Cephalosporin Antibiotics
Randal A. OUo, MD
Allen D. Noorily , MD
San Antonio, Texas
Abstract
The last three decades have seen the emergence of a
cornucopi a of antimicrobials in the cephalospo rin class.
This becomes even more appa rent when one realizes that
over 60 pages ofthe 1993 AHFS drug information text is
dedicated to the cephalosporin class. J Due to similarities
in nomenclature and the proliferation ofavaila ble agents,
the clinician is constantly challenged by this confusing
array of antimicrobials. The intent ofthis manuscript will
be to distill the volumes ofinf ormation available on cepha-
losporins into a more manageab lefo rmat and close with a
summary of the most clinically important cephalosporin
antimicrobials.
Introduction
As clinician s, we are constantly challenged to keep
abreast as new antimicrobial agents flood the market. This
is particularly true with the cephalosporin class of antimi-
crob ials. This is due, in part, to the similarity in nomenc la-
ture, multiplicity of available agents, overlappin g spec-
trum and a blurring of the definition of cephalosporin
agents. The intent of this manuscript is to provide the
reader with a brief synopsis of currently available agents,
their relative advantages and disadvantages and a sum-
mary of the most clinically relevant agents .
Background
The class of antimicrobials commonly referred to as the
"ceph alosporins" continues to expand and currently in-
cludes the four following subgroups: 1) true cephalospor-
ins, 2) cephamycins, 3) oxa B-Lactams and most recently,
with the introduction of Loracarbef, the 4)carbacephems.
However, for all practical purposes all four are considered
cephalosporins and arise from the basic cephalosporin
nucleus, 7 Aminocephalosporanic Acid, a fermentation
product of Cephalosporin acremonium, an inhabitant of
sewage-infested coas tal waters off Sardinia. The basic
Presented to the American Academy of Otolaryngology-Head and Neck
Surgery Annual Meeting , September 12-16, 1992, Washington, DC.
Reprin t requests to: Randal A. Otto, MD, Department of Otolaryngology-
Head and Neck Surgery, The University of Te xas Health Science
Center, San Antonio, TX 78284 -7777.
900
cephalosporin nucleu s co nsists of two elements: I)
Dihydrothiazine Ring; and 2) B-Lactam Ring (Figure 1).
The differences in the various cephalosporin antimicrobi-
als is accounted for by changes in the R3 position, affect ing
the antimicrobial activity, and the R2 position, affecting
pharmacok inetic properties. It is the alterations at these
sites that account for the longer half-life, increasd B-
Lactamase stability, better entry through the bacterial cell
wall and the increased ability to attack the enzymes in cell
wall synthesis. 2
Since cephalosporins, like penicillins, contain the B-
Lactam ring; 5-20% of penicillin-allergic patients may
develop an allergy to the cephalosporins. However, exper-
ience in treating penicillin- allergic patients .with cepha-
losporins suggest that cephalosporins are safe except when
a history of an IGE (Type I) allergy to penicillin exists.v'
Rarely is the reverse the case, i.e., that the patient has a
Type I reaction to a cephalospori n and not to penicillin.
When this does occur, it is thought to be determined by the
7-Aminocephalosporanic acid
o
II
COH
0'0
.-----N
o II I
II 7
R1-CNH- - - -f------J....
R3
Cephalosporin Nucleus
Figure 1. Chem ical structure of the cepha losporin antibiot-
ics. I = dihydrothiazene ring ; II = B-Iactam ring .
ENT Journal· December 1994
DEXACORT™ Phosphate
(dexamethasonesodiumphosphate) In
The Focus of Topical Therapy
TURBINAIRF (dispenser)
Aerosol for Intranasal Application
The Power of Dexamethasone
BRIEF SUMMARY Information forPatients
The following isa brief summary only. Beforeprescribing, see complete prescribing Susceptibiepatientswho are onimmunosuppressant doses ofcorticosteroidsshould be
informationinDEXACDRr Phosphate inTURBINAIRE' product labeling. warned toavoidexposure tochickenpoxor measles.Patients shouid also beadvised
CONTRAINDICATIONS that it they are exposed, medical advice should besought without delay.
Systemic fungal intections. AOVERSE REACTIONS
Hypersensitivily tocomponents. Nasal irritationand dryness are the most common adverse reactions. The follOl'nng
Tuberculous, viral and fungal nasal conditions, ocular herpes simplex. have been reported: headache, lightheadedness, urticaria, nausea, epistans. rebound
WARNIN GS congestion, bronchial asthma, pertoration ofthe nasal septum, and anosmia. Signs of
Inpatients ontherapy with OEXACORTPhosphateinTURBINAlRE subjected tounusual adrenai hypercorticism may occur in somepatients, especiallyI'nthoverdosage.
stress, increased dosage ofrapidly acting corticosteroidsbefore, during, and after the Systemic enects from therapy ,vith DEXACORr Phosphate(dexamethasonesodium
stressful situation ~ indicated. phosphate) inTURBINAlRE' (d ispense~ are less likely to occur than "nth
oral or par-
Drug·inducedsecondary adrenocortical insuffICiency mayresult from too rapidlvithdrawal enteral corticosteroidtherapy because ata100'IOr total dose administered. Nevertheiess,
ofcorticosteroidsand maybeminimizedbygradualreductionofdosage. This Iype ofrelativeinsuffICiency may persist patients should be observed forthe hormonal eHects described belOl'1because ofabsorption ofdexamethasonefrom
formonthsafterdiscontinuationoftherapy; therefore, inany situation ofstress occurnng dunng that perod, hormone the nasal mucosa.
therapy should bereinstituted. Ifthepatientis rece" ingsteroids already, dosage mayhavetobeincreased. Since Fluidand Electrolyte DisturlJances
mineralocorticoidsecretionmaybyimpaired, salt and/or amineralocorticoidshould beadministered concurrenliy, Sodiumretenlion
Dexamethasone may mask some signs ofinfection, and newinfectionsmayappear during its use. There may be Fluidretention
decreasedresistanceand inabilily to localizeinfecfion whencorticosteroids areused. Therefore, patientsI'nth bacter- Congestive heart failure insusceptiblepatients
ialinfectionsshould alsobegivenappropriateantibiotic therapy if OEXACORTPhosphate inTURBINAIRE isused. Potassium loss
Moreover, dexamethasonemayaHectthe nitroblue-tetrazolium testforbacterialinfectionandproducefalse negative Hypokalemic aikalosis
resulls. Hypertension
Corticosteroids may activatelatentamebiasis. Therefore, it isrecommended that latent oractive amebiasis beruled Musculoskeletal
outbefore initiating corticosteroid therapy inany patientwho has spenttime inthetropics orany patient with Muscle weakness
unexplained diarrhea. Steroid myopathy
Lossofmusclemass
Prolongeduseof DEXACORTPhosphateinTURBINAIREmay produceposteriorsubcapsular cataracts, glaucoma with Osteoporosis
possibiedamage totheoptic nerves, and mayenhance theestablishmentofsecondary ocular infections due tofungi Vertebralcompression fractures
orviruses. Asepticnecrosisoffemoral and humerai heads
Usageinpregnancy: Since adequatehumanreproduction studieshavenot beendone withDEXACORTPhosphate in Pathologic fractureoflong bones
