOUS DISEASES /e- e3ide ce &ho-& that i fectio$& a'e t& %a. ca$&e di&ea&e& "#e3io$&l. co &ide#ed o i fectio$&. Ao# e9a%"le= :1; H& i"o.a"t&% p+ o%i i& a&&ociated -ith "e"tic $lce# di&ea&e a d 'a&t#iti&. :2; !e9$all. t#a &%itted h$%a "a"illo%a3i#$& ha& bee li 8ed -ith ce#3ical ca ce#. :3; 4e"atiti& C 3i#$& i& o- #eco' i5ed a& a leadi ' ca$&e of ch#o ic li3e# di&ea&e a d ci##ho&i& i the @!. :4; Ch a*+'ia i fectio &, lo ' i%"licated i i fe#tilit., a#e te tati3el. a&&ociated -ith co#o a#. a#te#. di&ea&e. :5; Ca*p+ o.a"t&% 8&8$(i i& o- #e'a#ded a& the chief "#eci"ita t of *$illai -+a##e &. d#o%e. :6; )e#&i&te t M+"op as*a i fectio & %a. ca$&e #he$%atoid a#th#iti&, -ith &o%e e3ide ce that %i oc.cli e %a. be &afe a d effecti3e fo# t#eat%e t of %ild to %ode#ate ca&e&.

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RE=ERENCES 1. )elebach 0. 6%e#'i ' i fectio$& di&ea&e&. 0ab Med 1994,25=707-714. 2. !te3e & D0. !t#e"tococcal to9ic-&hoc8 &. d#o%e= &"ect#$% of di&ea&e, "atho'e e&i&, a d e- co ce"t& i t#eat%e t. 6%e#'i ' ( f Di& 1995,1=69-78. 3. *old 4!, Moelle#i ' >C C#. A ti%ic#obial-d#$' #e&i&ta ce. / 6 ' C Med 1996,335=1445-1453. 4. 4a5e 7C. /e- a d e%e#'i ' .ea&t "atho'e &. Cli Mic#obiol >e3 1995,8=462-478. 5. !$ C, +#a dt 0C. Es"h&%i"hia "o i O157=47 i fectio i h$%a &. A ( te# Med 1995,123=698-714. 6. Eablo &8. T. The %.&te#. of the ha ta3i#$&. 0ab Med 1994,25=557-560.

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=UNGAL IN=ECTIONS/ANTI=UNGAL AGENTS

!$&a 0. )e dla d, )ha#%.D. REDUIRED READING Pharmacotherap! % A Pathoph!siologic Approach. -hird Edition, 1997, Chapter 113, pp ##$1%##79 or "econd Edition, Chapter 14&, pp 1763%17&7. )OALS AND OB;ECTI>ES G! the end of this lecture the student should *e a*le to/ 1. dentif! a JclassicJ micro*iologic characteristic for identif!ing of Candida al!icans, Cryptococcus neo"ormans, and the dimorphic fungi. #. +escri*e epidemiologic factors important in the acquisition of fungal infections due to Candida, Cryptococcus, Aspergillus, and the dimorphic fungi. 3. +esign appropriate treatment regimens for the ,arious clinical manifestations of fungal infections due to Candida, Cryptococcus, Aspergillus, and the dimorphic fungi. 2. Dist ad,erse effects and appropriate monitoring parameters for amphotericin G, fluc!tosine, and the a;oles. =UNGAL IN=ECTIONS INTRODUCTION -he incidence of fungal infections has mar8edl! increased in recent !ears. "e,eral factors ha,e contri*uted to this increase. -hese include greater use of immunosuppressi,e drugs1 prolonged use of *road%spectrum anti*iotics1 7idespread use of ind7elling catheters1 and the acquired immunodeficienc! s!ndrome ?A +"@. (ungal infections ha,e emerged as a ma9or cause of death among cancer patients and transplant recipients. n addition, immunocompromised patients ?A +"@ often e:perience more frequent and se,ere fungal infection. (ungal infections are not as eas! to diagnose and treat as most *acterial infections. Goth diagnostic and suscepti*ilit! testing methods for fungi ha,e not progressed as quic8l! as those for *acteria. (ungi, especiall! molds, can *e ,er! slo7 gro7ing and difficult to identif!. Ihile tentati,e guidelines for antifungal suscepti*ilit! testing of !easts ha,e *een pu*lished, methods for filamentous fungi are 9ust *eginning to *e studied. "erum

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concentrations of most antifungal agents are not routinel! monitored. -he relationship *et7een clinical efficac!, suscepti*ilit! results, and plasma concentrations for fungi is not 8no7n. -he emergence of ne7 fungal pathogens and the de,elopment of resistance is also a ma9or concern. Candida s7ecies M C05G 5D5CN/ Candida species are !easts. -he! are small ?2%6 um@, unicellular, thin%7alled, o,oid cells that reproduce *! *udding. -he! gro7 7ell on commonl! used *acterial culture media and do not require special fungal media for culti,ation. n clinical specimens, a =5) prep ?146 potassium h!dro:ide@ is performed to identif! !east, pseudoh!phae, and h!phae1 identification of the fungal forms is facilitated 7ith the =5) 7hich clears the epithelial cells and other de*ris. -here are more than 1$4 species of Candida. 5f these appro:imatel! 14 are considered important pathogens for humans. -he! are C. al!icans# C. guilliermondii# C. $rusei# C. parapsilosis# C. stellatoidea# C. tropicalis# C. pseudotropicalis# C. lusitaniae# C. rugosa# and Torulopis ?formerl! Candida@ gla!rata. Gecause of differences in pathogenicit! and resistance, speciation is desira*le. A rapid, presumpti,e diagnosis of C. al!icans can *e made using the germ tu*e test. -his test is performed *! placing the !east in serum and o*ser,ing the formation of germ tu*es, 7hich are small pro9ections from the cell surface that appear 7ithin 1%# hours. Presence of chlam!dospores is also used to identif! C. al!icans. .arious *iochemical tests or 8its ?AP "trips@ can *e used to identif! !easts 7ithin # da!s. EP +EM 5D5CN/ Candida species are part of the normal flora in humans. -he! are commonl! found on s8in and throughout the gastrointestinal ?C @ tract. -hese sites are *elie,ed to *e the most li8el! ports of entr! into the *lood stream. Candida species are also commonl! found in e:pectorated sputum, the female genital tract, and in urine of patients 7ith ind7elling (ole! catheters. PA-)5CEFE" "/ ntact s8in and mucus mem*ranes are the most important defense mechanisms in maintaining resistance to mucocutaneous or s!stemic candidiasis1 an! process causing s8in maceration lea,es the site suscepti*le to

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Candida in,asion, e,en in health! indi,iduals. Pol!morphonuclear leu8oc!tes ?PMFs@ pla! a ma9or role in fighting Candida infections. PMFs damage pseudoh!phae and phagoc!tosi;e and 8ill *lastospores. nterruption of normal defense mechanisms is necessar! for Candida to *ecome a pathogen. -he factors responsi*le for immunocompromise fall into t7o categories/ naturall! occurring and iatrogenic. Faturall! occurring includes dia*etes mellitus, 7hich predisposes to cutaneous candidiasis. atrogenic factors are thought to *e the most important predisposing factors to Candida infections, especiall! disseminated infections. -he most common iatrogenic factors in,ol,e the use of anti*iotics and intra,enous catheters. Anti*iotics suppress normal *acterial flora 7hich then allo7s !east to proliferate, especiall! in the C tract. (actors that pro,ide a route for Candida to enter the *lood include . drug a*use, parenteral nutrition, chemotherap!, cardiac catheters and prosthetic ,al,es and other implanted prosthetic material. n general, an! immune suppression ?steroids, A +", organ transplantation@ can potentiall! lead to cutaneous or disseminated candidiasis. CD F CAD MAF (E"-A- 5F"/ ?1@ -hrush/ -he term thrush is used to identif! oral candidiasis characteri;ed *! cream! 7hite, curdli8e patches on the tongue and other oral mucosal surfaces, 7hich, 7hen remo,ed *! scraping, lea,e a ra7, *leeding, and painful surface. -he patches are a pseudomem*rane made up of Candida, epithelial cells, leu8oc!tes, *acteria, 8eratin, necrotic tissue, and food de*ris. -he diagnosis is made *! the clinical appearance of the lesion and *! =5) prep. -hrush is commonl! seen in patients 7ith cancer, A +", and asthma treated 7ith inhaled steroids. Patients 7ith thrush for no o*,ious reason should *e e,aluated for A +". -reatment usuall! consists of topical antifungals/ n!statin $ ml ?144,444 unitsAml@ Js7ish and s7allo7J O + or clotrima;ole trouches ?14 mg@ fi,e times dail!, for 14%12 da!s. Patients should *e treated for 2& hours after *ecoming as!mptomatic. n A +" and oncolog! patients, *oth 8etacona;ole ?#44%244 mgAda! po@ and flucona;ole ?$4%144 mgAda! po@ ha,e *een used for treatment and proph!la:is. A ma9or concern is the emergence of resistance in ) . infected patients recei,ing flucona;ole for long%term proph!lactic therap!. Darger doses of flucona;ole, change in therap! to itracona;ole, and the use of amphotericin suspensions ?1 ml P144 mgAmlQ O + s7ish R s7allo7@ ha,e all *een used as treatment options. "pecific regimens for ) . infected patients are co,ered in separate lectures. ?#@ Candida Esophagitis/ -his form of fungal infection is most commonl! seen in patients undergoing treatment for cancer and in A +" patients. Esophageal disease 7as thought to occur *! direct spread from oral disease, *ut has also *een reported to occur 7ithout thrush. -he most common s!mptoms include painful s7allo7ing, a feeling of o*struction on s7allo7ing, and su*sternal chest pain. Fausea and ,omiting ma! also occur. -he diagnosis is made *! *iops! during endoscop!. -reatment generall! consists of a minimum of 12 da!s 7ith

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either 8etocona;ole ?#44%244 mgAda!@ or flucona;ole ?144%#44 mgAda!@ or itracona;ole ?#44 mgAG +@. (lucona;ole has demonstrated greater efficac! than 8etocona;ole in some A +" patients, possi*l! due to achlorh!dria, resulting in decreased a*sorption of the 8etocona;ole. (or patients that do not respond to the a;oles, lo7%dose ?14%#4 mgAda!@ intra,enous amphotericin G should *e effecti,e. ?3@ Candida .aginitis/ -his common infection is most frequent in a setting of dia*etes melitis, anti*iotic therap!, and pregnanc!. Candida ,aginitis is usuall! accompanied *! a thic8, curdli8e discharge and intense pruritus. 0ecommended treatment has *een 7%da! topical treatment 7ith micona;ole or clotrima;ole. 0ecentl! 1% and 3% da! topical regimens ha,e *een sho7n to *e effecti,e. "e,eral of the topical antifungal agents are no7 a,aila*le as o,er%the%counter ?5-C@ preparations. 5ral therap! 7ith flucona;ole ?1$4 mgAda! : 3 da!s@ and 8etocona;ole ?#44%244 mgAdail! : 3 da!s@ has also *e used. ?2@ 3rinar! -ract Candidiasis/ -he presence of Candida in the urine is common and does not necessaril! indicate infection. Candiduria is often seen in association 7ith anti*iotics and (ole! catheters. n the a*sence of *ladder instrumentation, Candida c!stitis has *een associated most often 7ith dia*etes mellitus. "!mptoms ma! *e a*sent or identical to *acterial c!stitis. nitial therap! of candidal c!stitis consists of remo,al of urinar! catheters 7hene,er possi*le. Postcatheteri;ation persistent candiduria usuall! resol,es 7ithout specific antifungal therap!. f it persists *ut is as!mptomatic, there are # populations in 7hich it should *e treated/ renal transplant patients and neutropenic patients. -reatment generall! consists of local irrigation 7ith amphotericin G ?$4 mg in 1 liter sterile 7ater infused at 24 mlAhr@ for $%7 da!s. 5ral therap! 7ith flucona;ole ?$4%144 mgAda! for 7%14 da!s@ ma! also *e effecti,e, as this drug is e:creted in high concentrations in the urine. ?$@ Candidemia and +isseminated Candidiasis/ Pro*lems 7ith management of candidemia and detection of underl!ing disseminated candidiasis present ma9or enigmas for clinicians dealing 7ith patients 7ho are predisposed to disseminated disease. -he diagnosis of disseminated candidiasis is a clinical one. +efiniti,e diagnosis is made *! histopathologic demonstration of the organism in,ading tissues. +iagnosis is difficult *ecause man! patients 7ith disseminated disease do not ha,e positi,e *lood cultures. nterpretation of the significance of increased num*ers of Candida from sites such as sputum, urine, feces, and s8in is difficult, *ecause the organism is frequentl! cultured from these sites, 7ithout causing infection. Management of candidemia poses particularl! difficult pro*lems. "ome patients 7ith competent immune status, ha,e spontaneous resolution of candidemia 7ith remo,al of an ind7elling catheter. Among se,erel! immunocompromised patients, almost all 7ith candidemia ha,e disseminated disease. Assuming a positi,e *lood culture for Candida represents JcontaminationJ ma! *e dangerous1 an e:tensi,e e,aluation of the patient

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should *e conducted to rule out disseminated disease. -his e,aluation should consist of repeated *lood cultures and careful ph!sical e:am to loo8 for cutaneous manifestations and ocular in,ol,ement. n the immunocompetent patient the catheter, if present, should *e remo,ed, and repeat *lood cultures performed. nterpretation of repeat cultures should *e done 7ith the recognition that $46 of patients 7ith disseminated candidiasis do not ha,e positi,e *lood cultures. 0emo,al of an ind7elling intra,enous catheter is ,er! important in the management of candidemia and a ne7 catheter should not *e inserted o,er a 7ire in the site of the old one. 3ntil more comparati,e data on the efficac! of the a;oles is a,aila*le, Amphotericin G remains the gold standard of therap! for candidemia and disseminated Candida infection. -here are an increasing num*er of reports of serious Candida infections *eing successfull! treated 7ith flucona;ole. Although these reports are encouraging, the! either lac8 comparison 7ith amphotericin G or ha,e pro*lems in stud! design. (lucona;ole has emerged as an alternati,e to amphotericin G *ecause of se,eral factors/ ease of administration, a,aila*ilit! of *oth oral and intra,enous forms, and lo7 ad,erse effect profile. n patients 7ho are neutropenic or unsta*le ?or rapidl! 7orsening@, amphotericin G ?4.$%1 mgA8gAda!@ should *e selected for initial therap!. +epending on the se,erit! of the infection, $%fluoroc!tosine ?$%(C, fluc!tosine@ ma! *e added to the regimen ?144%1$4 mgA8dAda!@. )o7e,er, the addition of $%(C ma! result in *one marro7 suppression, therefore serum le,els of $%(C should *e monitored. -reatment 7ith amphotericin G or com*ination therap! is continued until o*,ious clinical impro,ement is seen. 3nfortunatel!, there are no controlled studies gi,ing guidelines for the total dose of amphotericin G or $%(C needed. Most therapies are continued for 7ee8s to months, 7ith total dosages of 4.$%1 gram or more generall! recommended. n patients 7ho are clinicall! sta*le and patients 7ithout neutropenia, the use of flucona;ole ?244 mgAda! .@ or other a;oles ma! *e considered. Cryptococcus neoformans M C05G 5D5CN/ Cryptococcus neo"ormans is an encapsulated !east that reproduces *! *udding. -he cell is round or o,al and generall! 2%6 um in diameter. -he surrounding capsule ma! ,ar! greatl! in si;e depending on gro7th conditions of the en,ironment. EP +EM 5D5CN/

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C. neo"ormans is found in the soil and other sources in nature. t has a 7orld7ide distri*ution. nfection occurs after the organism is aerosoli;ed and inhaled. PA-)5CEFE" "/ Gecause the organism is u*iquitous, it is assumed that e:posure is common. -here appears to *e high natural resistance to infection. Patients 7ith cell%mediated immune defects appear to *e at increased ris8 for infection. Currentl! A +" is the predisposing factor in the ,ast ma9orit! of cr!ptococcal infections. After A +", transplantation is the ne:t most frequent ris8 factor. -he ma9or ,irulence factor for this pathogen is the pol!saccharide capsule 7hich allo7s the organism to resist phagoc!tosis *! the host. CD F CAD MAF (E"-A- 5F"/ ?1@ Meningitis/ -he onset of CF" cr!ptococcoses ma! *e acute or insidious. Acute manifestations are more common in immunosuppressed patients. -hose 7ith more chronic courses ma! ha,e 7a:ing and 7aning manifestations o,er 7ee8s to months, often 7ith completel! as!mptomatic periods. Complaints ma! *e refera*le to the CF", although the! ma! *e mild and nonspecific. Commonl! reported s!mptoms include headache, fe,er, nausea, ,omiting, mental status changes, and stiff nec8. Di8e the histor!, ph!sical findings do not pro,ide specific clues to the diagnosis. Patients are often afe*rile or ha,e onl! a mildl! ele,ated temperature. 0outine la*orator! tests are often normal. E:cept for infections in se,erel! immunosuppressed patients, CF" in,ol,ement is almost al7a!s indicated *! a*normalities in the C"( ?ele,ated opening pressure, glucose decreased, protein increased, ele,ated IGC 7ith more l!mphoc!tes than neutrophils@. +etection of the organism *! culture is necessar! for diagnosis. ndia in8 smears can *e used to presumpti,el! identif! the organism. Date: agglutination tests rapidl! identif! antigens in C"( ?and serum@ from 946 or more of patients 7ith cr!ptococcal meningitis. Effecti,e treatment of CF" cr!ptococcoses in non%A +" patients has *een demonstrated 7ith either amphotericin G ?4.$%4.7 mgA8gAda! for 14 7ee8s@ or com*ination therap! 7ith amphotericin G ?4.3 mgA8gAda!@ and $%(C ?1$4 mgA8gAda! in 2 di,ided doses@ for 6 7ee8s. n patients 7ith A +", efficac! has *een demonstrated 7ith amphotericin alone, and in com*ination 7ith $%(C, and 7ith flucona;ole ?#44%244 mgAda! for 6%14 7ee8s@. Gecause cr!ptococcoses is seldom cured in ) .%positi,e patients, lifelong suppressi,e treatment is used. Man! authorities recommend an initial aggressi,e treatment course 7ith amphotericin G ?7ith or 7ithout $%(C@ for 6% 14 7ee8s, follo7ed *! lifelong maintenance therap! 7ith flucona;ole ?#44 mgAda! or higher if necessar!@.