TURBINAlRE, useof thisdrug inpregnancyorinwomenof childbearing potential requires thatthe anticipatedbenefits Tendonrupture
beweighed against thepossible hazards tothe mother andembryo orfetus. Infants bornofmothers woo have receved Gastrointestinal
substantial doses of dexamethasone dunng pregnancy, should becarefully observed forsigns of hypoadrenalism. Peptic ulcerwithpossible subsequent pertorationand hemorrhage
Dexamethasoneappears inbreastmilk and could suppress growth, intertere with endogenous corticosteroidproouc- Pertoration ofthe small and largebowel, particularlyin patients with inflammatory bowel disease
tion, or cause other unwanledeHects. Mothers taking pharmacologic doses ofdexamethasone should beadvised not Pancreatitis
to nurse. Abdominal distention
Average and largedoses of hydrocortisone or cortisone can cause elevation ofblood pressure, salt andwater reten- Ulcerat" eesophagitis
tion, and increased excretion of polassium. These eHects are less likely tooccur vnth the synthetic derivativesand Dermatologic
I'nth DEXACORT Phosphate inTURBINAlRE, except when used in large doses. Dietary salt restrictionand potassium Impaired wound healing
supplemenlation may benecessary. All corticosteroids increase calcium excretion. Thinfragileskin
Petechiae and ecchymoses
Administration oflive virusvaccines, including smallpox. iscontraindicated inindividuaisrece" ingimmunosuppres·
Erythema
s"e doses of corticosteroids. II inactivated viral orbacterial vaccines are administered toindividuals receiving
Increased S1'IOating
immunosuppress"e dosesofcorticosteroids. the expected serum antibody response may notbeobtained. May suppress reactions toskintests
Patients who are ondrugs whichsuppress the immune system are moresusceptible toinfections than healthy Other cutaneous reactions, such asallergic dermatitis, urticaria, angioneuroticedema
individuals. Chickenpox and measles. forexamplecan have a more serioas oreven fatal course in ron-immune chil· Neurologic
dren (see PRECAUTIONSregarding useof thisproductinchildren) oradults oncorticosteroids. Insuch children or Convulsions
adults who havenothad these diseases, particularcare shouldbetaken toavoid exposure. Therisk ofdeveloping a Increased intracranial pressure withpapilledema(pseudotumorcerebrij usually after treatment.
disseminatedinfectionvaries among individuals and canberelatedtothe dose, route and duration of corticosteroid Vertigo
administration aswell astothe underlyingdisease. If exposed tochickenpox, prophylaxis withvaricellazoster Headache
immuneglobulin (VZIG) may beindicated. Ifchickenpox develops,treatment withantiviralagentsmay beconsidered. Psychic disturbances
If exposed tomeasles, prophylaxis with immune globulin ~ G) may beindicated. (Seetherespectve packageinserts Endocrine
forVZIG and IG forcomplete prescribing information.) Menstrualirregularities
If DEXACORT Phosphate inTURBINAIRE isindicaled inpatientswithlatenl tuberculosisortuberculin reactivily,close Oevelopment ofcushingoid state
observationisnecessaryasreactvaton ofthe disease mayoccur. Ouringproiongedtherapy ¥nthDEXACORT Suppressionofgrowth inchildren
Phosphate inTURBINAIRE, these patients should receivechemoprophylaxis. Secondary adrenocortical and pituitary unresponsiveness, particularlyintimes of stress, as intrauma,
Literaturereports suggest anapparent association betweenuseof corticosteroids and left ventricularfreewall surgery, orillness.
ruptureafter a recentmyocardialinfarction; therefore, therapy withcorticosteroidsshould be usedwithgreat caution Decreasedcarbohydrate tolerance
inthesepatients. Manifestalionsoflatentdiabeticsmellitus
Increased requirements for insulin ororal hypoglycemic agentsindiabetics
Keep outofreachofchildren.
Hirsutism
PRECAUTIONS Ophthalmic
During local corticosteroid therapy, the possibilityofpharyngeal candidiasis shouldbe keptin mind. Posterior subcapsular cataracts
Althoughsystemicabsorptionislow when DEXACORTPhosphate inTURBINAIREisused inthe recommended Increased intraocularpressure
dosage,adrenal suppressionmayoccur. Inaddition, other systemic effectsat steroidadministration must beconsid· Glaucoma
erecas a possibility, Exophthalmos
Following prolongedtherapy, withdrawal of corticosteroidsmay resullinsymptomsofthecorticosteroid withdrawal Metabolic
syndrome inclUding fever, myalgia, arthralgia, and malaise. This mayoccur inpatients even without evidenceof Negative nitrogenbalancedue toprotein catabolism
adrenalinsufficiency. Replacementofsystemic steroid with DEXACORT Phosphate inTURBINAIREshould begradual Gardiovascular
andcarefUlly monitored bythe physician. Myocardial rupture following recent myocardial infarction(see WARNINGS).
Other
There isan enhancedeffect ofdexamethasonein patients lvith hypothyroidismandin those lvith cirrhosis. Hypersensitivity
DEXACORT Phosphate inTURBINAIRE shouldbeusedcautiouslyinpatients withocular herpes simplex forfear of Thromboembolism
comeal pertoration. Weight gain
The lowest possible dose ofOEXACORTPhosphateinTURBINAIREshouldbeused tocontrol the conditionunder Increased appetite
treatmenl, and when reductionindosageis possible, the reduction must begradual. If beneficial eHect isnotevident Nausea
lvithin 7 days after initiation oftherapy, the patient should bere·evaluated. Malaise
Psychicderangementsmay appear when dexamethasoneis used, ranging from euphoria, insomnia,mood S1'nngs, Hiccups
personaiity changes, and severe depression, totrank psychotic manifestations. Also, e~sting emotional instabilityor OVEROOSAGE
psychotictendencies may beaggravated. Reports ofacute toxicityand/or death follOl~ng overdosage ofglucoconicoidsare rare. Inthe event ofoverdosage,
Aspirin shouldbeused cautiously inconjunction with OEXACORTPhosphate inTURBINAlREinhypoprothrombinemia. nospecific antidote isavailable; treatment issupport"e and symptomatic.
DEXACORT PhosphateinTURBINAlREshould beused withcaution inpatients I'nth nonspecific ulcerative coiitis, if Significant lethalitywas observed infemale miceatsingie oral dosas of3630 mg/m2 (1210 mglkg) and singie
there isa probabilityofimpending pertoration, abscess orother pyogenicinfection; also in d"erticulit~ ; fresh intesfi· intravenous doses of2382 mg/m2 (794 mglkg).
nal anastomoses; act"e orlatent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis.
Signs ofperitoneal irritation follOl'nng gastrointestinal pertorationin patients receiving large doses of corticosteroids OOSAGE ANO AOMINISTRATION
may beminimal or absent, Fat embolism hasbeen reported asa possiblecomplication ofhypercortisonism. 00 NOTEXCEEDTHERECOMMENDED DOSAGE.
Because clinical studieshave notbeendone,the useofthisproduct inchildren underthe age of6 years is not The usual initial dosage ofOEXACORTPhosphate inTURBINAIREis:
recommended. GrOlvthand development ofchildren 6 years ofageorolder onprolonged therapy I',ithOEXACORT Adults-2 sprays ineach nostril 2 or3 times a day.
Phosphate inTURBINAlRE should becarefUllyfolioV/ed. Children (6 to 12 years ofage)-1 or2 sprays in each nostril 2 timesaday depending onage.