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Histoplasma capsulatum M C05G 5D5CN/ %istoplasma capsulatum is dimorphic, meaning it can gro7 as a m!celial form at am*ient temperatures and as a !east form at *od! temperature. -he macroconidia ?&%1$ um@ of the m!celial form are spherical and thic8% 7alled. -he! appear tu*erculated due to fingerli8e protrusions from the outermost la!er of the cell 7all. -he organism 7as originall! named %. capsulatum *ecause it appeared to ha,e a capsule1 ho7e,er, the pseudo% encapsulated appearance turned out to *e an artifact caused *! c!toplasmic shrin8age from the rigid cell 7all during tissue fi:ation. -he !east cells are small ?3%2 um@, round to o,al, and ha,e thin 7alls. -he !east reproduce *! polar *udding 7ith a narro7 nec8 *et7een the mother and daughter cell. EP +EM 5D5CN/ %. capsulatum is present in temperate ;ones around the 7orld. t is highl! endemic in the mid7estern and south central 3.". ?5hio and Mississippi ri,er ,alle!s@. -he natural ha*itat of the m!celium form is soil. nfections are acquired *! inhalation and deposition of conidia in pulmonar! al,eoli. PA-)5CEFE" "/ (ollo7ing deposition of conidia in the al,eolar spaces, con,ersion to the !east form is necessar! for pathogenesis. Con,ersion is *elie,ed to occur in #%3 da!s. Macrophages are a ma9or component of the earliest inflammator! response to %. capsulatum and ma! pla! a significant role in limiting infection. C+2B -% l!mphoc!tes are crucial to host defense, as indicated *! the mar8ed suscepti*ilit! to disseminated histoplasmosis of people 7ith A +" CD F CAD MAF (E"-A- 5F"/ ?1@ Acute Pulmonar! )istoplasmosis/ Appro:imatel! 996 of primar! pulmonar! infections are as!mptomatic or an acute, self%limiting illness 7ith flu%li8e pulmonar! s!mptoms. Most clinicall! apparent infections are mild to moderate in se,erit! 7ith nonspecific s!mptoms. -7o important factors that determine the degree of s!mptomolog! are the quantit! of inoculum inhaled and the immune status of the host. -he incu*ation period after e:posure ranges from 3%#1 da!s, 7ith pea8 onset of s!mptoms at 3%12 da!s. (e,er, chills, headache, m!algia, and nonproducti,e cough are common. Ieight loss secondar! to anore:ia, mar8ed fatigue, and m!algia also are frequent complaints. (i,e to 66 of patients e:perience rheumatologic manifestations in the

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form of arthralgias, fran8 arthritis, er!thema multiforme, andAor er!thema nodosum. 5ccasionall!, people 7ith se,ere infections 7ith present 7ith a clinical picture that resem*les adult respirator! distress s!ndrome ?A0+"@. Most patients *ecome as!mptomatic 7ithin # 7ee8s after onset of s!mptoms. Iea8ness and fatiga*ilit! ma! persist for se,eral months in more se,ere infections. 0outine la* studies are not distincti,e. Pulmonar! function tests ma! *e a*normal and CM0 t!picall! sho7s one or more patch! pneumonic infiltrates. Goth as!mptomatic and s!mptomatic infections require no specific treatment. Patients 7ith se,ere infections ma! *e treated 7ith 8etocona;ole ?244 mgAda!@ or itracona;ole ?#44 mgAG +@ for 3%6 months. f a;ole therap! is contraindicated or not tolerated, a *rief #%2 7ee8 course of amphotericin G ?4.3%4.7 mgA8gAda!@ ma! *e gi,en. ?#@ Chronic Pulmonar! )istoplasmosis/ CP) usuall! presents as an opportunistic infection imposed on a pre% e:isting structural a*normalit!. -he ma9orit! of patients are males o,er the age of $4 7ho ha,e C5P+. -he most common complaints are persistent cough, 7eight loss, malaise, and lo7%grade fe,er. Fight s7eats and pleuritic chest pain are also reported. 0outine la* tests are not helpful in the diagnosis. Patients e:hi*it chronic pulmonar! s!mptoms and apical lung lesions 7hich progress 7ith inflammation, calcified granulomas, and fi*rosis. Patients 7ith earl!, nonca,itor! disease generall! reco,er 7ithout treatment. Progression of disease occurs o,er a period of !ears ?in appro:imatel! #$6 of patients@, 7ith ca,itation, *ronchopleural fistulas, e:tension to the other lung, pulmonar! insufficienc!, and frequentl! death. mmunosuppressed patients 7ith persistent radiographic a*normalities should *e treated, as 7ell as those 7ho are s!mptomatic or 7ho present 7ith thic8%7alled ca,ities ?H# mm@. Amphotericin G is effecti,e 7hen gi,en to a total dosage of 3$ mgA8g. -reatment 7ith 8etocona;ole ?244%&44 mgAda!@ and itracona;ole ?#44 mgAG +@ for 6%1# months is also effecti,e. ?3@ +isseminated )istoplasmosis/ +isseminated infection can de,elop *! e:tension from primar! pulmonar! infection, *! e:ogenous reinfection, or *! reacti,ation of an endogenous focus of latent infection. -he clinical spectrum of disseminated histoplasmosis is *road. Most adults e:hi*it a mild, chronic form of the disease. 3ntreated patients are often ill for !ears, 7ith long as!mptomatic periods interrupted *! relapses of clinical illness characteri;ed *! 7eight loss, 7ea8ness, and fatigue. -reatment for chronic disseminated histoplasmosis is the same as for CP). Blastomyces dermatitidis M C05G 5D5CN/

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&. dermatitidis is dimorphic fungus, gro7ing as a m!celial form at room temperature and as a !east form at 37C. Con,ersion of the m!celial form to the !east form is necessar! for definiti,e identification. -he !east cells are &% 1$ um in diameter, 7ith a thic8 cell 7all that is highl! refractile. -he !east reproduce *! single *uds, 7ith a *road *ase *et7een parent and *ud. -he daughter cell is often nearl! as large as the mother cell *efore detachment. -hese characteristics are also seen in tissue samples and are used to distinguish &. dermatitidis from other fungi. EP +EM 5D5CN/ -he fungus is endemic in the 3.". in the southeastern and south central states, especiall! those *ordering the Mississippi and 5hio ri,er *asins, and in the mid7estern states that *order the Creat Da8es. &. dermatitidis is considered to *e an inha*itant of soil, although attempts to isolate the organism in nature ha,e *een difficult and the results inconsistent. PA-)5CEFE" "/ Glastom!cosis results from inhalation of spores from the soil, 7ith disease at other sites a result of dissemination from a primar! pulmonar! infection. mmunocompetent people are fairl! resistant to infection *! &. dermatitidis. Ihen conidia are inhaled, natural resistance is li8el! mediated *! neutrophils, monoc!tes, and macrophages, 7hich can phagoc!ti;e and 8ill the conidia. Al,eolar macrophages inhi*it the transformation of conidia to the pathogenic !east forms. )o7e,er, once con,erted in tissue, the !east forms are relati,el! resistant to phagoc!tosis and 8illing. CD F CAD MAF (E"-A- 5F"/ Glastom!cosis is a s!stemic disease 7ith a 7ide ,ariet! of pulmonar! and e:trapulmonar! manifestations. Pulmonar! disease ma! *e acute or chronic and is difficult to differentiate from infections 7ith *acteria, tu*erculosis, other fungi, or malignanc!. Acute pulmonar! *lastom!cosis is generall! as!mptomatic or a self% limiting disease characteri;ed *! fe,er, sha8ing chills, and a producti,e cough. Chronic disease is characteri;ed *! fe,er, malaise, 7eight loss, night s7eats, and cough. &. dermititidis ma! in,ol,e almost e,er! organ of the *od!, resulting in the di,ersit! of clinical manifestation. "8in, *one, and genitourinar! sites of infection are common. As no clinical s!ndrome is characteristic of *lastom!cosis, the definiti,e diagnosis requires gro7th of the organism from clinical specimens. A presumpti,e diagnosis can *e made *! ,isuali;ation of the fungus in specimens. =etocona;ole ?244 mgAda!@ or itracona;ole ?#44 mg G +@ Ptreat for 6 monthsQ can *e used to treat

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mild to moderate disease. Amphotericin G ?4.$%1 mgA8gAda!@ is the drug of choice for patients 7ho are se,erel! immunocompromised and for patients 7ith life%threatening disease, central ner,ous s!stem disease, or ha,e progression of disease on a;oles, or are not a*le to tolerate a;ole therap!. Although the e:act dose and optimal duration of therap! are un8no7n, relapse appears to *e more common if the total dose is less than 1.$ g. Most recommend a total dose of 1.$%#.$ g of amphotericin G. 0elapse is more common in immunocompromised patients, especiall! A +". Chronic suppressi,e therap! 7ith an a;ole is recommended for immunocompromised patients.

Coccidioides immitis M C05G 5D5CN/ -his dimorphic fungus e:ists in the soil in the m!celial phase. As it matures, alternate cells ?arthroconidia@ in the h!phae *ecome *arrel shaped. -he h!phae is easil! fragmented, and the arthroconidia *ecome air*orne, 7here the! ma! *e inhaled *! an animal host. n the host, the spores s7ell, *ecome spherical, and de,elop a thic8 7all. -his ne7 structure, the spherule, reproduces *! formation of internal spores ?endospores@. A single spherule ma! de,elop as man! as &44 endospores. Ihen the spherule ruptures, the endospores are released and each in turn can de,elop into a ne7 spherule.

EP +EM 5D5CN/ Coccidioidom!cosis is endemic in certain areas of the Americas. Almost all infections in the 3.". occur in 7 south7estern states. -he incidence of infections 7ill li8el! rise o,er time, since the endemic areas are in the sun*elt states and Datin America, 7hich has a rapidl! gro7ing population and *ecause of the increase in tra,el to these areas. PA-)5CEFE" "/

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Coccidioidom!cosis resem*les tu*erculosis in its pathologic manifestations. -he predominant tissue reaction is granulomatous. After the arthrospore first impacts in the lo7er air7a!s, the initial host response consists of macrophages and neutrophils. Feutrophils are prominent again 7hen spherules rupture. Arthroconidia, endospores, and particularl! spherules are quite resistant to 8illing *! neutrophils. "tudies in animals suggest that -%l!mphoc!tes pla! a critical role in immune response. CD F CAD MAF (E"-A- 5F"/ Appro:imatel! 646 of those infected ha,e as!mptomatic infections or mild non%specific s!mptoms. -he remainder de,elop s!mptoms of a primar! infection 1%3 7ee8s after e:posure. -hese infections resem*le a lo7er respirator! tract infection andAor s!stemic illness 7ith the follo7ing s!mptoms/ cough, sputum production, chest pain, malaise, fe,er, chills, night s7eats, anore:ia, 7ea8ness, and arthralgias. Er!thema nodosum or er!thema multiforme in,ol,ing the upper trun8 and e:tremities ma! occur. CM0 sho7 minimal changes, infiltrates, or pleural effusion. n most cases, these manifestations resol,e spontaneousl!. "ome de,elop acute progressi,e pneumonia, often 7ith a fatal outcome1 others progress to chronic pulmonar! disease. 3suall!, ca,itar! lesions are part of the chronic disease. A*out 4.$6 of infected patients de,elop disseminated disease. -he most common sites of disseminated infection are musculos8eletal ?muscles, tendons, *ones, 9oints@, cutaneous, and the meninges. +isseminated coccidioidom!cosis *ecame an A +"%defining e,ent in ) .% positi,e people in 19&7. +efiniti,e diagnosis of C. immitis infection is *! culture and identification of the spherule. Most patients impro,e 7ithout therap!1 ho7e,er patients 7ith se,ere primar! infection should *e treated. 5nce the disease has disseminated, anti*iotic therap! is mandator!. nitial doses of 1%1.$ mgA8gAda! of amphotericin G , 7ith total doses of 1%#.$ g are generall! used. Prolonged courses are necessar! if remission is not achie,ed. "tudies 7ith the a;oles ?8etocona;ole, flucona;ole, itracona;ole@ are encouraging and ma! *e used for treatment of some infections. Aspergillus species M C05G 5D5CN/ Aspergillus is an u*iquitous mold. -he three most common species in,ol,ed in human infections are A. "umigatus, A. "lavus and A. niger. Aspergillus species are identified *! appearance of the colon! and *! microscopic e:amination of the spore%*earing structures and spores. )!phae of Aspergillus are #%2 um 7ide, septate, and dichotomousl! *ranched. n the a*sence of sporulation, the h!phae cannot *e readil! differentiated from a large num*er of other molds.

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EP +EM 5D5CN/ Aspergillus are u*iquitous in the en,ironment of most countries of the 7orld. Aspergillus reaches the patient *! air*orne conidia that are small enough ?#.$%3 um@ to reach the al,eoli upon inhalation and hard! enough to sur,i,e for prolonged periods in fomites. Gesides the lung, Aspergillus can in,ade the nose and paranasal sinuses, e:ternal ear, or traumati;ed s8in. -he most important determinant of infection is the immune status of the patient, not the intensit! of e:posure. n acute leu8emia and *one marro7 transplantation, prolonged and intense neutropenia is pro*a*l! the most important predisposing factor, 9ust as return of marro7 function is ,ital to therapeutic response. )igh%dose corticosteroid therap! is the onl! predisposing factor in some patients. n pre,iousl! normal children, in,asi,e aspergillosis should suggest the possi*ilit! of granulomatous disease. PA-)5CEFE" "/ Aspergillus can in,ade the lung through the al,eoli or the tracheo*ronchial tree. Complement acti,ation recruits monoc!tes and neutrophils to the infected site. =illing *! these cells is poor until the conidia s7ell and germinate into h!phae. -hen, these cells as 7ell as acti,ated macrophages, can attach and damage the fungus. Ihere,er the initial lesion is, gro7th of h!phae into and e:tension along *lood ,essels is uni,ersal in the mar8edl! neutropenic patient, leading to hemorrhagic infarction and necrosis. nfection e:tends directl! across tissue planes as 7ell as hematogenousl!. Aspergillus can coloni;e *ronchi and pree:isting pulmonar! ca,ities, gro7ing as *alls of h!phae. -he fungal *all is composed entirel! of h!phae that are originall! ,ia*le. Iith time, central areas of the *all degenerate and soften. ntermittent o*struction of the *ronchial communication ma! cause the ca,it! to fill 7ith fluid in 7hich *acteria ma! gro7 and increase the inflammation of the ca,it! 7all. CD F CAD MAF (E"-A- 5F"/ -he term JaspergillosisJ is *roadl! defined as a spectrum of diseases attri*uted to allerg!, coloni;ation, or tissue in,asion *! Aspergillus species. Allergic manifestation range in se,erit! from mild asthma to allergic *ronchopulmonar! aspergillosis ?GPA@. GPA is caused *! A. "umigatus, and is characteri;ed *! se,ere asthma 7ith 7hee;ing, fe,er, malaise, 7eight loss, chest pain, and a cough producti,e of *lood%strea8ed sputum. GPA de,elops 7hen spores *ecome trapped in the ,iscous mucus of asthmatic patients. -he fungus gro7s, releasing to:ins and antigens. -herap! is aimed at minimi;ing the amount of antigenic material released in the tracheo*ronchial tree. Antifungal therap! is generall! not indicated, 7ith treatment consisting of parenteral corticosteroids. "uperficial infections of the ear and s8in can often *e managed 7ith topical antifungals. Aspergillus infections of the sinuses occurs follo7ing coloni;ation in a*normal sinus tissue, resulting in

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aspergillomas or fungus *alls. nfection is generall! locali;ed in the ma:illar! sinus1 treatment consists of remo,al of the aspergilloma. n immunocompromised patients, in,asi,e disease ranging from chronic to su*acute to fulminant infection can *e seen. A com*ination of surgical and antifungal therap! is generall! required. Pulmonar! aspergillomas are fungal *alls arising in pre%e:isting ca,ities due to tu*erculosis, histoplasmosis, or other pulmonar! condition. Patients commonl! e:perience chest pain, d!spnea, and sputum production. )emopt!sis is o*ser,ed in $4%&46 of patients, 7ith appro:imatel! 146 ha,ing hemorrhage se,ere enough to cause death. n,asi,e disease rarel! occurs, and therap! for aspergillomas is contro,ersial. "urgical e:cision is generall! performed. ntra,enous amphotericin G is generall! not useful in eradicating aspergillomas. n,asi,e aspergillosis is rare in immunocompetent hosts. -he lung is the most common site of in,asi,e disease. Feutropenic patients 7ith Aspergillus pneumonia can de,elop an acute necroti;ing, p!ogenic pneumonitis, caused *! h!phae in,ading the 7alls of *ronchi and surrounding parench!ma. -hese patients present 7ith classic signs and s!mptoms of acute pulmonar! em*olism/ pleuritic chest pain, fe,er, hemopt!sis, a friction ru*, and a 7edge%shaped infiltrate on CM0. -hrom*osis 7ith resultant infarction, necrosis, and dissemination to other tissues and organs in the *od! is caused 7hen h!phae in,ade *lood ,essels. Feutropenic patients 7ith in,asi,e aspergillosis do not generall! sur,i,e *e!ond #%3 7ee8s, unless *one marro7 function is restored. -reatment for in,asi,e aspergillosis is 7ith amphotericin G. -he optimal dose or duration of therap! has not *een determined. -herap! is usuall! started 7ith 1%1.$ mgA8gAda! of amphotericin G, and continued until clinical impro,ement is apparent, *one marro7 has reco,ered, or the drug can no longer *e tolerated. tracona;ole has *een useful in some of the more indolent, nonmeningeal cases.

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ANTI! N)AL A)ENTS

Am7'otericin B Mechanism of Action/ Amphotericin G is a lipophilic pol!ene that *inds ergosterol in the cell 7alls of suscepti*le fungi1 the resultant alteration of mem*rane permea*ilit! allo7s lea8age of the cellular contents and thus causes cell death. Pharmaco8inetics/ Amphotericin G has poor oral a*sorption. t is almost al7a!s gi,en intra,enousl!, the main e:ceptions *eing for *ladder irrigation and topical treatment of thrush. -he drug is highl! protein *ound. t is distri*uted to man! tissues, including lung, spleen, and 8idne!. Penetration into the C"( is poor1 intrathecal administration ma! *e necessar! for some infections of the CF". After an initial half%life of #2%2& hours, a terminal half%life of 1$ da!s reflects slo7 release from a peripheral compartment. -he drug has a large ,olume of distri*ution ?2 DA8g@. A dose of 4.$ mgA8g achie,es a serum concentration of appro:imatel! #%3 ugAml1 ho7e,er, the relationship of serum concentrations and clinical efficac! is un8no7n. -he meta*olism of amphotericin G is not clearl! understood. "ome of the drug is eliminated through renal and *iliar! routes. Meta*olic patho7a!s for a considera*le portion of the drug is un8no7n. )epatic or renal d!sfunction has minor effects on serum le,els, and hemodial!sis does not alter *lood le,els of the drug. Administration/ "olutions should *e prepared in $6 de:trose1 saline solutions should *e a,oided *ecause of precipitation of the drug. t is sta*le in normal light for usual durations and does not need to *e co,ered. -raditionall!, patients ha,e recei,ed a Jtest doseJ of amphotericin G to o*ser,e for ad,erse effects 7hile ,ital signs are monitored. -his is accomplished *! adding 1 mg in #$%$4 ml of $6 de:trose and administering o,er 34%64 minutes. Alternati,el!, a portion of the first regular dose ma! *e gi,en, 7ith the remainder administered later or the full dose then administered on the second da!. )o7e,er, anaph!la:is is e:tremel! rare and a test dose is not necessar!. n the past patients 7ere slo7l! escalated to full dose regimens. )o7e,er, it is no7 standard practice to initiate therap! at target doses, especiall! in patients 7ith se,ere infection or 7orsening condition. Ihile doses of 4.$%4.7$ mgA8gAda! are commonl! used, doses of 1.4%1.$ mgA8gAda! are recommended for some serious infections. Ihile the duration of infusion has traditionall! *een 2%6 hours, administration o,er 1%# hours sho7s no significant increase in the incidence of ad,erse reactions.

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"pectrum of Acti,it!/ Most species of fungi that cause human infection are suscepti*le to amphotericin G. t is considered the treatment of choice for most serious, s!stemic fungal infections. t is used to treat candidiasis, cr!ptococcoses, aspergillosis, histoplasmosis, *lastom!cosis, coccidioidom!cosis, as 7ell as most other fungi. Ad,erse Effects/ Ihile amphotericin G is ,er! efficacious, it is the ad,erse effects associated 7ith this agent that complicate therap!. -hese ad,erse effects are usuall! categori;ed as acute ?infusion%related@ or chronic ?non% infusion related@. -he most common infusion related side effects are sha8ing chills, fe,er, m!algias, arthralgias, and headache. -he fe,er and chills are thought to *e due to induction of tumor necrosis factor or production of prostaglandin E *! macrophages. Premedication 7ith acetaminophen ?6$4 mg po@, aspirin, or i*uprofen ma! *lunt this response. f unsuccessful, other measures include premedication 7ith diphenh!dramine ?#$%$4 mg poA .@, meperidine ?#$%$4 mg@, or h!drocortisone ?#$ mg@ or s!mptomatic treatment 7ith meperidine ?#$%$4 mg .A M@. -hrom*ophle*itis at the site of infusion ma! occur, *ut is less li8el! 7ith rapid infusion or central ,enous administration. )eparin ?1444 unitsAD@ ma! *e added to each infusion as a proph!lactic measure. Chronic ad,erse effects commonl! seen 7ith amphotericin G include anemia, renal d!sfunction, and potassiumAmagnesium 7asting. 0e,ersi*le normochromic, normoc!tic anemia is a frequent complication that is pro*a*l! due to suppression of er!thropoietin. -he most significant ad,erse effect of amphotericin G administration is nephroto:icit!. 0enal d!sfunction is generall! re,ersi*le upon discontinuation of the drug1 ho7e,er persistent impairment is common in those patients 7ho recei,e large cumulati,e doses. 0enal d!sfunction ma! *e manifested *! loss of urinar! concentrating a*ilit!, sodium and potassium 7asting, and renal tu*ular acidosis, in addition to a;otemia. Fephroto:icit! is potentiated *! depletion of sodium, such as 7ith the use of a diuretic, poor oral inta8e, or ,omiting. Coadministration of other nephroto:ic agents should *e a,oided 7hen possi*le. Administration of 4.$ liter of 4.96 FaCl *efore and after the infusion of amphotericin G has *een suggested to reduce nephroto:icit!. -he serum creatinine increases in the ma9orit! of patients. Mild to moderate increases in serum creatinine concentrations ?less than 3 mgAdl@ are common and should not prompt discontinuation of therap!. )!po8alemia and h!pomagnesemia generall! occur in association 7ith decreased renal function1 replacement of these elements should *e pro,ided as indicated. Monitoring Parameters/ 0egular monitoring of complete *lood count, creatinine, potassium, magnesium, and other pertinent la*s is essential for all patients. A flo7 sheet should *e used to record dail! and cumulati,e doses. Dipid Preparations of Amphotericin G/ n recent !ears, no,el approaches ha,e *een de,eloped to impro,e the deli,er! and decrease the to:icit! of amphotericin G. -his products include/

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?1@ AGDC ?A*elcet@ % amphotericin G lipid comple: ?#@ AGC+ ?Amphocil or Amphotec@ % amphotericin G colloidal dispersion ?3@ liposomal amphotericin G ?AmGisome@ % simple unilamellar ,esicle around amphotericin G -hese lipid formulations allo7 much larger doses of amphotericin G to *e administered. Ihile nephroto:icit! appears to *e significantl! reduced, the acute infusion%related ad,erse effects are still seen. -hese products are ,er! e:pensi,e ?i.e., AGDC appro:imatel! S244 ,s S#4 per da! for standard therap!@. n addition, clinical trials comparing the lipid formulations 7ith amphotericin G are lac8ing. Attempts ha,e *een made to prepare a cheap lipid formulations using lipid emulsions, such as ntralipid. -hese admi:tures ha,e *een sho7n to *e unsta*le and should not *e used until further data are a,aila*le on their sta*ilit! and efficac!. !lucytosine Mechanism of Action/ (luc!tosine, or $%fluoroc!tosine ?$(C@, is a fluorinated p!rimidine. "uscepti*le fungi contain c!tosine deaminase, 7hich con,erts fluc!tosine to $%fluorouracil, 7hich in turn inhi*its s!nthesis of +FA and 0FA. Ihen used in com*ination 7ith amphotericin G, the altered permea*ilit! of the fungal cell mem*rane allo7s enhanced upta8e of fluc!tosine *! strains that are usuall! resistant. Pharmaco8inetics/ (luc!tosine is 7ell a*sor*ed after oral administration. -he drug demonstrates little protein *inding and good penetration into most *od! sites and fluids, including the C"(. Pea8 serum concentrations of 74%&4 ugAml occur 1%# hours after oral administration of 37.$ mgA8g. -he half%life is appro:imatel! 3 hours in patients 7ith normal renal function and &$ hours in those 7ith anuria. -he drug is e:creted in the urine. 0enal d!sfunction considera*l! prolongs e:cretion and necessitates ma9or modifications in dosage. (luc!tosine is remo,ed *! hemodial!sis and peritoneal dial!sis. Administration/ (luc!tosine is onl! administered orall!. -he usual dose is 1$4 mgA8gAda!, di,ided into 2 doses of 37.$ mgA8g. "tudies are currentl! *eing conducted to e,aluate lo7er dosages of $4%7$ mgA8gAda!. "pectrum of Acti,it!/ (luc!tosine has a narro7 spectrum of acti,it! and is used primaril! for Candida and Cryptococcus neo"ormans. t is rarel! used as a single agent due to the rapid de,elopment of resistance 7hich can occur during therap!, especiall! cr!ptococcal infections. Ad,erse Effects/ "uppression of the *one marro7 is the main serious complication of fluc!tosine therap!. -he suppression is usuall! re,ersi*le. -arget pea8 serum

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concentrations ?o*tain # hours post dose@ should range from $4%144 ugAml1 to:icit! is related to the dose and occurs frequentl! 7hen le,els e:ceed 144 ugAml. C intolerance is also reported 7ith fluc!tosine. Gecause of possi*le teratogenicit!, fluc!tosine is contraindicated in pregnanc!. Monitoring Parameters/ Complete *lood count, renal function, and serum concentrations. Imida,oles and Tria,oles Mechanism of Action/ All a;oles interfere 7ith the s!nthesis and permea*ilit! of fungal cell mem*ranes. -he mechanism in,ol,es inhi*ition of the c!tochrome P%2$4 en;!me responsi*le for con,ersion of lanosterol to ergosterol, the ma9or sterol of most fungal cell mem*ranes. -hese agents are generall! considered to *e fungistatic. Monitoring Parameters/ All a;oles inhi*it the c!tochrome P2$4 en;!me s!stem resulting in potential drug interactions 7ith other agents meta*oli;ed in the li,er. Medications must *e carefull! 7atched to pre,ent to:icities or su*therapeutic le,els due to these drug interactions. Patients on 8etocona;ole and itracona;ole should ha,e li,er function monitored, 7hile those recei,ing flucona;ole should ha,e renal function routinel! monitored. Detocona,ole/ ?imida;ole@ Pharmaco8inetics/ Castric acidit! must *e normal for a*sorption of the drug. Patients 7ith achlorh!dria do not adequatel! a*sor* the drug. =etocona;ole is highl! protein *ound. t adequatel! penetrates most areas1 ho7e,er, C"( le,els are undetecta*le at the usual recommended doses ?#44%244 mgAda!@. =etocona;ole is e:tensi,el! meta*oli;ed in the li,er and e:creted in inacti,e form in the *ile. Gecause onl! a minimal amount of drug enters the urinar! tract, the dose need not *e altered in patients 7ith renal insufficienc!. Although ad9ustment of the dose is not necessar! for mild to moderate hepatic insufficienc!, the dose should *e decreased or the drug a,oided entirel! in patients 7ith se,ere li,er failure. -he drug is not remo,ed *! hemodial!sis or peritoneal dial!sis. Administration/ =etocona;ole is solu*le onl! at a p) of less than 3 and is therefore not a,aila*le in parenteral form.

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"pectrum of Acti,it!/ =etocona;ole has in ,itro acti,it! against most Candida species, C. neo"ormans, and the dimorphic fungi. t does not ha,e good acti,it! against Aspergillus. Ad,erse Effects/ -he most common ad,erse effects of 8etocona;ole in,ol,e the gastrointestinal tract. Anore:ia, nausea, ,omiting, or some com*ination of these factors occurs frequentl!. "!mptoms ma! *e minimi;ed *! di,iding the dail! dose or ta8ing the drug 7ith food. 0ash and pruritus occur in a small percentage of patients, as does as!mptomatic increases in serum transaminases. )epatitis has *een reported, *ut is rare. =etocona;ole can cause pro*lems 7ith steroidogenesis ?decreased cortisol production@ resulting in ,arious endocrine%related pro*lems. 5ther ad,erse effects include impotence, decreased li*ido, g!necomastia, or some com*ination of these findings in men. -hese effects are due to the transient dose%dependent inhi*ition of s!nthesis of testosterone. +rug nteractions/ Man! drug interactions ha,e *een reported 7ith 8etocona;ole. Most occur *! 1 of # *asic mechanisms1 inhi*ition of a*sorption leading to decreased *ioa,aila*ilit! or interference 7ith the acti,it! of hepatic microsomal en;!mes ?c!tochrome P2$4@ 7hich alters the meta*olism and plasma concentration of the a;ole, the interacting drug, or *oth. +rugs 7hich decrease the concentration of 8etocona;ole include antacids, )%# *loc8ers, phen!toin, rifampin, and dd . =etocona;ole can increase the concentration of the follo7ing drugs/ c!closporin, terfenadine, astemi;ole, and saquina,ir.

!lucona,ole6 Etria,oleF Pharmaco8inetics/ A*sorption is essentiall! complete, 7ith &$%946 *ioa,aila*ilit!. (ood does hinder a*sorption. )igh le,els of flucona;ole can *e found in most *od! fluids and tissues1 it enters the C"( e:tremel! 7ell. 3nli8e 8etocona;ole, flucona;ole is a*out &46 e:creted unchanged in the urine. -he dose must *e ad9usted in patients 7ith se,ere renal d!sfunction. )emodial!sis remo,es a*out $46 of the drug. Administration/ Goth P5 and .. 3nli8e 8etocona;ole, flucona;ole is highl! 7ater solu*le and can *e administered intra,enousl! in patients 7ho are too ill to ta8e medication orall!. "pectrum of Acti,it!/ (lucona;ole has in ,itro acti,it! against fungi that is similar to 8etocona;ole. -he main ad,antages of this a;ole are penetration into the C"( to pro,ide co,erage of meningeal infections and high urine concentrations for Candida 3- s.

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Ad,erse Effects/ (lucona;ole appears to ha,e less ad,erse effects that 8etocona;ole. -he most common side effects are gastrointestinal, especiall! nausea. A*dominal pain, ,omiting, and diarrhea ma! also occur. )eadache and s8in rashes ha,e also *een reported. Mild transient increases in li,er function tests ha,e *een reported also. n contrast to 8etocona;ole, flucona;ole does not interfere 7ith s!nthesis of testosterone or 7ith adrenocortical function. +rug nteractions/ (lucona;ole inhi*its the meta*olism and there*! increases plasma concentrations and potentiates the effects of phen!toin, orall! administered h!pogl!cemic agents, and 7arfarin. C!closporine le,els ha,e *een increased in some patients. Concurrent administration of rifampin decreases the serum concentration of flucona;ole.

Itracona,ole6 Pharmaco8inetics/ tracona;ole is 7ell a*sor*ed, 7ith a*sorption enhanced *! the presence of food in the stomach. Appro:imatel! 996 of the drug in serum is *ound to protein. tracona;ole is meta*oli;ed entirel! *! the li,er and e:creted in the feces. 5nl! a minimal amount of drug is measura*le in urine and C"(. Fo ad9ustment of dosage is necessar! in patients 7ith renal failure1 7hether ad9ustment is necessar! in hepatic d!sfunction is unclear and therefore should *e monitored. Feither hemodial!sis nor peritoneal dial!sis alters serum concentrations of itracona;ole. Administration/ Currentl! itracona;ole is onl! a,aila*le in oral dosage forms. "pectrum of Acti,it!/ -he spectrum of acti,it! of itracona;ole is similar to the other a;oles. -he ma9or ad,antage o,er 8etocona;ole and flucona;ole is good acti,it! against Aspergillus. Ad,erse Effects/ -he most common side effects of itracona;ole also include the gastrointestinal s!stem/ nausea, a*dominal discomfort, and diarrhea. )eadache, pruritis, and di;;iness ha,e *een reported occasionall!. Mild re,ersi*le increases in li,er en;!mes ha,e *een noted, *ut no reports of serous hepatoto:icit!. 3nli8e 8etocona;ole, itracona;ole has a minimal inhi*itor! effect on the s!nthesis of testosterone or cortisol1 ho7e,er, reports ha,e descri*ed a possi*le s!ndrome of mineralocorticoid e:cess manifested *! h!po8alemia,

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h!pertension, and edema. mpotence has de,eloped in a fe7 patients, *ut serum testosterone le,els 7ere found to *e normal. +rug nteractions/ Coadministration of rifampin or phen!toin ma! lo7er the plasma concentrations of itracona;ole. tracona;ole has *een reported to increase c!closporine le,els in some *ut not all patients recei,ing *oth drugs.