N0rns
Dexamethasone may increase ordecrease motilityand numberof spermatozoa in some pauents. See instructions on the proper useofTURBINAlRE.
Phenytoin, phenobarbital, ephedrine and rifampin mayenhance the metabolicclearance ofdexamethasone, resulting When improvement occurs the dosageshould begradually reduced. Some patients I'nllbesymplom·free onone
in decreasedblood levelsandlessenedphysiologic activity,thus requiringadjustment in dexamethasonedosage. spray ineach nostrii 2 times aday. The maximumdailydosage for adults is12sprays, andforchildren, 8 sprays.
Therapyshouldbediscontinuedas soon asteasole. it maybereinstituted if recurrenceof symptomsoccurs.
Theprothrombintimeshould becheckedfrequenliy inpatientswho are rece" ingDEXACORTPhosphate inTURBINAlRE
and coumarin anticoagUlantsat the same time because of reportsthat corticosteroidshavealtered theresponseto Manufactured by: Merck & Co., Inc.,
these anticoagulanls. Studies have shownthat the usual eHect producedbyaddingcorticosteroids isinhibitionof
responsetocoumarins, althoughthere havebeensomeconflictingreports ofpotentiation, not substantiated bystudies.
When DEXACORTPhosphate inTURBINAIRE isused concomitantly withpotasslum-depletnqdiuretics, patients
West Point, Pennsylvania,U.S.A.
For: Adams Laboratories, Inc.,
Fort Worth, Texas, U.S.A.
lPBORATO
FORT\\'ORTH,
~ES ,
nrsm. 76t55·2645

should be observedclosely fordevelopment ofhypokalemia. Reference: " HaynesRCJr.Adrenocorticotropic hormone: adrenocortical steroidsand theirsynthetic analogs:
Since thecontents ofOEXACORTPhosphate in TURBINAIREare under pressure, thecontainer should not bebroken, inhibitorsof thesynthesis andactions ofadrenocortical hormones. In: GilmanAG, Rail TW, Nies AS, Taylor P, eds.
stored in extremeheat, orincinerated. It should bestoredatatemperature below 120'F, ThePharmacological83sis of Therapeutics. 8th eo. NewYork, NY: PergamonPress Inc.; 1990:1 447.

© Adams l aboratories, Inc. 1994 PrintedinU.S.A. 0334 August 1994

 CEPHALOSPORIN ANTIBIOTICS

side chain of the cephalosporin rather

than the 13-Lactam ring.3 Also, like other
13-lactam antimicrobials, cephalospor- PRECURSOR COAGULATION COMPLETED COAGULATION
FACTOR MOLECULE FACTOR MOLECULE
ins may be associated with bleeding
disorders due to the tendency of 13-
lactams to alter Vitamin K metabolism. (Glutam ic acid residues) (Y -Carboxyglutamic acid
residues
This may be further potentiated by those
cephalosporin antimicrobials which con- ~
CH2
tain the methyl-thiotetrazole (MIT) side I
Vitamin-K-dependent
chain . This side chain directly inhibits He-COOH
carbo xylase I
the microsomal carboxylase activity re- COOH
sponsible for conversion of inactive co-
agulation precursors into their active 02
Vitamin KH2 Vitamin K 2,3-Epoxide
forms.' Thus for those cephalosporins
which contain the MTT side chain, a
"double whammy" on the coagulation Vitamin K epoxide reductase
system may occur by depleting vitamin
K and directly inhibiting the microso-
mal carboxylase activity , resulting in Figure 2. Site of action of the MTT side chain on the post-translational
the procoagulants II,VII, IX and X re- modification of Vitamin K-dependent procoagulant proteins.
maining in their inactive decarboxy-
lated forms. (Fig 2) also demonstrate activity against gram (+) bacillus such as
Generally speaking, cephalosporins are classified into Clostridium and Corynebacterium diphtheria. Like most
three "generations," roughly corresponding to the past other cephalosporins, the first generation agents are not
three decades, based on their gram (-) spectrum. Thus, the active against methicillin resistant S. aureus, penicillin-
first generation cephalosporins have the narrowest and the resistant S. pneumonia, enterococcus or Listeria
third generation cephalosporins have the broadest gram (-) monocytogenes; a cause of neonatal meningitis . The gram
coverage. This has provided a useful, although somewhat (-) clinically relevant spectrum is limited to E. coli, Kleb-
arbitrary, means of grouping the many cephalosporins siella pneumoniae and Proteus mirabilis. Important to
available. Currently, 19 cephalosporins and five chemi- note is the lack of H. influenrae activity among the first
cally-related antimicrobials are being marketed in the generation agents, thus limiting their usefulness for many
United States (Table I). In the following sections, we will pediatric infections.
discuss the various agents, highlighting the clinically im- Considering there are only minor differences in the first
portant aspects the practicing clinician should be familiar generation cephalosporins, one can simply "pick a favor-
with . ite" . Of the parenteral forms, many prefer cefazolin
(Ancef, Kefzol) for a number of reasons . These include its
First Generation Cephalosporin Antimicrobials higher peak levels, longer half-life, economical cost and
The first generation cephalosporins currently marketed less pain when given intramuscularly. Cephalexin (Keflex)
in the United States consist of six antimicrobials (cephal- is considered the gold standard for the first generation oral
othin, cefazolin, cephapirin, cephradine, cephalexin, and cephalosporin agents.
cefadroxil). Three of these are limited to parenteral admin-
istration (cephalothin, cefazolin and cephapirin), two are Second Generation Cephalosporins
only available in oral preparations (cephalexin and The emergence of the second generation agents came
cefadroxil), while only cephradine is available for parenteral about with the introduction of cefamandole and cefoxitin;
or oral administration. Generally speaking, the parenteral cephalosporins demonstrating a major increase in the gram
agents are more active than the oral agents, in vitro and in (-) activity associated with a moderate loss of gram (+)
vivo, against the aerobic gram (+) organisms. The antimi- activity . The subsequent introduction of additional agents
crobial spectrum of these first generation cephalosporins is has now expanded the list of second generation cepha-
quite similar and includes most gram (+) and some gram losporin antimicrobials to include six true cephalosporins
(-) organisms. They have, in fact, the highest gram (+) (cefamandole, cefonicid , ceforanide, cefuroxime, cefaclor,
coverage of all the cephalosporins making them useful in cefprozil), three cephamycins (cefoxitin, cefotetan,
treating many common skin and soft tissue infections and cefmetazole), and one carbacephem (loracarbef). Unlike
in wound prophylaxis. Their gram (+) coverage includes the first generation cephalosporins, these agents differ
S. aureus, S. pneumoniae and anaerobic streptococci. They among themselves with regard to their in vitro activity

Volume 73, Number 12 903

 Prescribe LORABID
It's tough on otitis media
Proven clinically effectfve'" Gentle to your patients
in otitis media due to the 49% fewer cases of diarrhea with LORABID
most common pathogens: vs amoxicillin /c1avulanate (P<O .OOl ).2t
Streptococcus pneumoniae Only a 1% discontinuation rate in pediatric
patients due to GI-related events."
Haemophilus influenzae, including
11 lactamase-producing strains' Great strawberry
Moraxella catarrhalis, including bubble gum taste
lactama se-producing strains'
In a blind comparative test, 3
ptococcus pyogenes LORABID ranked #1 in taste.

onvenience parents
will appreciate
'S mple BID dosing may enhance patient Clinical trial patients aged 6 months to 12 years .
In a patient population WIth significant numbers of
ompJiance. And there's no need to B-lactamase-producing organisms, loracarbef's
e rigerate LORABID suspension... clinical cure and bacteriological eradication rates
were somewhat less than those observed with a
. stab e for up to 14 days at room product containing a B-Iactamase inhibitor.
LORABID's decreased potential for toxicity com-
pera ure. pared to products contammg B·lactamase
Inhibitors along With th susceptibility patterns of
the common microbes In a given geographic area
should be taken mto account when considerinq
the use of an antimkrobial.
LORABID I LORABID: 32/240 patients; Augmentin: 61 /232
for Oral patients.
Suspension, t The most commonly occurring gastrointestinal
adverse events In clinical trials with all patients in
200 mg /5mL, all indications were : diarrhea (4.1 %), nausea (1.9%),
with new vornitinq (1.4%), and abdominal pain (1.4%).
special seal After mIxing, store at controlled room tempera-
ture (59 0 to B6° F) for up to 14 days.