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BACTERIAL RESISTANCE
!$&a 0. )e dla d, )ha#%.D. GOALS AND OBCECTIVES +. the e d of thi& lect$#e the &t$de t &ho$ld be able to= 1. De&c#ibe the %echa i&%& i 3ol3ed i bacte#ial #e&i&ta ce of a tibiotic&. 2. De&c#ibe the 3a#io$& -a.& i -hich bacte#ia ac?$i#e #e&i&ta ce. 3. 0i&t #i&8 facto#& that co t#ib$te to the de3elo"%e t of #e&i&ta ce. 4. (de tif. the #e&i&ta t bacte#ia that ha3e #ece tl. e%e#'ed a d the #e&$lti ' the#a"e$tic dile%%a& a d cli ical co &e?$e ce&. 5. De&c#ibe i te#3e tio & that %a. "#e3e t the e%e#'e ce a d &"#ead of #e&i&ta t o#'a i&%&. INTRODUCTION >ece tl. the#e ha& bee co &ide#able i te#e&t i the e%e#'e ce of bacte#ial #e&i&ta ce. +acte#ial #e&i&ta ce -a& #eco' i5ed &ho#tl. afte# a tibiotic& -e#e i t#od$ced. The &$lfo a%ide& -e#e the fi#&t a ti%ic#obial a'e t& to be $&ed cli icall.. The. -e#e fi#&t $&ed i 1935, -ith #e&i&ta ce doc$%e ted b. 1939. Co%%e#cial "#od$ctio of "e icilli be'a i 1941, -ith #e"o#t& of "e icilli i acti3atio b. &ta"h.lococci a""ea#i ' b. 1944. (t -a& the #eco' itio of bacte#ial #e&i&ta ce that led to the de3elo"%e t of e- a tibiotic&= the &e%i&. thetic "e icilli & i the 1950N& a d 1960N&, the e9te ded &"ect#$% ce"halo&"o#i &, %o obacta%&, a d ca#ba"e e%& i the 1970N& a d 1980N&, a d fl$o#o?$i olo e& i the 1980N& a d 1990N&. >e&i&ta ce -o$ld de3elo" &oo afte# each e- a tibiotic beca%e a3ailable. The c$##e t c#i&i& diffe#& f#o% tho&e of the "a&t beca$&e &e3e#al diffe#e t o#'a i&%& a#e i 3ol3ed a d beca$&e the#e a#e o e- a'e t& c$##e tl. a3ailable, o# o the ho#i5o , to t#eat the&e #e&i&ta t %ic#oo#'a i&%&. )#oble%& -ith #e&i&ta ce ha3e beco%e &o co%%o that %a . e9"e#t& belie3e Gthe 1990N& i& be'i i ' to loo8 li8e the "#e-a tibiotic e#aG. MECHANISMS O= RESISTANCE +acte#ial #e&i&ta ce to a tibiotic the#a". %a. be ca$&ed b. &e3e#al %echa i&%&. Cli icall. i%"o#ta t #e&i&ta ce i& ca$&ed "#i%a#il. b. th#ee %echa i&%&= 1. a tibiotic i acti3atio 2. alte#atio of the ta#'et &ite 3. dec#ea&ed acce&& to &ite of actio

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A tibiotic ( acti3atio = :1; b-lacta%a&e&= The be&t 8 o- e9a%"le of e 5.%atic i acti3atio of a tibiotic& i& that of the b-lacta%a&e&. The&e e 5.%e& #e de# b-lacta% a tibiotic& i acti3e b. clea3i ' the lacta% #i ' of &$&ce"tible a tibiotic& 3ia a i##e3e#&ible h.d#o9.latio of the a%ide bo d. b-lacta%a&e& a#e a co%%o #e&i&ta ce %echa i&% a%o ' *#a%-"o&iti3e a d *#a%- e'ati3e o#'a i&%&, both ae#obic a d a ae#obic. *#a%-"o&iti3e bacte#ia "#od$ce la#'e ?$a titie& of b-lacta%a&e -hich the. %$&t e9c#ete i to thei# e9te# al e 3i#o %e t to i acti3ate the ta#'eted a tibiotic befo#e it #eache& the o#'a i&%. Ao# *#a%- e'ati3e bacte#ia, the b-lacta%a&e& a#e co tai ed i a "e#i"la&%ic &"ace, a d %a. be "#od$ced i %$ch &%alle# ?$a titie&. The#e a#e $%e#o$& b-lacta%a&e& a d &e3e#al cla&&ificatio &che%e& ha3e bee de&c#ibed i a effo#t to '#o$" e 5.%e& -ith &i%ila# "h.&ical a d che%ical "#o"e#tie&. @ til #ece tl. the %o&t -idel. $&ed cla&&ificatio &.&te% -a& o e "#o"o&ed b. >ich%o d a d !.8e&. Thi& &.&te% co &i&t& of 6 cla&&e& ba&ed o the follo-i ' cha#acte#i&tic&= 1. 2. 3. 4. 5. 'e etic locatio :ch#o%o&o%e o# "la&%id; 'e e e9"#e&&io :i d$cible o# co &tit$ti3e; "#i%a#. "#od$ce#& :%ic#oo#'a i&%&; i hibitio b. cla3$la ate a d &$lbacta% %a<o# &$b&t#ate& :a tibiotic cla&&;

C$##e tl. the "#efe##ed &che%e fo# cla&&ificatio of b-lacta%a&e& i& the o e de3elo"ed b. +$&h. The follo-i ' table li&t& &o%e of the cha#acte#i&tic&, a& -ell a& e9a%"le&, of the '#o$"& i thi& cla&&ificatio &che%e. G$ %) P$e!e$$ed S%2#"$a"e# Inhi2i"i n 2+ C1a*%1anic Acid E4am)1e# 1 2a 2b 2bN 2c Ce"halo&"o#i & )e icilli & Ce"halo&"o#i &, )e icilli & Ce"halo&"o#i &, )e icilli & )e icilli & /o Ee& Ee& Ee& Ee& Ch#o%o&o%al e 5.%e& f#o% *#a%- e'ati3e bacte#ia *#a%-"o&iti3e "e icilli a&e& T6M-1, T6M-2 T6M-3, T6M-5 )!6-1, )!6-3

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2d 2e 3 4

)e icilli & Ce"halo&"o#i & 1a#iable )e icilli &

Ee& Ee& /o /o

OIA-1, )!6-2 e 5.%e f#o% P%ot&$s 3$ ,a%is e 5.%e f#o% St&(ot%opho*o(as *a tophi ia e 5.%e f#o% Ps&$'o*o(as "&pa"ia

+$&h '#o$" 2= The b-lacta%a&e& "#od$ced b. *#a%- e'ati3e bacte#ia a#e the %o&t f#e?$e tl. e co$ te#ed a d ha3e bee &t$died the %o&t. The %a<o#it. of the&e "la&%id-%ediated e 5.%e& a#e %e%be#& of '#o$" 2. The %o&t co%%o of thi& '#o$" a#e the T6M a d !41 e 5.%e&. The. ca h.d#ol.5e %a . "e icilli & a d the fi#&t-'e e#atio ce"halo&"o#i &. The thi#d-'e e#atio ce"halo&"o#i &, %o obacta%&, a d ca#ba"e e%& a#e 'e e#all. #e&i&ta t to i acti3atio b. thi& '#o$" of e 5.%e&. +$&h '#o$" 1= The b-lacta%a&e& belo 'i ' to '#o$" 1 a#e a co ce# beca$&e the. a#e able to h.d#ol.5e all c$##e tl. %a#8eted b-lacta%& e9ce"t the ca#ba"e e%&. The&e e 5.%e& a#e ch#o%o&o%all. %ediated, b$t a#e 'e e#all. ot "#od$ced i hi'h ?$a tit.. 69te ded-&"ect#$% b-lacta%a&e& :6!+0&;= Thi& '#o$" of e 5.%e& i& e%e#'i ' a& a %a<o# "#oble% i the @.!. The&e b-lacta%a&e& a#e 3a#ia t& of the co%%o T6M-1, T6M-2, a d !41-1 e 5.%e&. The %ai "#od$ce# i& K &.si& a p(&$*o(ia, b$t the e 5.%e i& fo$ d i othe# co%%o *#a%- e'ati3e "atho'e &, &$ch a& E. "o i a d E(t&%o.a"t&%. The&e e 5.%e& a#e "la&%id %ediated, b$t ha3e a e9"a ded &$b&t#ate "#ofile that i cl$de& the thi#d-'e e#atio ce"halo&"o#i &. @ til #ece tl. the&e e 5.%e& -e#e i hibited b. the b-lacta%a&e i hibito#& cla3$la ic acid, &$lbacta%, a d ta5obacta%. /e- 6!+0& :T6M-10; ha3e bee ide tified -hich a#e #e&i&ta t to all b-lacta%& e9ce"t the ca#ba"e e%&. ( the f$t$#e, "#oble%& a#e e9"ected -ith a othe# cla&& of b-lacta%a&e&, the %etallo-e 5.%e&. The&e b-lacta%a&e& diffe# f#o% othe# e 5.%e& i that the. h.d#ol.5e the b-lacta% #i ' -ith a acti3e-&ite %etal, $&$all. 5i c. The&e b-lacta%a&e& a#e "#od$ced "#i%a#il. b. o "atho'e &, -ith the %ai e9ce"tio bei ' St&(ot%opho*o(as *a tophi ia. Thei# &$b&t#ate& i cl$de the ca#ba"e e%&. The %o obacta%& a""ea# to be #e&i&ta t to %etallo-e 5.%e h.d#ol.&i&. b-lacta%a&e "#od$ctio %a. be co &tit$ti3e o# i d$cible. Mith co &tit$ti3e "#od$ctio , a co &ta t ba&al le3el of e 5.%e i& "#od$ced that i& ot affected b. e9te# al &ti%$li, &$ch a& e9"o&$#e to a tibiotic&. ( d$cible b-lacta%a&e& a#e "#od$ced afte# e9"o&$#e to ce#tai b-lacta% a tibiotic& :i%i"e e%, cefo9iti ;. ( d$ctio ca #e&$lt i la#'e i c#ea&e& i b-lacta%a&e "#od$ctio , -ith ce#tai d#$'& ha3i ' a hi'he# "ote tial fo# i d$ci ' e 5.%e& tha othe#&. Thi& i& $&$all. ot cli icall. #ele3a t beca$&e bacte#ia a#e ?$ic8l. 8illed b. the&e bacte#icidal a'e t& befo#e &i' ifica t i d$ctio ca occ$#. )#oble%& %i'ht occ$# -ith o#'a i&%& ca"able of "#od$ci ' +$&h '#o$" 1 b-lacta%a&e&, #e&$lti ' i the "o&&ible &electio of co &tit$ti3e %$ta t&

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d$#i ' t#eat%e t. The&e %$ta t& co$ld #e&$lt i the "e#%a e t "#od$ctio of la#'e ?$a titie& of b-lacta%a&e i de"e de t of a tibiotic e9"o&$#e. Thi& t."e of co &tit$ti3e b-lacta%a&e "#od$ctio i& te#%ed &table de#e"#e&&io a d i& a&&ociated -ith #a"id e%e#'e ce of #e&i&ta ce to -ea8 i d$ce#&. :2; Othe# Modif.i ' 6 5.%e&= 6 5.%atic i acti3atio i& al&o the %a<o# #e&i&ta ce %echa i&% to-a#d a%i o'l.co&ide&. The&e a'e t& ca be %odified a d the#eb. i acti3ated b. acet.latio , "ho&"ho#.latio , o# ade .latio . The e 5.%e& ca"able of i acti3ati ' a%i o'l.co&ide& a#e "#e3ale t i both *#a%-"o&iti3e :S. a$%&$s/ S. )a&"a is/ S. p(&$*o(ia; a d *#a%- e'ati3e bacte#ia :6 te#obacte#iaceae a d P. a&%$,i(osa;. A othe# e9a%"le of a a tibiotic that ca be i acti3ated b. acet.latio i& chlo#a%"he icol. +oth *#a%-"o&iti3e a d *#a%- e'ati3e o#'a i&%& a#e able to "#od$ce a e 5.%e :chlo#a%"he icol t#a &acet.la&e; -hich bi d& h.d#o9.l '#o$"& o the a tibiotic. The acet.lated chlo#a%"he icol bi d& le&& a3idl. to the 50! &$b$ it of bacte#ial #ibo&o%e&. Alte#atio of the Ta#'et !ite= :1; b-lacta% a tibiotic& The ta#'et &ite of b-lacta% a tibiotic& i& a '#o$" of e 5.%e& :"e"tido'l.ca t#a &"e"tida&e&; 8 o- a& the "e icilli -bi di ' "#otei & :)+)&;. The&e e 5.%e& o# )+)& a#e 3ital fo# &. the&i& a d %ai te a ce of the bacte#ial cell -all. +i di ' of a b-lacta% a tibiotic to a )+) #e&$lt& i #a"id cell death. !o%e bacte#ia ha3e ada"ted b. cha 'i ' the &t#$ct$#e of thei# )+)& &o that the. bi d le&& a3idl. to the&e a tibiotic&. Thi& i& the %echa i&% of %ethicilli -#e&i&ta t &ta"h.lococci, -hich "#od$ce a alte#ed )+)2 :)+)2a o# 2N;. Thi& ha& al&o bee de&c#ibed fo# S. p(&$*o(ia&. :2; Othe# A tibiotic& Othe# cla&&e& of a tibiotic& al&o e co$ te# #e&i&ta ce 3ia alte#atio & i ta#'et &ite. A alte#ed D/A '.#a&e ca$&e& #e&i&ta ce to the ?$i olo e&. Mac#olide& a d cli da%.ci a#e i hibited b. the fo#%atio of alte#ed #ibo&o%al >/A. >e&i&ta ce to #ifa%"i occ$#& follo-i ' alte#atio & i >/A "ol.%e#a&e. >e&i&ta ce to t#i%etho"#i% a d &$lfo a%ide& al&o occ$#& -he ta#'et &ite& a#e %odified. A alte#ed dih.d#o"te#oic &. theta&e that bi d& )A+A %o#e a3idl. tha &$lfo a%ide& a d a alte#ed dih.d#ofolate #ed$cta&e -ith #ed$ced affi it. fo# t#i%etho"#i% acco$ t fo# %$ch of the #e&i&ta ce &ee -ith the&e t-o a'e t&. >e&i&ta ce to 3a co%.ci occ$#& 3ia a alte#ed cell -all "e"tide. 1a co%.ci i hibit& cell -all &. the&i& b. bi di ' to the D-ala .l-Dala i e te#%i $&, the#eb. "#e3e ti ' the e9te &io of the cell -all. The "#od$ctio of a e- "#otei that "#e3e t& thi& bi di ' i& the %o&t

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co%%o %echa i&% of 3a co%.ci #e&i&ta ce. Mhile co%%o a%o ' e te#ococci, thi& #e&i&ta ce %echa i&% ha& ot :.et; bee t#a &fe##ed to S. a$%&$s. Dec#ea&ed Acce&& to Ta#'et !ite= :Dec#ea&ed $"ta8e o# i c#ea&ed effl$9; *#a%- e'ati3e bacte#ia ha3e a o$te# "ho&"holi"id2li"o"ol.&accha#ide %e%b#a e -ith "o#e&, called "o#i &, -hich allo- &o%e a tibiotic& acce&& to the bacte#ial cell -all. +. %odif.i ' the&e "o#i cha el& i the o$te# %e%b#a e, bacte#ia ca "#e3e t 3a#io$& a tibiotic& f#o% #eachi ' the ta#'et &ite. !o%e a tibiotic& 'ai acce&& to bacte#ial cell& th#o$'h e e#'.-de"e de t "#oce&&e&. Thi& i cl$de& the a%i o'l.co&ide&, the ?$i olo e&, t#i%etho"#i%, chlo#a%"he icol, the b-lacta%&, a d the tet#ac.cli e&. Mith tet#ac.cli e&, #e&i&ta ce ca al&o de3elo" d$e to i c#ea&ed effl$9 3ia acti3e t#a &"o#t of tet#ac.cli e f#o% the cell, a& &ee -ith '#o$" A beta &t#e"tococci. Thi& %echa i&% of #e&i&ta ce i& al&o &ee -ith ?$i olo e& a d S. a$%&$s, a d -ith e#.th#o%.ci a d S. &pi'&%*i'is. ACDUISITION O= RESISTANCE >e&i&ta ce ca be eithe# i t#i &ic o# ac?$i#ed. Ma . bacte#ia "o&&e&& i t#i &ic #e&i&ta ce 3ia i bo# 'e etic %ate#ial. Mo&t cli ical "#oble%& -ith bacte#ial #e&i&ta ce ha3e act$all. e3ol3ed d$e to cha 'e& i 'e etic i fo#%atio . +acte#ia ca %$tate to #e&i&ta t fo#%&, ho-e3e#, %$tatio acco$ t& fo# a 3e#. &%all "o#tio of #e&i&ta ce. Mo&t bacte#ia ac?$i#e #e&i&ta ce th#o$'h the ac?$i&itio of e- 'e etic %ate#ial. *e e& fo# #e&i&ta ce %a. be o a ch#o%o&o%e, "la&%id, o# t#a &"o&o . Mo&t #e&i&ta ce 'e e& a#e ca##ied o "la&%id&, -hich a#e e9t#ach#o%o&o%al "iece& of D/A. )la&%id& ca #e"licate -ithi the bacte#ial cell b$t a#e li%ited i t#a &fe# bet-ee bacte#ial cla&&e& :ie, ot f#o% '#a%-"o&iti3e to '#a%- e'ati3e o#'a i&%&;. T#a &"o&o & ha3e a b#oade# #a 'e of ho&t& tha "la&%id& a d %a. "la. a '#eate# #ole i di&&e%i atio of #e&i&ta ce bet-ee &"ecie&. T#a &"o&o & a#e "iece& of D/A that ha3e the abilit. to G<$%"G f#o% "la&%id to "la&%id, ch#o%o&o%e to ch#o%o&o%e, o# bet-ee a "la&%id a d ch#o%o&o%e :t#a &"o&itio ;. >e&i&ta ce ca be &"#ead f#o% o#'a i&% to o#'a i&% b. co <$'atio , t#a &d$ctio , o# t#a &fo#%atio . +oth "la&%id& a d t#a &"o&o & ca di#ectl. t#a &fe# 'e etic %ate#ial 3ia co <$'atio . T#a &fo#%atio i 3ol3e& $"ta8e of f#ee D/A f#o% the e 3i#o %e t, -hile t#a &d$ctio #e?$i#e& bacte#io"ha'e& fo# e9cha 'e of 'e etic %ate#ial. RIS9 =ACTORS A 3a#iet. of #i&8 facto#& ha3e bee ide tified -hich a#e #e&"o &ible fo# the e%e#'e ce a d &"#ead of #e&i&ta t o#'a i&%&. :1; A tibiotic $&e=

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A tibiotic& %a8e co ditio & fa3o#able fo# o3e#'#o-th of &o%e %ic#oo#'a i&%&, i cl$di ' tho&e that "o&&e&& %echa i&%& of d#$' #e&i&ta ce. @ de# d#$'-f#ee co ditio &, the 3a#io$& o#'a i&%& i a 'i3e locatio :i.e., o#%al flo#a; 8ee" o e a othe# i chec8. (f all o#'a i&%& a#e &$&ce"tible, the i t#od$ctio of a tibiotic& -ill affect the e ti#e the "o"$latio . 4o-e3e#, if a #e&i&ta t o#'a i&% i& "#e&e t, a tibiotic& -ill c#eate G&electi3e "#e&&$#eG fa3o#i ' the '#o-th of that o#'a i&%. +. 8illi ' off the &e &iti3e &t#ai &, the a tibiotic -ill facilitate the &$#3i3al of the #e&i&ta t o#'a i&%&. The %o#e a tibiotic& a#e $&ed, the fa&te# #e&i&ta t o#'a i&%& -ill e%e#'e. A tibiotic& ot o l. "#o%ote the e%e#'e ce of #e&i&ta t "atho'e &, the. al&o fo&te# o3e#'#o-th of o#%al flo#a that "o&&e&& %echa i&%& fo# #e&i&ta ce. :2; >e&e#3oi#& fo# #e&i&ta ce = A ti%ic#obial #e&i&ta ce i $#&i ' ho%e& a d da.-ca#e ce te#& i& -ell-8 o- . ( $#&i ' ho%e&, #e&i&ta ce ot o l. e3ol3e&, b$t i& li8el. i c#ea&ed b. the t#a &fe# of "atie t& al#ead. colo i5ed b. #e&i&ta t o#'a i&%& f#o% ho&"ital&. +oth da.-ca#e ce te#& a d a i%al feed lot& #e"#e&e t othe# "ote tial #e&e#3oi#& fo# #e&i&ta t o#'a i&%&. ( the&e &etti '&, #e&i&ta ce i& li8el. &elected fo# a d "e#"et$ated b. the hi'h $&e of a tibiotic& a d the ea&e -ith -hich o#'a i&%& ca be &"#ead. >e&i&ta ce i& al&o hi'h i %a . de3elo"i ' co$ t#ie&, e3e i health. i di3id$al&, a d ca be &"#ead to othe# co$ t#ie&. Thi& i& d$e i "a#t to $ co t#olled $&e of a tibiotic&, a d to "#oble%& -ith &a itatio -hich "#o%ote& the &"#ead of bacte#ia. :3; Medical ad3a ce&= )#o'#e&& i the t#eat%e t of %a . di&ea&e& ha& led to a i c#ea&e i life &"a of 10-20 .ea#& fo# "atie t& -ho -o$ld "#e3io$&l. had died f#o% thei# di&ea&e. (%"#o3e%e t& i t#a$%a a d &$#'e#. ha3e led to i c#ea&ed &$#3i3al #ate&. !i' ifica t ad3a ce& ha3e bee %ade i the a#ea& of o colo'. a d t#a &"la tatio . A& a #e&$lt of the 3a#io$& %edical ad3a ce&, "eo"le a#e li3i ' lo 'e#. Co &e?$e tl., -ith ad3a ced a'e, ch#o ic di&ea&e, o# i%%$ o&$""#e&&io , "eo"le ca be %o#e &$&ce"tible to bacte#ial i fectio &, #e&$lti ' i '#eate# $&e of a ti%ic#obial a'e t&. :4; !ocietal cha 'e&= ( c#ea&ed $&e of da. ca#e ce te#&, $#&i ' ho%e&, a d e9te ded ca#e facilitie& "#o%ote the e%e#'e ce a d &"#ead of bacte#ial #e&i&ta ce. Mo#ld-ide &"#ead of #e&i&ta ce ha& occ$##ed d$e to the i c#ea&ed %obilit. of toda.N& &ociet.. A othe# &i' ifica t "#oble% i& the #ed$ctio i "$blic health &e#3ice& that a#e a3ailable to %o ito# a d co t#ol the &"#ead of #e&i&ta ce. CURRENT PROBLEMS

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/o&oco%ial "atho'e &= 1. Methicilli -#e&i&ta t &t#ai & o- %a8e $" 60-90L of all i&olate& of coa'$la&e- e'ati3e &ta"h.lococci, the %o&t f#e?$e t ca$&e of i fectio & #elated to i t#a3a&c$la# cathete#& a d "#o&thetic de3ice&. Data f#o% 1995 at @(C &ho-& 72L of all coa'$la&e- e'ati3e &ta"h.lococci &t#ai & te&ted -e#e #e&i&ta t to %ethicilli . 2. ( la#'e teachi ' ho&"ital&, the "#o"o#tio of %ethicilli -#e&i&ta t S. a$%&$s :M>!A; i c#ea&ed f#o% 8L to 40L i 1992. Data f#o% 1995 at @(C &ho-& 30L of all S. a$%&$s &t#ai & te&ted -e#e #e&i&ta t to %ethicilli . 3. ( the @.!., e te#ococci ha3e beco%e the &eco d %o&t co%%o o#'a i&% ca$&i ' ho&"ital-ac?$i#ed i fectio &. 1a co%.ci -#e&i&ta t E. )a&"i$* -a& fi#&t #e"o#ted i 6$#o"e i 1987 a d i the @.!. i 1989. +. 1993, 14L of e te#ococcal i&olate& f#o% "atie t& i (C@& -e#e #e&i&ta t to 3a co%.ci , 88L of the &t#ai & -e#e al&o #e&i&ta t to b-lacta%&, a%i o'l.co&ide&, fl$o#o?$i olo e&, chlo#a%"he icol, a d teico"la i . 4. /o3el, "la&%id-bo# e, e9te ded-&"ect#$% b-lacta%a&e& ca"able of i acti3ati ' all "e icilli , ce"halo&"o#i , a d %o obacta% a tibiotic& ha3e bee detected i o&oco%ial i&olate& of K &.si& a a d P. a&%$,i(osa. Co%%$ it.-ac?$i#ed "atho'e &= 1. >e&i&ta ce ha& bee #eco' i5ed a& a "#oble% fo# a $%be# of co%%$ it.-ac?$i#ed "atho'e &, i cl$di ' N. ,o(o%%ho&a&, Sa *o(& a, a d Shi,& a. 2. M$lti"le-d#$' #e&i&ta t M. t$.&%"$ osis ha& e%e#'ed a& a %a<o# co ce# . The i cide ce of T+ ha& bee #i&i ' &i ce 1985 i the @.!., -ith a 18L i c#ea&e &i ce 1992. The %o#talit. of %$lti-d#$' #e&i&ta t &t#ai & i& hi'h, 40-60L i "atie t& -ith o#%al i%%$ it. a d K80L i i%%$ oco%"#o%i&ed "atie t&. 3. S. p(&$*o(ia& ca$&e& &e3e#al &e#io$& a d "ote tiall. life-th#eate i ' di&ea&e&. )e icilli -#e&i&ta t &t#ai & a#e o- 'lobal "atho'e &, -ith #e&i&ta ce to thi#d-'e e#atio ce"halo&"o#i & i c#ea&i 'l. #e"o#ted. CLINICAL CONSEDUENCES O= BACTERIAL RESISTANCE The "ote tial co &e?$e ce& of bacte#ial #e&i&ta ce, e&"eciall. -ide&"#ead %$lti-d#$' #e&i&ta ce, a#e of %a<o# co ce# . The &ce a#io of a "atie t d.i ' f#o% a i fectio ca$&ed b. a %$lti-d#$' #e&i&ta t o#'a i&% i& o- a #ealit.. ( fectio & ca$&ed b. #e&i&ta t &t#ai & of bacte#ia a#e #elated to hi'he# %o#bidit. a d %o#talit.. +acte#ial #e&i&ta ce #e&$lt& i i c#ea&ed health ca#e co&t&. The&e i c#ea&ed co&t& a#e d$e to &$ch facto#& a& i c#ea&ed $tili5atio of labo#ato#. &$&ce"tibilit. te&t&, i c#ea&ed &$#3eilla ce fo# #e&i&ta t o#'a i&%&, hei'hte ed i&olatio #e?$i#e%e t& fo# i fected "atie t&, a d the #e?$i#ed $&e of %o#e e9"e &i3e, a d "o&&ibl. %o#e to9ic, a tibiotic&. INTERVENTIONS

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The &"#ead of #e&i&ta t "atho'e & ca be c$#tailed b. %ea & of i te &i3e i fectio -co t#ol %ea&$#e&, co t#ol of a tibiotic $&e, a d &$""o#t f#o% the %ic#obiolo'. labo#ato#.. 6 fo#ci ' ba&ic h.'ie e "#oced$#e& i the ho&"ital i& a %a<o# "#oble%. The "#i ci"le ca$&e fo# &"#ead of i fectio & i ho&"ital& i& o co%"lia ce -ith ha d -a&hi ' a d cha 'i ' 'lo3e& afte# &eei ' "atie t&. )ha#%aci&t& eed to be fa%ilia# -ith, &$""o#t, a d "#actice the i &tit$tio N& i fectio co t#ol "olicie&. +a##ie# i&olatio a d f#e?$e t ha d-a&hi ' a#e -ell-8 o- , effecti3e %ea&$#e& i "#e3e ti ' the &"#ead of i fectio &. !$#3eilla ce :i co <$ ctio -ith the %ic#obiolo'. labo#ato#.; ca ide tif. "atie t& -ith #e&i&ta t %ic#oo#'a i&%& &o that affected i di3id$al& ca be i&olated. )ha#%aci&t& &ho$ld -o#8 clo&el. -ith the %ic#obiolo'. lab ot o l. to detect #e&i&ta ce "#oble%& ea#l., b$t al&o to hel" a3e#t a d co t#ol the%. Co t#ol of the $&e of a tibiotic& i& e9t#e%el. i%"o#ta t, b$t ca be 3e#. diffic$lt to achie3eTTT !t#ict fo#%$la#ie& a#e o e %ea & of co t#ol. 1a#io$& tactic& ha3e bee $&ed i the "a&t. !o%e i &tit$tio & ha3e li%ited the &$&ce"tibilit. #e&$lt& #e"o#ted to cli icia & to the a##o-e&t&"ect#$%, lea&t-e9"e &i3e a'e t& to -hich the o#'a i&% i& &$&ce"tible. Ma . i &tit$tio & #o$ti el. li%it a tibiotic $&e to tho&e a'e t& -ith a##o- &"ect#$%& a d lo- i%"act o #e&i&ta ce, -ith a""#o3al f#o% i fectio$& di&ea&e& o# "ha#%ac. #e?$i#ed to $&e %o#e b#oad-&"ect#$%, a d %o#e e9"e &i3e, a'e t&. !o%e i 3e&ti'ato#& ha3e &$''e&ted #otati ' a tibiotic& befo#e #e&i&ta ce e%e#'e& a d &"#ead& a& a -a. to dec#ea&e the &electi3e "#e&&$#e fo# a &"ecific a'e t. )ha#%aci&t& ha3e a ce t#al #ole i co t#olli ' a tibiotic $&a'e -ithi thei# i &tit$tio &. A 8e. #ole i& to "#e3e t the i a""#o"#iate $&e of a tibiotic&. 69te ded $&e of &$#'ical "#o"h.la9i&, e9ce&&i3e $&e of b#oad-&"ect#$% a'e t&, a d i co%"lete o# i a""#o"#iate :&$bthe#a"e$tic, etc; the#a". all lead to the de3elo"%e t of #e&i&ta ce. RE=ERENCES 1. +$&h 7. Cha#acte#i5atio of b-lacta%a&e&. A ti%ic#ob A'e t& Che%othe# 1989, 33=259-263. 2. /e$ 4C. The c#i&i& i a tibiotic #e&i&ta ce. !cie ce 1992,257=1064-1073. 3. +o&&o CA. A tibiotic #e&i&ta ce i bacte#ia. ( = )!A) !.llab$&, Mod$le 3, ( fectio$& Di&ea&e&,+oo8 A. A%e#ica Colle'e of Cli ical )ha#%ac., 7a &a& Cit., MO. 1995=89-101. 4. Da 5i'e# 04, )e dla d !0. +acte#ial #e&i&ta ce to b-lacta% a tibiotic&. A% C 4ealth-!.&t )ha#% 1995,52:&$""l 2;=!3-!8. 5. 7$ i CM. >e&i&ta ce to a ti%ic#obial d#$'& - a -o#ld-ide cala%it.. A ( te# Med 1993,118=557-561. 6. M$##a. +6. )#oble%& a d dile%%a& of a ti%ic#obial #e&i&ta ce. )ha#%acothe#a". 1992,12:6 )t 2;=86!-93!. 7. Cacob. *A, A#che# *0. /e- %echa i&%& of bacte#ial #e&i&ta ce to a ti%ic#obial a'e t&. / 6 ' C Med 1991,324=601-612. 8. /e$ 4C. The "#oble% of bacte#ial #e&i&ta ce. Challe 'e& i ( fect Di& :/e-&lette#; 1993,1=1-8.

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9. Madd$9 M!. 6ffect& of b-lacta%a&e-%ediated a ti%ic#obial #e&i&ta ce= the #ole of b-lacta%a&e i hibito#&. )ha#%acothe#a". 1991,11:2 )t 2;=40!-50!. 10. To%a&5 A. M$lti"le a tibiotic-#e&i&ta t "atho'e ic bacte#ia. A #e"o#t o the >oc8efelle# @ i3e#&it. -o#8&ho". / 6 ' C Med 1994,330=1247-1252. 11. *old 4!, Moelle#i ', >C, C#. A ti%ic#obial-d#$' #e&i&ta ce. / 6 ' C Med 1996,335=1445-1453.

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ANAEROBIC A)ENTS G INTRAABDOMINAL IN!ECTIONS

)a$la A. Teich e#, )ha#%.D. G a1# and O2;ec"i*e#& +. the e d of thi& lect$#e, the &t$de t &ho$ld be able to=

1. 2. 3. 4. 5. 6. 7. 8.

De&c#ibe the %echa i&% of actio a d &"ect#$% of acti3it. fo# cli da%.ci a d %et#o ida5ole. De&c#ibe the "ha#%aco8i etic "a#a%ete#& a d the %a<o# cli ical i dicatio & fo# $&e of cli da%.ci a d %et#o ida5ole. 0i&t the %a<o# ad3e#&e effect& a d d#$' i te#actio & fo# cli da%.ci a d %et#o ida5ole. De3i&e a #atio al t#eat%e t "la fo# the $&e of cli da%.ci o# %et#o ida5ole ba&ed o the cli ical i dicatio a d "atie t &"ecific cha#acte#i&tic&. /a%e the %o&t co%%o bacte#ia that a#e &ee i the 3a#io$& t."e& of "e#ito iti& a d i a i t#aado%i al ab&ce&& De&c#ibe the cli ical %a ife&tatio & "#e&e t i "atie t& -ith eithe# "e#ito iti& o# i t#aabdo%i al ab&ce&& De&c#ibe the %o&t co%%o a ti%ic#obial #e'i%e & $&ed to t#eat "e#ito iti& a d i t#aaabdo%i al ab&ce&& a d thei# #atio al fo# $&e De3i&e a #atio al the#a"e$tic "la fo# t#eat%e t of "e#ito iti& o# i t#aabdo%i al ab&ce&& ba&ed o cli ical "#e&e tatio a d "atie t &"ecific cha#acte#i&tic&.

Re7%i$ed Readin/& )ha#%acothe#a".. A )atho"h.&iolo'ic A""#oach. 3#d 6ditio , 1996. Cha"te# 107. ( t#aabdo%i al ( fectio &. )a'e& 2145-2161. o# 2 d 6ditio . 1992. Cha"te# 102. )a'e& 1666-1679.

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ANAEROBIC A)ENTS
P#$I I%%I$
Co3e#& Go#al a ae#obe&G o# a ae#obe& abo3e the dia"h#a'% :!ee )e cilli ote&;.

%I$D&M' I$
MECHANISM O= ACTION +i d& to 50! #ibo&o%e a d i hibit& "#otei &. the&i&. Ca be 2ac"e$i #"a"ic o# 2ac"e$icida1 de"e di ' the the bacte#ial &"ecie&, i oc$l$% a d co ce t#atio of the a tibiotic a3ailable at the &ite of i fectio . SPECTRUM O= ACTIVITY Ae$ 2ic G$am P #i"i*e C cci - acti3e a'ai &t st%&pto"o""i, i cl$di ' 0! h&*o +ti" st%&pto"o""$s/ *i"%oa&%ophi i" st%&pto"o""i a d %o&t p(&$*o"o""i. Al&o acti3e a'ai &t %o&t S. a$%&$s, e9ce"t M>!A. /ot acti3e a'ai &t e(t&%o"o""i. G$am Ne/a"i*e Ae$ 2e# - ot acti3e a'ai &t the&e o#'a i&%&. Anae$ 2e# - Cli da%.ci i& acti3e a'ai &t %o&t a ae#obic '#a%-"o&iti3e cocci :p&ptost%&pto"o""$s spp.; a d '#a%- e'ati3e bacilli :0a"t&%oi'&s/ P%&3ot& a/ F$so.a"t&%i$* spp.;. *ood acti3it. a'ai &t 0. )%a,i is, altho$'h #e&i&ta ce i& i c#ea&i '. O"he$ - Ch a*+'ia t%a"ho*atis/ To-op as*a ,o('ii/ P(&$*o"+stis "a%i(ii. PHARMACO9INETICS Mell ab&o#bed :90L; f#o% the *( t#act. Co ce t#ate& -ell i %o&t ti&&$e& 6IC6)T C!A. Metaboli5ed i the li3e# a d %etabolite& %o&tl. eli%i ated i the bile. T122 2-2.5 ho$#&. /o do&a'e ad<$&t%e t #e?$i#ed i #e al fail$#e, ho-e3e# ad<$&t%e t %a. be ece&&a#. i "atie t& -ith &e3e#e li3e# i%"ai#%e t. CLINICAL USE O= CLINDAMYCIN 1. In"$aa2d mina1 In!ec"i n# - a""e diciti&, bilia#. t#act i fectio &, i&che%ic bo-el, i t#aabdo%i al ab&ce&&. @&ed i co%bi atio -ith a a%i o'l.co&ide.