References:
1. Data on file, LillyRes rch Laboratories.
2. Pediarrtnt«: Dis /. 1992;I(suppl):S12-S19.
3. PedlQlrlnfecr ou t. 1994;13 :1-3.

'-------
See following page for briet summary
of prescribing information.

L00354- 840100FZ3
, Ell uuv
AND COMPANY

L flABZD
TM

FOR ORAL
SUSPENSION
lORACARBEF
Tough on otitis media, gentle on the GI tract

Ell Lilly and Company

Indianapolis. Indiana
46285
"-----'
I nrabld' (Ioracarbef) Population/Infection Dosage (mg) Duration (days)
Pulvules' , 200 mg and 400 mg ADULTS (<<13 years)
For Oral Suspension, 100mgor200 mgl5mL (50-mLand 100-mLsize) SecondaryBacterial Infection 200-400 q1 2h
BriefSummary. Consult thepackage insert for complete prescrib inginformation. of Acute Bronchitis
Acute BacterialExacerbation 400 q1 2h
Indications and Usage: Lorabid is a syntheticJHactam antibiotic of the carbacephem class for of ChronicBronchitis
oral administration. Lorabid is indicated in the followingmild to moderate infections caused by Pneumonia 400 q12h 14
susceptibie strainsofdesignated microorganisms.
Secondary Bacferial Infection of Acute Bronchitis caused by Streptococcus Pharynqitis/Ionsillitis 200 q12h 10
Sinusitis 400 q12h 10
pneumoniae, Haemophilus influenzae (including ,8-lactamase-producing strains), or (See CLINICAL STUDIES and INDICATIONS AND USAGE forfurtherlntorrnation.)
Moraxel/a (Branhamel/a) catarrhalis (including,B-Iactamase-producingstrains).
Acute Bacterial Exacerbations of Chronic Bronchitis caused by S. pneumoniae, H. infiuenzae Uncomplicated Skinand 200 q12h
(including ,8-lactamase-producing strains), or M. catarrhalis (including ,8-lacta mase- SkinStructureInfections
producingstrains).
Pneumonia caused by S. pneumoniae, or H. influenzae (non-,8- lactamase -producing Uncomplicatedcystifis 200q24h
(See CLINICAL STUDIES and INDICATIONS AND USAGE for further information.)
strainsonly). Uncomplicatedpyeionephritis 400 q1 2h 14
Otilis Media' caused by S. pneumoniae, H. influenzae (including ,8-lactamase-producing
strains), M. catarrhalis (including ,8-lactamase-producing strains), or Streptococcus INFANTS AND CHILDREN (6 months to12yrs)
pyogenes. . AcuteOtitis Media' 30mglkg/day q1 2h 10
AcuteMaxitlary Sinusitis' caused by S. pneumoniae, H. influenzae (non-,8-lactamase- (divideddoses)
producing strainsonly), or M. catarrhalis(including,B-Iactamase-producing strains). (See CLINICAL STUDIES and INDICATIONS AND USAGEforfurther information.)
PharyngitislTonsiliitis 15mg/kg/day q12h 10
'NOTE: Inapatientpopulationwith significantnumbers of ,B-Iactamase-producingorganisms, (divideddoses)
loracarbef's clinical cure and bacterioiogical eradication rates weresomewhat less thanthose
observed with a product containing a ,B-Iactamase inhibitor. Lorabid's decreasedpotentialfor Impetigo 15mg/kg/day q1 2h
toxicity compared to products containing ,B-Iactamase inhibitors along with the susceptibility (divideddoses)
patterns of thecommon microbes in agivengeographicareashould betaken into accountwhen 'Clinical studiesof otitis mediawereconductedwiththesuspensionformulationonly.Therefore,
considering theuseof anantimicrobial (see CLINICAL STUDIES section). thecapsule should notbesubstituted forthesuspension inthetreatment of otitis media.
Pharyngitis and Tonsitlilis caused by S. pyogenes. (The usual drug of choice Clinical Studies:
in the treatment and prevention of streptococcal infections,inciud ing the prophylaxis of
Loracarbef (Ll vs,B-l actamaseInhibitor (C)inAcute Otitis Media (US)
rheumatic fever, is penicillin administered by the intram uscular route. Lorabid is generally Efficacy:Astudy of acute otitismediaperformed inapopulationwitha significantincidenceof
effective in the eradication of S. pyogenes from thenasopharynx; however, data establishing ,B-Iactamase-producing organisms compared loracarbef witha,B-Iactamaseinhibitor. Usingvery
theefficacy of Lorabid in the subsequent prevention of rheumatic fever are not available strict evaluability and microbiologic/clinical response criteriaat the 10- to 16-day posttherapy
at present.)
follow-up, thefollowingpresumptivebacterialeradication/clinical cure outcomes (success rates)
Uncomplicafed Skin andSkinSfructurefnfectionscausedby Staphylococcusaureus (including wereobtained:
penicillinase-producingstrains)or S. pyogenes. Abscesses should be surgically drainedas ~ % Dueto Pathogens (N= 204) Success Rate
clinicallyindicated. S. pneumoniae 42.6% L equivalentto C
UncomplicatedUrinaryTract Infeclions(cystitis)caused by Escherichia colior Staphylococcus H. influenzae 30.4% L 9% lessthan C
saprophyticus'.
M. catarrhalis 20.6% L 19% lessthanC
NOTE: In consideringthe use of Lorabid in the treatment of cystitis, Lorabid's lower bacterial S. pyogenes 6.4% L equivalent toC
eradication rates and lower potential for toxicity should be weighed against the increased Overall 100.0% L 12% lessthanC
eradication rates and increasedpotential for toxicity demonstrated by some other classes of
approved agents (see CLINICAL STUDIES section). Safety: The incidences of the most common adverse events were clinically and statistically
Uncomplicafed Pyelonephrifis caused by E. coli. significantlyhigherinthecontrol groupversustheloracarbefgroup.
•Although treatmentof infectionsdue to this organism in the organ system demonstrated a ~ ~ Cl1n1rQl
clinically acceptable overall outcome, efficacy was studied infewer than10infections. Diarrhea 15% 26%
Contraindication: Known allergy to loracarbefor cephalosporin-class antibiotics. Rash' 8% 15%
Warnings: Becausecross-hypersensitivitycan occur among,B-Iactams, Lorabid should begiven
cautiously to penicillin-sensitivepatients anddiscontinuedif anallergic reactionoccu rs. •Primarily inthe diaper area inyoung children.
Pseudomembranous colitis has beenreported with nearly all antibacterial agents and should Loracarbef (Ll vsAmoxicillin (A)in Acute OlilisMedia (Europe)
beconsideredin differentialdiagnosis of antibiotic-associated diarrhea. Efficacy: A study of acute otitis media performed in a population with a lower incidence of ,8-
Precautions: Lorabid may be administered to patients with impaired renalfunction. Total daily iactamase-producing organisms than thatusually seen in UStrials compared loracarbetto amoxicillin.
dosage should bereduced inpatients with known or suspected renal impairment becauseof the Usingverystrict evaluability andmicrobiologic/clinicalresponsecriteria at the 10- to16-dayposttherapy
possibility of high and/orprolongedplasma concentrations. follow-up, thefollowing presumptivebacterialeradication/clinical cure outcomes (success rates) were
Loracarbefshouldbegiven cautiously to patients receiving diuretics concurrently. obtained: .
Prolongedusemay resultin overgrowth of nonsusceptibleorganisms. Ea1hQlWl %DuetoPathogen (N- 291) SuccessRate
Loracarbefshould be given cautiouslyto patients with ahistoryof colitis. S.pneumoniae 51.5% Lequivaient toA
Renal excretion of ,B-Iactamsis inhibited by probenecidand resulted in aboutan 80%increase H. influenzae 29.2% L14%greaterthanA
inthe AUCfor loracarbef. M. catarrhalis 15.8% L31%greaterthan A
Safetyand effectiveness havenot been determined inpregnancy, lactation, andinfants under6 S.pyogenes 3.4% Lequivalent toA
months of age. Caution shouldbeexercised in prescribingLorabidforthesepatients. Overall 100.0% Lequivalent toA
In geriatric patients who receivedthe usual recommendedadult doses in clinical studies, Loracarbef (L)vsDoxycycline (D)in Acute MaxillarySinusitis (Europe)
efficacy andsafetywerecomparableto resultsin nongeriatricadult patients. Efficacy: Astudy of acutemaxillarysinusitis performedin apopulation with a lower incidence '
Adverse Reactions: Most adverse reactions in clinical trials weremildand transient.Only 1.5% of ,B-Iactamase-producing organismsthanthat usually seen in US trials compared loracarbef
of patients discontinuedbecause of drug-related reactions, themost common of which were with doxycycline. Using very strict evaluabil ity (sinus-puncture) criteria and
diarrhea, abdominal pain,and skin rashes. microbiologic/clinical response criteriaat the 1- to 2-week posttherapy follow-up, the following
8l!..Mim presumptivebacterialeradication/clinical cure outcomes (success rates) were obtained:
Theincidence ofthefollowing adverse eventswas lessthan1%, exceptasotherwise noted: ~ % Dueto Pathogeo(N- 210) Success Rate
Gastrointestinal: Diarrhea, 4.1%;nausea, 1.9%; vomiting, 1.4%; abdominal pain, 1.4%; and S. pneumoniae 47.6% L equivalentto D
anorexia. H. influenzae 41.4% L equivalent to D
Hypersensitivity: Skin rashes (1.2%), urticaria, pruritus, anderythema multiforme. M. catarrhalis 11.0% L equivalent to D
Central Nervous System: Headache (2.9%), somnolence, nervousness, insomnia, and Overall 100.0% L equivalent to D
dizziness. loracarbef (L)vsCefaclor (C) in Uncomplicated Cyslilis Study (US)
Hemic and Lymphatic Systems: Transientthrombocytopenia, leukopenia, and eosinophilia. Efficacy: A study of cystitis compared loracarbef with cetaclor Using very strict evaluability
Hepatic: TransientelevationsinAST (SGOT), ALT (SGPT),and alkalinephosphatase. criteriaand microbiologic/clinical response criteria at the 5- to 9-day posttherapy follow-up,the
Renal: Transientelevationsin BUN and creatinine. following bacterialeradication rateswereobtained:
Cardiovascular System: Vasodilatation. ~ % Duetg Pathogen(N- 186) EradicatiooRate
Genitourinary: Vaginitis:(1.3%), vaginal moniliasis (1.1%). E. coli 77.4% L4%greater than C
As with other,B-Iactam antibiotics, the following potentially severe adverse experiences have (L = 80%)
been reported rarely with loracarbef in worldwidepostmarketing surveillance: anaphylaxis, Othermajor 12.5% L equivalent to C
hepatic dysfunctionincluding cholestasis, prolongation of the prothrombin time with clinical Enterobacteriaceae (L =61%)
bleedinginpatients takinganticoagulants, and Stevens-Johnson syndrome. S. saprophyticus 3.8% L equivalent to C
Ped iatric Patients
Theincidences of several adverse eventswere significantlydifferentinthepediatric population Loracarbef (L)vsOuinolone (0) in Uncomplicated Cystitis (Europe)
versustheaduit population respectively asfollows: Diarrhea (5.8%vs 3.6%);nausea (0.0% vs Efficacy: A study of cystitis compared loracarbef with an oral quinolone. Using very strict
2.5%); vomiting (3.3% vs 0.5%); anorexia (2.3% vs. 0.3%); headache (0.9% vs. 3.2%); evaluability criteriaand microbiologic/clinical response criteriaat the 5- to 9-day posttherapy
somnolence (2.1%vs0.4%);rhinitis (6.3% vs 1.6%); rash(2.9%vs0.7%). follow-up, thefollowingbacterialeradication rateswere obtained:
Jl::lactamAntimicrobial Class Labeling' ~ % Dueto Pathogens (N -1 89) EradicationRate
The following adverse reactions and altered laboratory test results have beenreported in E. coli 82.0% L7% lessthan Q
patients treated with,B-Iactam antibiotics: (L=81%)
Adverse Reactions-Allergic reactions, aplastic ane mia, hemolytic anemia, hemorrhage, Othermajor 10.1 % L32% lessthan Q
agranulocytosis, toxic epidermal necrolysls, renal dysfunction, and toxic nephropathy. Aswith Enterobacteriaceae (L =50%)
other ,8-lactam antibiotics, serum sickness-like reactions have been reported rare ly with PV 2762AM P [042694]
loracarbef.
Altered Laboratory Tests-Increased prothrombintime, positivedirectCoombs' test, elevated Additional informa tion available to the profession on request from Eli Liliy and Company,
LDH, pancytopenia, and neutropenia. Indianapolis, Indiana 46285. ..
Overdosage: Hemodialysis has been shown to be effectivein hastening the elimination of Eli Lilly Industries,Inc