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2. Pe1*ic In!ec"i n# - )el3ic i fla%%ato#. di&ea&e, e do%et#iti&. 3. Anae$ 2ic )%1m na$+ in!ec"i n# - &$ch a& a&"i#atio " e$%o ia, l$ ' ab&ce&& o# e%".e%a. 4. !8i 2!oft ti&&$e i fectio &. 5. O&teo%.eliti& - d$e to e9celle t bo e "e et#atio . 6. To9o"la&%o&i& 7. P(&$*o"+stis "a%i(ii " e$%o ia 8. Ac e ADVERSE E==ECTS 1. Dia$$hea - i $" to 20L of "atie t&. Mo&t fea#ed *( co%"licatio i& P#e%d mem2$an %# c 1i"i# ca$&ed b. o3e#'#o-th of C ost%i'i$* 'i))i"i &. ( cide ce #a 'e& f#o% 0.1L-10L. Ca ca$&e &e3e#e dia##hea -hich %a. be life-th#eate i '. 2. Ra#h - i $" to 10L of "atie t&. 3. Inc$ea#ed L=T# - $&$all. %i o#. AVAILABLE PREPARATIONS AND DOSING O$a10 Co%e& a& 75, 150, a d 300 %' ca"&$le&. @&$al do&e #a 'e i& 300-450 %' "o ?6-8 ho$#& de"e di ' o i dicatio a d &e3e#it.. Pa$en"e$a10 A3ailable a& "ho&"hate e&te#. @&$al do&e i& 600-900 %' ?8 ho$#&.

M#TRO$ID&(O%#
MECHANISM O= ACTION Met#o ida5ole i& a 2ac"e$icida1 a'e t. D#$' e te#& bacte#ial cell, -he#e the it#o '#o$" o the d#$' i& #ed$ced b. lo--#edo9 "ote tial elect#o t#a &"o#t "#otei &. The to9ic i te#%ediate "#od$ced act& li8e a f#ee #adical a d ca$&e& da%a'e to the bacte#ial cell b. i te#actio -ith D/A a d othe# %ac#o%olec$le&.

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SPECTRUM O= ACTIVITY Ae$ 2e# - Met#o ida5ole i& ot acti3e a'ai &t t."ical ae#obe& &$ch a& '#a% "o&iti3e cocci o# 6 te#obacte#iaceae. Anae$ 2e# - bacte#icidal a'ai &t a ae#obe& i cl$di ' 0. )%a,i is a d othe# 0a"t&%oi'&s spp/ P%&3ot& a/ C ost%i'i$* spp i cl$di ' C. 'i))i"i &/ F$so.a"t&%i$* a d %o&t &"ecie& of a ae#obic '#a% "o&iti3e cocci. /ot acti3e a'ai &t *i"%oa&%ophi i" st%&pto"o""i. O"he$ - H& i"o.a"t&% p+ o%i P$ " 5 a - E(ta*o&.a histo +ti"a/ Gia%'ia a*. ia/ T%i"ho*o(as 3a,i(a is.PHARMACO9INETICS Ab&o#"tio - #a"id a d al%o&t co%"lete ab&o#"tio f#o% the *( t#act. !e#$% le3el& obtai ed 3ia o#al #o$te a#e co%"a#able to tho&e achie3ed -ith "a#e te#al the#a".. Di&t#ib$tio - "e et#ate& -ell i to %o&t fl$id& a d ti&&$e& i cl$di ' C!A, bo e, b#ai ab&ce&&, "el3ic ti&&$e, etc. Metaboli&%26li%i atio - Metaboli5ed i the li3e# to 5 %etabolite&, i cl$di ' the h.d#o9.%etabolite, -hich ha& &i' ifica t a tia ae#obic acti3it.. )a#e t d#$' a d %etabolite& eli%i ated i the $#i e. T122 O 8 ho$#&. Metabolite& %a. acc$%$late i e d-&ta'e #e al fail$#e &o%e #eco%%e d do&a'e ad<$&t%e t. (f &e3e#e li3e# i%"ai#%e t, $&$al do&e& &ho$ld be dec#ea&ed b. 50L. CLINICAL USES 1. Anae$ 2ic In!ec"i n# - Met#o ida5ole i& $&ed e9te &i3el. fo# &e#io$& a ae#obic i fectio & &$ch a& i t#aabdo%i al a d "el3ic i fectio &, b#ai ab&ce&&, etc. Co &ide#ed the D>@* OA C4O(C6 fo# i fectio & ca$&ed b. +. f#a'ili&. 2. An"i2i "ic-a## cia"ed dia$$hea ca$&ed b. C. difficile. 3. T$ich m na# *a/ini"i# 4. +acte#ial 3a'i o&i& 5. A%ebia&i& - d$e to 6. hi&tol.tica 6. *ia#dia&i& 7. 4elicobacte# ".lo#i

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ADVERSE E==ECTS Ne$* %# S+#"em - "e#i"he#al e$#o"ath., &ei5$#e& le&& co%%o a d a&&ociated -ith la#'e do&e& a d "#olo 'ed the#a".. Ca$cin /enic P "en"ia1 - &ho- i a i%al&. R #i&8 i h$%a &. A1O(D @!6 (/ )>6*/A/T20ACTAT(/* MOM6/. GI - a$&ea, a o#e9ia, %etallic ta&te. A$##. to '$e, 'lo&&iti&, &to%atiti& a d d#. %o$th ca occ$#. DRUG INTERACTIONS 1. A1c h 1- )atie t& -ho i 'e&t alcohol -hile o %et#o ida5ole %a. e9"e#ie ce a D(!@0A@>AM-0(76 #eactio : a$&ea, abd. c#a%"&, fl$&hi ', etc.;. )atie t& &ho$ld be ad3i&ed /OT TO D>(/7 A0CO4O0 -hile ta8i ' %et#o ida5ole. 2. Ea$!a$in- Met#o ida5ole i hibit& the %etaboli&% of -a#fa#i %a. lead to to9icit.. A ticoa'$la t do&e &ho$ld be #ed$ced a d "#oth#o%bi ti%e ca#ef$ll. %o ito#ed. AVAILABILITY AND DOSING O#al - 250, 500 %' tablet&. )a#e te#al - 500 %' do&e. A ae#obic ( fectio &......... 0D 15 %'28', 7.5 %'28' ?6-8h C. 'i))i"i &......... 250 %' "o ?6h T%i"ho*o(as......... 2 '#a% "o 9 1 do&e +acte#ial 3a'i o&i&......... 500 %' "o bid 9 7 da.& A%ebia&i& ......... 750 %' "o tid 9 10 da.& *ia#dia&i&......... 250 %' "o tid 9 5 da.&

H%OR&MPH#$I O%
SPECTRUM O= ACTIVITY 69celle t acti3it. a'ai &t *#a% "o&iti3e a d *#a% e'ati3e a ae#obe& i cl$di ' +. f#a'ili&. :Al&o co3e#& *#a% "o&iti3e a d &o%e *#a% e'ati3e ae#obe&;.

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ADVERSE E==ECTS B ne Ma$$ 6 S%))$e##i n - do&e-#elated. Mo#e co%%o i tho&e #ecei3i ' "#olo 'ed the#a". -ho&e &e#$% le3el& a#e '#eate# tha 20-25 '2%l. A)1a#"ic Anemia - A #a#e to9icit., occ$##i ' i 1 i 25,000-40,000 co$#&e&. @&$all. fatal. Doe& ot a""ea# to be do&e-#elated. G$a+ Ba2+ S+nd$ me - d$e to i%%at$#e he"atic a d #e al f$ ctio i "#e%at$#e i fa t& a d e-bo# &, d#$' ca acc$%$late. !.%"to%& i cl$de 3o%iti ', ab o#%al #e&"i#atio , c.a o&i&, abdo%i al di&te tio . O3e# the e9t 24 ho$#&, 3a&o%oto# colla"&e, h."othe#%ia a d a a&he -'#a. colo# ofte de3elo". Mo#talit. 40L. !e3e#it. of the &. d#o%e a""ea#& to be d$e to hi'h f#ee le3el& of d#$' :$ co <$'ated;. B-%& T&M)B-%& T&M&*# I$HIBITOR OMBI$&TIO$* 69celle t acti3it. a'ai &t a ae#obic bacte#ia i cl$di ' 0. )%a,i is :&ee )e icilli ote&;.

INTRAABDOMINAL IN!ECTIONS
( t#aabdo%i al i fectio & a#e tho&e co tai ed -ithi the "e#ito e$% a d #et#o"e#ito eal &"ace. Thi& lect$#e -ill foc$& o 2 t."e& of i fectio &= )e#ito iti& :both "#i%a#. a d &eco da#.; a d ( t#aabdo%i al Ab&ce&&. PRIMARY PERITONITIS 3a.a& SPONTANEOUS BACTERIAL PERITONITIS KSBPL( ( fectio of the "e#ito eal ca3it. -itho$t a e3ide t &o$#ce. ETIOLOGY ( ad$lt&, $&$all. #e"o#ted i "atie t& -ith alcoholic ci##ho&i& a d a&cite&. !t#o ' co##elatio bet-ee the "#e&e ce of a&cite& a d "#i%a#. "e#ito iti&. Occ$#& i 15L of "atie t& -ith ci##ho&i&. BACTERIOLOGY - @&$all. a %o o%ic#obial i fectio . G$am 3-( 2aci11i 3@BA( G$am 3Q( c cci 3<BA(

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#+ coliNN K &.. p(&$*o(ia& Othe# '#a% :-; bacilli /ote= Anae$ 2e# a#e $a$e ca$&e& of "#i%a#. "e#ito iti&T PATHOGENESIS

*trep+ pneumoniae :19L; Othe# st%&pto"o""i9/I9 TD: E(t&%o"o""i :5L;

1. )o#tal h."e#te &io i c#ea&e& bacte#ial t#a &locatio to l.%"hatic &.&te% a d "o#tal 3ei . 2. De3elo"%e t of "#olo 'ed bacte#e%ia &eco da#. to #ed$ced bacte#ial clea#a ce f#o% blood a d i t#ahe"atic &h$ ti '. 3. (%"ai#%e t of bacte#icidal acti3it. i a&cite& fa3o#& bacte#ial '#o-th. 4. /o lo 'e# felt that bacte#ia #each "e#ito eal ca3it. b. di#ect t#a &%$#al %i'#atio f#o% the '$t. )#i%a#. bacte#e%ia i co <$ ctio -ith &eco da#. &eedi ' of the a&citic fl$id i& the %o&t li8el. e9"la atio fo# de3elo"%e t of !+). CLINICAL MANI=ESTATIONS Ae3e# :60-80L; Abdo%i al )ai Diff$&e abdo%i al te de# e&& >ebo$ d Te de# e&&

/a$&ea21o%iti '2Dia##hea 4."oacti3e o# ab&e t bo-el &o$ d& ( "atie t& -ith ci##ho&i&, "#e&e tatio %a. be at."ical. Othe# feat$#e& of e d &ta'e li3e# di&ea&e %a. be "#e&e t &$ch a& e ce"halo"ath., 3a#iceal bleedi ', etc. DIAGNOSIS 1. )a#ace te&i& :a&"i#ate of a&citic fl$id; -PMN# R ?BB/mm< i& be&t "#edicto# of !+) -*#a% &tai ofte ot hel"f$l

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2. +lood C$lt$#e& - )o&iti3e i 33L of "atie t& 3. A&cite& C$lt$#e TREATMENT +eca$&e the *#a% &tai i& f#e?$e tl. e'ati3e, i itial choice of a tibitotic& i& ofte 6M)(>(C a d di#ected at the %o&t li8el. "atho'e & :6 te#ic '#a%:-; bacilli a d &t#e"tococci;. 1. <$d Gene$a"i n Ce)ha1 #) $in# :ie. Cefota9i%e; - Co &ide#ed the DOC. -&i 'le a'e t, b#oad &"ect#$% of acti3it. a d dec#ea&ed to9icit. co%"a#ed to a%i o'l.co&ide-co tai i ' #e'i%e &. 2. Am)ici11in Q Amin /1+c #ide - C$#e of at lea&t 75L, ho-e3e# "#obabl. &ho$ld be a3oided &eco da#. to hi'h #ate of e"h#oto9icit. i "atie t& -ith $ de#l.i ' li3e# di&ea&e. 3. A%"icilli 2!$lbacta% o# othe# +-lacta%2+-lacta%a&e i hibito# co%bi atio . RESPONSE TO THERAPY !ho$ld &ee i%"#o3e%e t -ithi 24-48 ho$#&. >e"eat "a#ace te&i& i 48 ho$#&. @tili5e c$lt$#e a d &$&ce"tibilit. #e&$lt& to &t#ea% li e the#a".. T#eat 10-14 da.&. !ho#te# co$#&e& :5 da.&; ha3e bee &ho- to be e?$all. efficacio$&.

SECONDARY #ERITONITIS
( fectio that a#i&e& d$e to lo&& of i te'#it. of the 'a&t#oi te&ti al t#act. Defi ed a& the "#e&e ce of a "$#$le t e9$date i the abdo%i al ca3it. de#i3ed f#o% a e te#ic &o$#ce. ETIOLOGY 1. ( <$#ie& to the *( t#act - ie. "e#fo#ated "e"tic $lce#, t#a$%atic "e#fo#atio of the bo-el :ie. *!M;, di3e#tic$liti&, a""e diciti&, etc;.

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2. *a '#e e of the bo-el - &t#a '$latio , bo-el ob&t#$ctio , %e&e te#ic 3a&c$la# ob&t#$ctio . 3. Othe# - "a c#eatiti&, i fectio & of the fe%ale 'e ital t#act, #$"t$#ed 3i&ce#al ab&ce&&, co%"licatio of "e#ito eal dial.&i& o# "e#ito eal &h$ t&. MICROBIOLOGY Mo&t ca&e& ca$&ed b. o#%al flo#a of the *( t#act :Cli )ha#% 1986,5=34-8; Mo&t co%%o o#'a i&%& fo$ d i &eco da#. "e#ito iti& i cl$de Ae$ 2ic G$am Ne/a"i*e 2aci11i and Anae$ 2e#0 PATHOGENESIS ( t#aabdo%i al Model of !e"&i& i >at& - Mei &tei , 1974 A T-o-!te" "#oce&&= 6a#l. !ta'e :&e"&i&; - 'e e#ali5ed "e#ito iti& a&&ociated -ith a 40L %o#talit. ae#obe& "#edo%i ate. 0ate !ta'e - ab&ce&& fo#%atio . P*e ta%ici %o othe#a". 6a#l. &$#3i3al 0ate ab&ce&& fo#%atio . PCli da%.ci %o othe#a". 6a#l. death :2Y &e"tic &hoc8; /o late ab&ce&& fo#%atio . PCli da F *e t 6a#l. !$#3i3al /o late ab&ce&& fo#%atio . 9e+ i the t#eat%e t of 2 "e#ito iti& i& to $&e a'e t& that ha3e ac"i*i"+ a'ai &t both G$am ne/a"i*e ae$ 2e# a d anae$ 2e#. CLINICAL MANI=ESTATIONS abdo%i al "ai fe3e#2chill& #ebo$ d te de# e&& h."oacti3e o# ab&e t bo-el &o$ d&

a o#e9ia2 a$&ea23o%iti ' 3ol$ ta#. '$a#di '

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tach.ca#dia DIAGNOSIS

#i'id Gboa#d-li8eG abdo%e

1. 69"lo#ato#. la"a#oto%. - "#o3ide& 3i&$ali5atio of the &o$#ce of i fectio . 2. I-#a. - ot 3e#. &e &iti3e, b$t hel"f$l if f#ee ai# ide tified "e#fo#atio . 3. (%a'i ' &t$die& - @lt#a&o$ d, Co%"$ted To%o'#a"h. :CT;, M+C !ca &. 4. ( c#ea&ed M+C : o -&"ecific; 5. +lood c$lt$#e& TREATMENT PRINCIPLES 1. !$#'e#.. To= P&to" co ti $i ' co ta%i atio P#e%o3e fo#ei' %ate#ial f#o% "e#ito eal ca3it. Pd#ai "$#$le t collectio & 2. A ti%ic#obial The#a".. To= Pco t#ol bacte#e%ia P"#e3e t local &"#eadi ' of e9i&ti ' i fectio 3 . !$""o#ti3e Ca#e :ie. fl$id&, 3e tilato#. &$""o#t, "a#e te#al $t#itio ; ANTIMICROBIAL THERAPY Ma . #e'i%e & a#e "o&&ible, b$t the. %$&t co tai ade?$ate co3e#a'e a'ai &t /$am ne/a"i*e ae$ 2e# and anae$ 2e#S Amin /1+c #ide 3%#%a11+ Gen"amicin( Q C1indam+cin/Me"$ nida5 1e Ao# c#iticall. ill "atie t&, co &ide# addi ' A%"icilli fo# e te#ococcal co3e#a'e. /ot ece&&a#. fo# %ild-%ode#atel. ill "atie t&.

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O> <$d Gene$a"i n Ce)ha1 #) $in Q C1indam+cin/Me"$ nida5 1e :Ceft#ia9o e, Cefota9i%e, Cefti5o9i%e; O> B-Lac"am/B-Lac"ama#e Inhi2i" $ Q Amin /1+c #ide A%"icilli 2!$lbacta% Z@ a&. [ Tica#cilli 2Cla3$la ate ZTi%e ti [ )i"e#acilli 2Ta5obacta% Z Do&. [ = $ Penici11in A11e$/+& A5t#eo a% F Cli da%.ci O> H$i olo e :ci"#oflo9aci ; F Cli da%.ci =ACTORS TO CONSIDER EHEN SELECTING ANTIMICROBIAL THERAPY 1. !e3e#it. of (ll e&& 2. Alle#'ie& 3. )atie t&N #i&8 fo# to9icit. 4. !etti ' i -hich i fectio de3elo"ed :co%%$ it. 3&. ho&"ital- ac?$i#ed; 5. )#io# a ti%ic#obial the#a". 6. 0ocal #e&i&ta ce "atte# & RESPONSE TO THERAPY @tili5e c$lt$#e a d &e &ti3it. #e&$lt& to &t#ea% li e the#a"..

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D$#atio of the#a". i& 1A>(A+06. De"e d& o the &e3e#it. of i fectio , cli ical #e&"o &e, a d #et$# of M+C to o#%al. *e e#all. 5-14 da.&, b$t &ho#te# co$#&e& :ie. 1-2 da.&; %a. be ade?$ate -he acco%"a ied b. co##ecti3e &$#'e#.. (f "atie t doe& ot i%"#o3e -ithi 4 da.&, co &ide#=

#e&i&ta ce &$"e#i fectio $ d#ai ed foc$& of i fectio

CAPD PERITONITIS :Co ti $o$& A%b$lato#. )e#ito eal Dial.&i&; )e#ito iti& i& a %a<o# co%"licatio of CA)D 45L of CA)D "atie t& de3elo" "e#ito iti& at lea&t o ce i thei# 1&t 6 %o th& of dial.&i&. >ec$##e ce i& co%%o . PATHOGENESIS @&$all. co ta%i atio of cathete# b. &8i o#'a i&%& 3ia=

T#a &l$%i al, #e&$lti ' f#o% b#ea8 i tech i?$e d$#i ' dial.&i&. Co ti'$o$& &"#ead - o#'a i&%& o &8i %i'#ate alo ' cathete#.

MICROBIOLOGY G$am P #i"i*e C cci - 60-80L of the i&olate&. S. &pi'&%*i'is i& %o&t co%%o follo-ed b. S. a$%&$s. G$am Ne/a"i*e Baci11i - 15-30L. 6. coli i& %o&t co%%o , follo-ed b. 7leb&iella, 6 te#obacte#, )#ote$&, etc. CLINICAL =INDINGS DIAGNOSIS - ba&ed o cli ical a d labo#ato#. fi di '&.

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Cli ical= &ee abo3e 0abo#ato#.= P)e#ito eal fl$id '#a% &tai a d c$lt$#e -Dial.&ate co tai i ' K 100 e$t#o"hil&2%%3 -O#'a i&%& '#o-i ' i fl$id TREATMENT ( itial the#a". i& $&$all. e%"i#ic to co3e# the %o&t li8el. "atho'e &. Vanc m+cin Q Gen"amicin :D#$'& 'i3e eithe# i t#a3e o$&l. o# i t#a"e#ito eall.;

INTRAABDOMINAL ABSCESS
ABSCESS A "$#$le t collectio of fl$id &e"a#ated f#o% &$##o$ di ' ti&&$e b. a %o#e o# le&& -ell-defi ed -all. @&$all. a co%"licatio of 1 o# 2 "e#ito iti&. MICROBIOLOGY - !i%ila# to that &ee i 2 "e#ito iti&. )#edo%i a tl. '#a% e'ati3e bacilli a d A/A6>O+6!, ho-e3e# a ae#obe& "#edo%i ate. PATHOGENESIS 1. Co ta%i atio follo-ed b. locali5atio of i fectio . 2. 0ocatio de"e d& o &i'ht of "#i%a#. "#oce&&. 3. Ma. ta8e da.& to e3ol3e. 4. Ab&ce&& e 3i#o %e t Ph."e#to ic a d acidic

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Pco tai & e$t#o"hil&, bacte#ia a d ec#otic deb#i& Pfib#i o$& ca"&$le CLINICAL PRESENTATION 1. Ofte o -&"ecific a d de3elo"& -ith a i dole t co$#&e.

2. Abdo%i al "ai %a. be "#e&e t a& -ell a& lo- '#ade fe3e#. 3. Ma. #e&$lt i "e#ito iti& if #$"t$#e&. DIAGNOSIS 1. Defi iti3e dia' o&i& #e?$i#e& e9"lo#ato#. la"a#ato%. 2. @lt#a&o$ d ca detect ab&ce&&. 3. CT %o&t acc$#ate fo# dia' o&i ' i t#aabdo%i al ab&ce&&e&. 4. !ho$ld be co &ide#ed i a . "o&t-o"e#ati3e "atie t -ho de3elo"& fe3e# &e3e#al da.& to -ee8& afte# &$#'e#.. THERAPY 1. S%$/e$+ - !$#'ical d#ai a'e i& the MA(/!TAE of %a a'i ' i t#aabdo%i al ab&ce&&e&. Ma. be eithe# "e#c$ta eo$& o# &$#'ical d#ai a'e. 2. An"i2i "ic# - Di#ected at the %o&t co%%o "atho'e &, e te#ic */+ a d a ae#obe&. T#eat%e t &i%ila# to that of &eco da#. "e#ito iti&. Amin /1+c #ide Q C1indam+cin/Me"$ nida5 1e A tibiotic& alo e ot effecti3e d$e to=

)oo# "e et#atio of a tibiotic& i ab&ce&& ce te#. ( acti3atio b. %ic#oe 3i#o %e t :ie. lo- "4 A* do Nt -o#8 -ell; ( acti3it. of d#$' a'ai &t la#'e i oc$l$%.

3. *e e#al !$""o#ti3e Ca#e

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IN!ECTI>E ENDOCARDITIS
)a$la A. Teich e#, )ha#%.D. G a1# and O2;ec"i*e#& +. the e d of thi& lect$#e, the &t$de t &ho$ld be able to=

1. 2. 3. 4.

5. 6. 7. 8.

De&c#ibe the "atho"h.&iolo'., #i&8 facto#& a d cli ical "#e&e tatio of i fecti3e e doca#diti&. O$tli e the %o&t co%%o o#'a i&%& that ca$&e i fecti3e e doca#diti&. +a&ed o cli ical "#e&e tatio a d "atie t hi&to#., dete#%i e the %o&t li8el. %ic#obiolo'ic etiolo'. fo# thei# e doca#diti&. De&i' a a""#o"#iate t#eat%e t #e'i%e t :i cl$di ' a tibiotic:&;, ad$lt do&e, a d d$#atio of the#a".; fo# the follo-i ' t."e& of e doca#diti&= a. 1i#ida & &t#e"tococci b. !ta"h.lococci= %ethicilli -&$&ce"tible a d #e&i&ta t. c. 6 te#ococci d. )#o&thetic 1al3e e doca#diti& De&i' a t#eat%e t #e'i%e fo# the abo3e t."e& of e doca#diti& i a "atie t -ho ha& a "e icilli alle#'.. De&c#ibe the diffe#e ce& bet-ee !. a$#e$& e doca#diti& i a i t#a3e o$& d#$' ab$&e# 3&. a "atie t -ho i& ot. De&c#ibe the #ole of %o ito#i ' &e#$% le3el& i the t#eat%e t of e doca#diti&. De&c#ibe the #ole of &$#'e#. i the %a a'e%e t of e doca#diti&.

Re7%i$ed Readin/& )ha#%acothe#a".. A )atho"h.&iolo'ic A""#oach. 3#d 6ditio , 1996. Cha"te# 104. ( fecti3e 6 doca#diti&. )a'e& 2081-2099. o# 2 d 6ditio . 1992. Cha"te# 99. )a'e& 1614-31. BAC9GROUND End ca$di"i# i& defi ed a& a i fectio of the hea#t 3al3e& o# %$#al e doca#di$%. ( the "a&t -a& cla&&ified a& ac$te o# &$bac$te ba&ed o the cli ical "#e&e tatio of the di&ea&e. Altho$'h $&ef$l co ce"t$all., thi& cla&&ificatio i& o lo 'e# $&ed, b$t i& o- ba&ed o the etiolo'ic

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a'e t. Thi& cla&&ificatio &.&te% i& "#efe#able &i ce it ha& i%"licatio & fo# the co$#&e $&$all. follo-ed, the li8elihood of $ de#l.i ' hea#t di&ea&e a d the a""#o"#iate a ti%ic#obial a'e t& to $&e. Ac%"e Bac"e$ia1 End ca$di"i# t."icall. i& a&&ociated -ith a f$l%i a t co$#&e, $&$all. -ith hi'h fe3e#, &.&te%ic to9icit., le$coc.to&i&, a d death -ithi a fe- da.& to -ee8& if $ t#eated. Thi& i fectio i& cla&&icall. ca$&ed b. 3i#$le t o#'a i&%& &$ch a& S. a$%&$s -hich occ$#& i "atie t& -ith "#e3io$&l. o#%al 3al3e&. S%2ac%"e Bac"e$ia1 End ca$di"i# $&$all. occ$#& i "atie t& -ith "#io# 3al3$la# di&ea&e a d i& cha#acte#i5ed b. a &lo-, i dole t co$#&e a&&ociated -ith lo- '#ade fe3e#, i'ht &-eat&, -ei'ht lo&& a d 3a'$e &.&te%ic co%"lai t&. Cla&&icall. ca$&ed b. 3i%i'a(s st%&pto"o""i. PATHOGENESIS 1. 6 doca#dial da%a'e 2 i fla%%ato#. co ditio & o# t$#b$le t blood flo-. 2. Aollo-i ' cha 'e& i the e dothelial &$#face, &te#ile "latelet-fib#i th#o%bi fo#% o da%a'ed e dothelial &$#face. The&e de"o&it& a#e #efe##ed to a& o bacte#ial th#o%botic e doca#diti& :/+T6;. 3. ( the "#e&e ce of bacte#e%ia, the e doca#dial &$#face o- &e#3e& a& a id$& fo# bacte#ial i 3a&io . +acte#e%ia i& $&$all. a #e&$lt of t#a$%a to a %$co&al &$#face ha3i ' hi'h co ce t#atio & of bacte#ia &$ch a& o#al ca3it.. 4. St%&pto"o""i a d staph+ o"o""i a#e o#'a i&%& co%%o l. ca$&i ' e doca#diti& ha3e the abilit. to adhe#e to e doca#dial &$#face& %o#e tha '#a% e'ati3e o#'a i&%&. Thi& a""ea#& to be d$e to thei# abilit. to "#od$ce e9t#acell$la# de9t#a a d a''#e'ate "latelet&. RIS9 =ACTORS PREDISPOSING TO ENDOCARDITIS 1. @ de#l.i ' hea#t di&ea&e o t$#b$le ce of floo #he$%atic 3al3$la# da%a'e o %it#al 3al3e "#ola"&e o co 'e ital hea#t di&ea&e 2. )#o&thetic 3al3e& 3. ( t#a3e o$& d#$' ab$&e 4. )atie t& -ith i t#a3e o$& cathete#& -ho de3elo" bacte#e%ia :ie. T)/; 5. A'e K50 - i 50L of the "atie t& 6. /o $ de#l.i ' ca$&e :25-50L of "atie t&; CLINICAL PRESENTATION

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Ac$te e doca#diti& - $&$all. ac$te o &et of fe3e#, chill& bac8 "ai , %.al'ia&. )atie t& loo8 ill. !$bac$te e doca#diti& - i &idio$& o &et of a 3a#iet. of &.%"to%& &$ch a& -ea8 e&&, fati'$e, a o#e9ia, i'ht &-eat&, -ei'ht lo&&, fe3e#. !.%"to%& %a. be "#e&e t fo# -ee8& to %o th&. O &et %a. be #elated to a tecede t e3e t& &$ch a& de tal -o#8. 1. Ca$diac #i/n# Hea$" m%$m%$ - "#e&e t i 85L o# %o#e of ca&e&. 1e'etatio & o hea#t 3al3e %a. be &i 'le o# %$lti"le a d co &i&t of fib#i , "latelet a''#e'ate&, a d bacte#ial %a&&e&. @&$all. affect& ao#tic o# %it#al 3al3e&. C4A %a. be "#e&e t if &i' ifica t 3al3$la# i &$fficie c.. 2. Em2 1ic )hen mena -he%at$#ia :e%boli to 8id e.&; 3. Cen"$a1 Ne$* %# S+#"em -&t#o8e, &e &o#. lo&&, a"ha&ia, alte#ed %e tal &tat$& 4. S)1en me/a1+ :25-60L of "atie t&; 5. M%#c%1 #.e1e"a1 -a#th#al'ia&, %.al'ia&, lo- bac8 "ai 6. S.in Mani!e#"a"i n# -)etechiae :20-40L of ca&e&; -O&le# ode& - &%all "ai f$l od$la# le&io & $&$all. i "ad& of fi 'e#&2toe&. -Ca e-a. le&io & - he%o##ha'ic, %ac$la# "la?$e& $&$all. &ee o "al%& a d &ole&. -!"li te# he%o##ha'e& - fo$ d i 7. E+e ->oth !"ot& - #eti al le&io & &$##o$ ded b. he%o##ha'e. LABORATORY STUDIES A0 N n-S)eci!ic =indin/# 1. ( c#ea&ed 6#.th#oc.te !edi%e tatio >ate :6!>;. 2. A e%ia - o#%och#o%ic, o#%oc.tic 3. M+C - $&$all. o#%al o# %ode#atel. i c#ea&ed.

ail bed&.

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4. Th#o%boc.to"e ia 5. >he$%atoid Aacto# - "#e&e t i 40-50L of "atie t& -ith di&ea&e K &e3e#al -ee8&. 6. Mic#o&co"ic he%at$#ia a d "#otei $#ia - detected o $#i al.&i&. B0 B1 d C%1"%$e# The #in/1e m #" im) $"an" 1a2 $a" $+ "e#"S M$&t be obtai ed if e doca#diti& i& &$&"ected. C$lt$#e& a#e "o&iti3e i 85-95L of ca&e&. 3-4 blood c$lt$#e& &ho$ld be obtai ed, ta8e f#o% &e"a#ate 3e i"$ ct$#e &ite&, at 15-30 %i $te i te#3al&. +lood c$lt$#e& &ho$ld be held fo# 3 -ee8&. @&$all. a c n"in% %#, 1 6-/$ade 2ac"e$emia. C0 Ech ca$di /$a)h+ 3ECHO( - 2D 6C4O -ill #e3eal 3e'etatio & i 40-80L of "atie t&. A e'ati3e 6C4O doe& ot #$le o$t bacte#ial e doca#diti&. T#a &e&o"ha'eal 6C4O :T66; %o#e &e &iti3e tha 2D i detecti ' 3e'etatio & :85-90L;. The dia' o&i& of e doca#diti& &ho$ld be co &ide#ed i a . "atie t -ith fe3e# fo# &e3e#al da.& a d o ob3io$& &o$#ce of i fectio a d i a&&ociatio -ith a &i' ifica t hea#t %$#%$#. ETIOLOGIC AGENTS CAUSING ENDOCARDITIS 1. S"$e)" c cci- occ$# i 60-80L of ca&e& of e doca#diti&. @&$all. &ee i child#e a d .o$ ' -o%e -ith %it#al 3al3e i 3ol3e%e t. -35L of ca&e& ca$&ed b. 3i#ida & &t#e"tococci :!. %iti&, &a '$i&, %$ta &, &ali3a#i$&, i te#%edi$&, bo3i&, %itio#;. -10L of ca&e& ca$&ed b. e te#ococc$&. -10L of ca&e& d$e to !. " e$%o iae :&ee i alcoholic&; o# othe# &t#e"tococci.. 2. S"a)h+1 c cci - A""#o9i%atel. 35L of ca&e& of i fecti3e e doca#diti&. Of the&e, 80- 90L a#e ca$&ed b. !. a$#e$&. 3. O"he$ - Mi o#it. of ca&e& ca$&ed b. e te#ic '#a% e'ati3e bacilli, P. a&%$,i(osa/ f$ 'i, a ae#obe&, etc. 4. C%1"%$e Ne/a"i*e - Ma. be d$e to &lo--'#o-i ', fa&tidio$& o#'a i&%& :4AC67; o# ca occ$# i "atie t& -ho ha3e #ecei3ed "#io# a tibiotic& TREATMENT PRINCIPLES +acte#ia i 3e'etatio & a#e &$##o$ ded b. fib#i KK i acce&&ible to "ha'oc.tic cell&. Al&o bacte#ia -ithi 3e'etatio & a#e i hi'h de &it. :1081010 o#'2'#a% of ti&&$e;. At the&e de &itie&, the#e i& dec#ea&ed %etaboli&% a d cell di3i&io KK dec#ea&ed bacte#icidal effect& of "e icilli &.

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Ba#ic P$inci)1e#& Bac"e$icida1 an"i2i "ic# ece&&a#. P$ 1 n/ed "he$a)+ :to e#adicate all o#'a i&%& f#o% 3al3e; /eed (1 the#a". 4i'h do&e& to "#od$ce &$&tai ed, bacte#icidal le3el& Ma. $&e a ti%ic#obial co%bi atio & :&. e#'.; !electio of a tibiotic& &ho$ld be ba&ed o &$&ce"tibilitie& The ea&e of bacte#iolo'ic c$#e 'e e#all. te d& to be #elated to the de'#ee of a tibiotic &$&ce"tibilit. of the i fecti ' o#'a i&%. La2 $a" $+ Aid# in T$ea"in/ End ca$di"i# 1. M(C2M+C of o#'a i&% - &ho$ld be dete#%i ed b. t$be dil$tio te&t&, i additio to the $&$al di&c &$&ce"tibilitie&. 2. !e#$% +acte#icidal Te&t :!+T; - i& the hi'he&t dil$tio of the "atie t&N &e#$% :obtai ed -hile the. a#e #ecei3i ' a tibiotic the#a".; that 8ill& a &ta da#d i oc$l$% of the "atie t&N o#'a i&% i 3it#o. )ea8 !+T K'#eate# tha o# e?$al to 1=8 i& de&i#able. /ot #o$ti el. $&ed, b$t %a. be hel"f$l -he #e&"o &e to t#eat%e t i& &$bo"ti%al, e doca#diti& i& d$e to a $ $&$al o#'a i&%, o# -he $ co 3e tio al t#eat%e t i& $&ed. 3. D#$' 0e3el& - &ho$ld be %o ito#ed fo# &"ecific a ti%ic#obial&. Mhe a%i o'l.co&ide& a#e $&ed fo# &. e#'., )ea. 1e*e1# ! < //m1 fo# 'e ta%ici a d -B //m1 fo# &t#e"to%.ci a#e de&i#able. Ini"ia"in/ The$a)+ Ao# ac$te bacte#ial e doca#diti&, 'et 3-4 blood c$lt$#e& o3e# a 1 ho$# "e#iod &ta#t the#a". "#o%"tl. to "#e3e t "#o'#e&&io . ( a "atie t -ith a &$bac$te "#e&e tatio , obtai blood c$lt$#e& o3e# a 1-2 da. "e#iod. A-ait c$lt$#e #e&$lt& befo#e &ta#ti ' a ti%ic#obial the#a".. ANTIBIOTIC THERAPY =OR SPECI=IC ORGANISMS CAUSING ENDOCARDITIS A0 VIRIDANS STREPTOCOCCI :!ee Table 104.3, "a'e 2086; Mo&t co%%o i &$bac$te e doca#diti& i "atie t& -ith ati3e 3al3e& a d $ de#l.i ' hea#t di&ea&e. St%&p .o3is i& ot a 3i#ida & &t#e"tococci, b$t a o -e te#ococcal *#o$" D &t#e"tococci. Mill i cl$de i thi& &ectio beca$&e it i& "e icilli &e &iti3e a d the t#eat%e t #e'i%e i& the &a%e a& that fo# 3i#ida & &t#e"tococci. Penici11in Sen#i"i*e :M(C J 0.1 '2%l; -)e icilli * i& the d#$' of choice, eithe# alo e o# i co%bi atio -ith a a%i o'l.co&ide.

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1. Penici11in a1 ne0 Do&e of 12-18 %illio $ it&2da. 'i3e ?4 ho$#& 9 4 -ee8&. +acte#iolo'ic c$#e i 99L of "atie t&. @&e i "atie t& -ith i%"ai#ed #e al f$ ctio o# at #i&8 fo# e"h#oto9icit.. 2. Penici11in )1%# an amin /1+c #ide0 Co%bi atio #e&$lt& i &. e#'i&tic 8illi ' of bacte#ia. )e icilli 12-18 %illio $ it&2da. 'i3e ?4 ho$#& "l$& eithe# &t#e"to%.ci 7.5 %'28' : ot to e9ceed 500 %'; (M ?12 ho$#& O> 'e ta%ici 1.0 %'28' : ot to e9ceed 80 %' do&e; (12(M, fo# 2 -ee8&. Thi& ca be the total le 'th of the#a"., o# thi& #e'i%e ca be follo-ed b. a othe# 2 -ee8& of "e icilli alo e. The 2--ee8 co%bi atio -the#a". #e'i%e i& the %o&t co&t-effecti3e, b$t &ho$ld o l. be $&ed i $ co%"licated, "e icilli -&e &iti3e ca&e& -he#e the "atie t i& at lo- #i&8 fo# e"h#oto9icit.. The 4 -ee8 co$#&e &ho$ld be $&ed i "atie t& -ith a co%"licated co$#&e o# hi&to#. of di&ea&e K 3 %o th&. 3. Amin /1+c #ide %#e0 A%i o'l.co&ide& a#e $&ed fo# &. e#'. a'ai &t &t#e"tococci. Altho$'h &t#e"to%.ci a d 'e ta%ici a#e i te#cha 'eable, /en"amicin i# )$e!e$$ed d$e to co&t, d#$' a3ailabilit., "h.&icia fa%ilia#it., a d the abilit. to obtai &e#$% le3el&. !e#$% "ea8 co ce t#atio & of < //m1 ! $ /en"amicin a d 20 '2%l fo# &t#e"to%.ci . ZThe&e a#e &i' ifica tl. lo-e# tha tho&e t."icall. $&ed fo# the t#eat%e t of &e#io$& '#a% :-; i fectio &.[ 4. Ce!"$ia4 ne 2 '#a% (1 o# (M ?d 9 4 -ee8&. +acte#iolo'ic c$#e of $" to 98L. @&ef$l fo# "atie t& t#eated i o$t"atie t &etti '. T 1e$an" S"$e)" c cci :M(C K0.1 a d J 0.5; :!ee Table 104.4, "a'e 2086; )e icilli 20 %illio $ it&2da. i 6 di3ided do&e& X > 6ee.# )0@! eithe# 'e ta%ici 1.0 %'28' : ot to e9ceed 80 %'; (12(M ?8 ho$#& o# &t#e"to%.ci 7.5 %'28' : ot to e9ceed 500 %' ; (M ?12 ho$#& fo# at lea&t 2 -ee8&. Penici11in $e#i#"an" #"$e) *i$idan# :M(C K 0.5; - $ co%%o . T#eat -ith both "e icilli a d a%i o'l.co&ide. T#eat%e t i& the &a%e a& fo# e te#ococcal e doca#diti& :!ee +elo-;. Penici11in A11e$/ic Pa"ien"# - Ma8e &$#e "atie t #eall. ha& a t#$e alle#'. beca$&e e9"e#ie ce -ith "e icilli i& fa# %o#e fa3o#able. Ma. co &ide# &8i -te&ti ' to dete#%i e if t#$e alle#'.. :!ee Table 104.5, "a'e 2087;. 1. Penici11in h+)e$#en#i"i*i"+ 3n " immedia"e h+)e$#en#i"i*i"+( Ce"halothi 2 '% (1 ?4 ho$#& o# cefa5oli 1 '% (1 ?8 ho$#& 9 > 6ee.#. A%i o'l.co&ide %a. be added fo# the fi#&t 2 -ee8&. 2. Immedia"e-T+)e PCN h+)e$#en#i"i*i"+

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1a co%.ci 30 %'28'2da. 'i3e i 2 di3ided do&e& 9 4 -ee8&. Do&a'e ad<$&t%e t %a. be #e?$i#ed i "atie t& -ith #e al d.&f$ ctio . !e#$% "ea8 co ce t#atio & of 30-45 '2%l a#e de&i#able. B0 STAPHYLOCOCCI :!ee Table 104.6, "a'e 2088; !ta"h.lococcal e doca#diti& i& &ee i "atie t& -ith i t#a3e o$& cathete#&, "atie t& -ho $&e i t#a3e o$& d#$'&, a d i "atie t& -ith "#o&thetic 3al3e&. Ma a'e%e t of thi& di&ea&e #e?$i#e& co &ide#atio of &e3e#al facto#&= 1. (& the o#'a i&% %ethicilli -#e&i&ta tR 2. !ho$ld co%bi atio the#a". be $&edR 3. (& the i fectio o a ati3e o# "#o&thetic hea#t 3al3eR 4. (& the "atie t a i t#a3e o$& d#$' ab$&e#R A2#ence ! P$ #"he"ic Ma"e$ia1 3Na"i*e Va1*e( : +oth !. a$#e$& a d !. e"ide#%idi&; 1. Me"hici11in S%#ce)"i21e0 *i3e /afcilli 2 '% (1 ?4 ho$#& X >-M 6ee.#, )0@! 'e ta%ici 1.0 %'28' : ot to e9ceed 80 %'; (12(M ?8 ho$#& fo# 3-5 da.& :a%i o'l.co&ide o"tio al;. Altho$'h co%bi atio the#a". t#ial& ha3e failed to &ho- a i%"#o3ed o$tco%e, co%bi atio the#a". ca$&e& a %o#e #a"id 8illi ' of the bacte#ia a d &te#ili5atio of the 3al3e. 2. Penici11in A11e$/ic 3n " immedia"e h+)e$#en#i"i*i"+(. Ce"halothi 2 '% (1 ?4 ho$#& o# Cefa5oli 2 '% (1 ?8 ho$#& I 4-6 -ee8&, -ith the o"tio of 'e ta%ici fo# the fi#&t 3-5 da.& :do&e a& abo3e;. 3. Penici11in A11e$/ic 3immedia"e h+)e$#en#i"i*i"+ $eac"i n(. 1a co%.ci 30 %'28'2da. i 2 di3ided do&e& I 4-6 -ee8&. A3oid a%i o'l.co&ide d$e to co ce# of i c#ea&ed e"h#oto9icit.. 1a co%.ci i& le&& #a"idl. bacte#icidal tha afcilli i( 3it%o a'ai &t Staph a$%&$s. Aail$#e #ate& $" to 40L. 4. Me"hici11in-Re#i#"an" S"a)h+1 c cci :M>!A;. 1a co%.ci 30 %'28'2da. i 2 di3ided do&e& I 4-6 -ee8&. 0e3el& a& abo3e. 5. O$a1 The$a)+. Afte# 2 -ee8& of "a#e te#al the#a"., %a. t#. hi'h do&e& of o#al &e%i&. thetic "e icilli &. *i3e I 4 -ee8&, afte# 2 -ee8& (1. !+T %a. be of be efit to a&&$#e ade?$ate bacte#icidal acti3it.. Ci"#oflo9aci "l$& #ifa%"i 'i3e o#all. al&o &ho- to ha3e &o%e be efit i &ta"h.lococcal e doca#diti&. A$#the# &t$die& eeded befo#e thi& the#a". ca be #eco%%e ded. C0 ENTEROCOCCI :!ee Table 104.8, "a'e 2090;.

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Mhe t#eati ' e te#ococcal i fectio &, the#e a#e &e3e#al 8e. thi '& to #e%e%be#= a. /o &i 'le a tibiotic i& bacte#icidal a'ai &t E. )a&"a is :ie. +-lacta%& a d 3a co%.ci a#e bacte#io&tatic;. b. 6ffecti3e bacte#icidal the#a". #e?$i#e& additio of a%i o'l.co&ide fo# f$ll t#eat%e t co$#&e. c. Cell--all a tibiotic& )0@! a%i o'l.co&ide& act &. e#'i&ticall. a'ai &t e te#ococci. d. 0o- do&e a%i o'l.co&ide i& a& 'ood a& hi'h do&e :ie. "ea8 le3el 3 '2%l;. e. 6 te#ococci a#e /OT i hibited b. ce"halo&"o#i &. N n-Penici11in A11e$/ic Penici11in G -B-<B %illio $ it&2da. i 6 di3ided do&e& O> Am)ici11in 2 '% (1 ?4 I >-M 6ee.# )0@! &t#e"to%.ci 7.5 %'28' : ot to e9ceed 500 %'; (M ?12 ho$#& O> 'e ta%ici 1 %'28' : ot to e9ceed 80 %'; (12(M ?8 ho$#& I >-M 6ee.#. (f &t#e"to%.ci M(C K 2000 '2%l, $&e 'e ta%ici . (f &t#ai of e te#ococc$& e9hibit& hi'h-le3el #e&i&ta ce to all a%i o'l.co&ide& KK DO /OT $&e. @ li8el. to "#o3ide a . cli ical be efit. )ea8 le3el of &t#e"to%.ci O 20 '2%l. )ea8 le3el& of 'e ta%ici &ho$ld be 3 '2%l. Penici11in A11e$/ic Pa"ien" 1a co%.ci 30 %'28'2da. i 2 di3ided do&e& fo# 4-6 -ee8& )0@! a%i o'l.co&ide :#e'i%e & &a%e a& abo3e; I 4-6 -ee8&. !e#$% le3el& fo# 3a co%.ci a d a%i o'l.co&ide a& %e tio ed abo3e. CA//OT @!6 C6)4A0O!)O>(/! TO T>6AT 6/T6>OCOCCA0 (/A6CT(O/!

PROSTHETIC VALVE ENDOCARDITIS ( cide ce 1-2L. Di3ided i to 2 cate'o#ie&= 1. 6a#l. - tho&e i fectio & occ$##i ' -ithi 12 %o th& :$&$all. fi#&t 2 %o th&; of 3al3e #e"lace%e t. ( fectio & ac?$i#ed at the ti%e of &$#'e#. o# ea#l. "o&t-o". U#%a11+ ca%#ed 2+ *+ epi,ermi,is+ Ca be '#a% e'ati3e bacilli, f$ 'i o# !. a$#e$&. 2. 0ate - occ$# K 12 %o th& "o&t-o". @&$all. d$e to &t#e"tococci.

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Re/imen ! $ Me"hici11in S%#ce)"i21e S"a)h+1 c cci 3E)ide$midi# a d a$#e$&( :Table 104.7, )a'e 2089; /afcilli 2 '% (1 ?4 ho$#& )0@! #ifa%"i 300 %' "o ?8 ho$#& I a" 1ea#" M 6ee.#, )0@! 'e ta%ici 1.0 %'28' (1 ?8 ho$#& fo# the fi#&t 2 -ee8&. *e ta%ici le3el& a& abo3e. Re/imen ! $ Me"hici11in-Re#i#"an" S"a)h+1 c cci 3E)ide$midi# a d a$#e$&( :Table 104.7, )a'e 2089; 1a co%.ci 30 %'28'2da. 'i3e i 2 di3ided do&e& )0@! #ifa%"i 300 %' "o ?8 ho$#& fo# a" 1ea#" M 6ee.# )0@! 'e ta%ici I 2 -ee8&. @&e of #ifa%"i fo# S. a$%&$s i fectio & a&&ociated -ith "#o&thetic 3al3e& i& ba&ed o fa3o#able cli ical e9"e#ie ce. ENDOCARDITIS IN INTRAVENOUS DRUG ABUSERS Mic$ 2i 1 /+ 1. S"a)h+1 c cc%# a%$e%# i# "he m #" c mm n ca%#e o e doca#diti& i thi& "o"$latio . Occ$#& i 60-80L of ca&e&. 2. !t#e"tococci :20L; - $&$all. ca$&e& left-&ided e doca#diti&. 3. *#a% e'ati3e bacilli a d )&e$do%o a& :10-15L;. 4. Ca dida &"". :5L;. =ea"%$e# ! End ca$di"i# 1. ( fectio $&$all. locali5ed to the "$ic%#)id *a1*e ca$&e& >i'ht-&ided e doca#diti&. 2. Death a d &e#io$& co%"licatio & of hea#t fail$#e a d &t#o8e a#e le&& li8el. to occ$#. 3. @&$all. o "#io# hi&to#. of hea#t di&ea&e. 4. !.%"to%& $&$all. 1-2 -ee8& i d$#atio , fe3e# al%o&t al-a.& "#e&e t. 5. Ma. ha3e i c#ea&ed #i&8 fo# M>!A. 6. )atie t& ofte ha3e co$'h, d.&" ea, "le$#itic che&t "ai a&&ociated -ith " e$%o ia. An"imic$ 2ia1 The$a)+ T#eat%e t i& the &a%e a& fo# othe# "atie t& -ith &ta"h.lococcal e doca#diti& :-itho$t "#o&thetic %ate#ial;. >i'ht-&ided e doca#diti& %a. be ea&ie# to c$#e 2 fe-e# o#'a i&%& "#e&e t. !ho#te# co$#&e& :2 -ee8&; of the#a". ha3e bee &ho- to be &$cce&&f$l i (1DA -ith #i'ht &ided e doca#diti&=

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/afcilli 1.5 '% (1 ?4 ho$#& )0@! tob#a%.ci 1 %'28' (1 ?8 ho$#& I - EEE9S. :Ma& &t$died -ith tob#a%.ci , 'e ta%ici i& al&o acce"table;. A& 3a co%.ci a""ea#& le&& effecti3e tha +-lacta%&, ot #eco%%e ded fo# $&e i &ho#t-co$#&e t#eat%e t of &ta"h e doca#diti& !ho#t-co$#&e the#a". &ho$ld o l. be co &ide#ed i "atie t& -itho$t e3ide ce of #e al fail$#e, e9t#a"$l%o a#. co%"licatio &, ao#tic o# %it#al 3al3e i 3ol3e%e t, %e i 'iti& o# i fectio -ith M>!A. ROLE O= SURGERY IN THE MANAGEMENT O= ENDOCARDITIS !o%eti%e& a ti%ic#obial the#a". alo e i& i ade?$ate to &te#ili5e the ca#diac 3al3e. ( the&e ca&e&, 3al3e #e"lace%e t %a. be i dicated. +eloa#e &o%e #ea&o & fo# &$#'ical i te#3e tio . 1. =%n/a1 end ca$di"i# 2. P$ /$e##i*e $ #i/ni!ican" CH= that doe& Nt #e&"o d to %edical the#a".. 3. Pe$#i#"en" 2ac"e$emia :7-10 da.&; de&"ite a""#o"#iate a tibiotic&. 4. Se)"ic em2 1i - K 1 &e#io$& e%bolic e3e t. 5. P$ #"he"ic *a1*e end ca$di"i#. 6. >ela"&e of i fectio . 7. 63ide ce of e9te &io of i fectio ie. "e#ica#diti&, 3al3$la# #i ' ab&ce&&, etc. 8. 1e'etatio & - de"e d& o &i5e, locatio , a d cli ical a&&e&&%e t. RESPONSE TO THERAPY (%"#o3e%e t i &.%"to%&, dec#ea&ed fe3e# a d e'ati3e blood c$lt$#e& occ$#& fai#l. ?$ic8l. -ith &e &iti3e o#'a i&%& :24-48 ho$#&;, b$t -ith o#'a i&%& &$ch a& !. a$#e$& KK %a. ta8e da.& to a -ee8 befo#e defi ite i%"#o3e%e t i& oted. (f !e*e$ #ec$##e ce, %a. be ca$&ed b.= 1. Aail$#e to co t#ol i fectio 2. )hlebiti& 3. Meta&tatic ab&ce&& fo#%atio 4. >ec$##e t e%boli 5. !$"e#i%"o&ed i fectio 6. D#$' fe3e#

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