~
loracarbef from plasma in patientswithchronicrenalfailure. . Carolina, Puerto Rico 00985
Dosage and Administration: Lorabid is administered orally either at least 1 hour priorto eating
~ ASubsidiary of EiiLilly and Company
Indianapolis, Indiana 46285
orat least 2 hours aftereating.
l.orabid " (Ioracarbef) Lorabid' (Ioracarbef)
L0 0354-CLK8401 00FZ3 ©1994, ELI LILLYANDCOMPANY
 CEPHALOSPORIN ANTIBIOTICS

against various bacteria . Although some will approach the
first generation cephalo sporins in their gram (+) coverage,
in general none offer any clinical advantage over the first
generation cepha losporins for infection s due to gram (+)
bacteria. The exception to this would be cefuroxime,
which crosses the blood-brain barrier . Against gram (+)
organisms; cefamandole, cefuroxime and cefmetazole are
the most active against staphylococci, while cefamandole
and cefuroxime are the most active against streptococci
and pneumococci. ' Cefoxiti n, cefonicid, ceforani de, and
cefotetan tend to be less active against the staphylococcal
organis ms.' Oral cefaclor is comparable to cephalexin in
its gram (+) cocci activity and the newer cephalosporins,
cefprozi l and loracarbef, appear to have some enhanced in
vitro activity against the gram (+) cocci.
Like the first generation cephalosporins the second gen-
eration cephalosporins are not active against methicillin-
resistant S. aureus, enterococci, penicillin-resistant pneu-
mococci or Listeria monocytogenes. The single exception
is cefprozil, which may be active in vitro again st L.
monocytogenes and intermediate penicillin-resistant S.
pneumoniae.
The gram (-) spectrum of seco nd generation cepha-
losporins includes the gram (-) cocci including Moraxella
cata rrha lis, Neisseria gonorrhoeae and Neisse ria menin-
gitides. Of particular importance is the high degree of
activity of cefoxitin and cefotetan vsNeisseriagonorrhoeae,
including the penicillinase producing strains. Addition-
ally, cefuroxime has very good activity against meningo-
cocci, making it the only seco nd generation cephalosporin

Table 1. Cephalosporins Currently Marketed in the U.S.

T1/2 Administra-
Cephalosporin MTT (hours) tion Route Comments

First Generation:
Cephalothin (Keflin) 0.5-0 .9 IV
Cafazolin (Kefzol, Ancef) 1.8 IV/1M "Prefer red" 1st Gen . parenteral agent
Cep hap irin (Cefadyl) 0.6-0.8 IV/1 M
Ceph radine (Velosef) 0.8 IV/1M/PO
Cephal exin (Keflex, Keftab ) 0.9 PO "Preferred" 1st Gen. oral age nt
Cefadro xil (Duricef) 1.4 PO

Seco nd Generation:
Cefamandole (Mandol ) + 0.6-1 .0 IV/1M Poor CSF penetration, bleed ing problems .
Cefon icid (Monocid) + 3.5-4.5 IV/1M Similar to cefamandole withou t bleeding problems.
Ceforanide (Percef) + 2.7-3.0 IV/1M Similar to cefamandole without bleeding problems.
Cefuro xime (Zinacef , Ceftin) 1.3-1.7 IV/1M/PO Penetrates CSF
Cefo xitin (Mefoxin) 0.7-1.0 IV/1M Best B. trag. activity
Cefotetan (Cefotan) + 3.0-4.6 IV/1M Best 2nd Gen. vs . Enterobacteriaceae
Cefmetazole (Zefazone ) + 1.2 IV/1M
Cefaclor (Ceclor) 0.6-0.9 PO
Cefprozil (Cefzil) 1.3 PO lin vitro activity vs. L. monocytogenes
Laracarbef (Lorabid) 1 PO

Thi rd Gene ration:

Cefotaxime (Claforan) 1-1.1 IV/1M Penetrates CSF
Ceftizoxime (Cefizox) 1.4-1.8 IV/1M Penetrates CSF
Ceftriaxone (Rocephin) 6.0-9.0 IV/1M Penet rates CSF, Best choice for meningitis, compli -
cated Lyme disease and ora l gonorr hea. OK in
renal failure at <2gm/day. Use with caution in
jaundiced and pre mature infants.
Ceftazidime (Fortaz, Ta xicef, 1.9 IV/1M Best pseudo monas activity, Penetrates CSF when
Taz idime) inflammed.
Cefopera zone (Cefob id) + 1.9-2.1 IV/1M Active vs. pseudomonas, least active of 3rd Gen . vs.
Enterobacteriaceae
Moxalactam (Moxam) + 2-2.3 IV/1M Assoc . with bleeding and enterococcal superin fec-
tions ; no longer recommended.
Cefixime (Suprax) 3.0-4.0 PO Weaker than 1st Gen . vs. Gram-
Cefpodoxime (Vantin) 3.3-4.2 PO

Volume 73, Number 12 907

 ana, NOORILY
to achieve therapeutic concentrations against this organ-
ism in the cerebral spinal fluid (CSF).
All second generation cephalosporins are clearly more
active against gram (-) bacilli than the first generation
cephalosporins. Cefoxitin is the best cephalosporin of any
generation with regard to its activity against bacteroides.s?
Of the second generation cephalosporins, cefotetan has the
best activity against the Enterobacteriaceae, although the
third generation cephalosporins are generally superior.'
The other second generation cephalosporins are also more
active against the Enterobacteriaceae than the first genera-
tion cephalosporins including resistant strains of E coli,
Klebsiella and Proteus. For the other Enterobacteriaceae,
the activity varies with the particular agent. None of the
second gene ration cephalosporins are active against
pseudomonas.
Due to variations of activity of the individual second
generation agents, some comments regarding specific agents
are warranted .
Cefamandole (Mandol)
When cefamandole was first introduced, it was consid-
ered a drug of choice by pediatricians because it allowed a
single drug treatment for Group A Streptococcus, pneumo-
coccus , staphylococcus, Neisseria and H. influen za caus-
ing joint infections, buccal and orbital cellulitis and
epiglottitis. However, since it does not penetrate the CSF,
breakthrough meningitis sometimes developed. Addition-
ally , due to the MTT group present on cefamandole,
hypoprothrombinemia, bleeding and disulfiram-like reac-
tions have been associated with this antibiotic. For these
reasons it is rarely considered a drug of choice.
Cefonicid (Monocid) . Ceforanide (Pereef)
Cefonicid and ceforanide are quite similar tocefamandole.
Their sole advantage consists of their longer half-lives,
with cefonicid having the longest half-life among any of
the currently available first or second generation cepha-
losporins. Only ceftriaxone (a third generation cepha-
losporin) has a longer half-life. Both cefonicid and
ceforanide have less activity against staphylococci and
ceforanide is considerably less active against H. influenza
than cefamandole, cefonicid or cefuroxime. Both cefonicid
and ceforanide also contain the MIT group but have not
been associated with hypothrombinemia or disulfiram-
type reaction , possibly related to substitutions of the me-
thyl group on the MTT side chain.'
Cefuroxime (Zinaeef). Cefuroxime axetil (Ceftin)
Cefuroxime is also similar to cefamandole with several
distinct advantages . These include its CSF penetration,
longer half-life, lack of an MTT side chain and the associ-
ated bleeding and disulfiram-type reactions. Additionally,
it is available in an oral preparation (cefuroxime axetil) .
908
Cefuroxime is the only second generation cephalosporin
with adequ ate CSF concentrations and has been reported to
be equivalent to ampicillin and chloramphenicol in the
treatment of pediatric meningitis.8 However , cefuroxime' s
activity against H. influenza is not as good as those of the
third generat ion cephalosporins and reports of delayed
sterilization of the CSF and moderate to severe hearing loss
associated with this drug have raised serious concern about
the use of cefuroxime for this indication ."
Cefoxitin (Mefoxin) , Cefotetan (Cefotan) ,
Cefmetazole (Zefazone)
The cephamycin (cefoxitin, cefotetan, cefmetazole) sec-
ond generation cephalosporins are less active against gram
(+) organisms but demonstrate good gram (-) and anaero-
bic activity, with cefoxitin demonstrating the most activity
of any cephalosporin against Bacteroides fra gilis and
cefotetan demonstrating the most activity of the second
generation cephalosporins against the Enterobacteriaceae."
Indeed, cefotetan ' s activity again st these organisms is such
that some experts would classify cefotetan as a third
generation cephalosporin. Of the cephamycins, only
cefoxitin does not contain the MTT side chain . Both
cefotetan and cefmetazole do contain this side chain and
therefore may be associated with hypothrombinemia and
disulfiram-type reactions, Clinical experience with
cefmetazole has been limited and its role would appear at
this time to be that of an alternative to cefoxitin orcefotetan,
although cefmetazole has considerably less activity against
members of the Enterobacteriaceae family and the gram
(+) organisms than cefoxitin.
Cefador (Cedor), Cefprozil (Cefzil)
Cefaclor and cefprozil are solely oral agents which
demonstrate a similar antimicrobial spectrum as the first
generation cephalosporins, with the exception of increased
activity againstH. influen za andM. catarrhalis. Between
these two, cefprozil is clearly superior in regard to its H.
influen za activity. Additionally, cefprozil demon strates in
vitro activity against L. mono cytogenes and some entero-
cocci.
Loraearbef (Lorabid)
Loracarbef, a new entry into the cephalo sporin arena , is
chemically identical to cefaclor except that the sulfur atom
in the dihydrothiazine ring has been replaced by a methyl-
ene group . This change makes the new drug a carbacephem
rather than a cephalosporin. However, due to loracarbef's
possessing similar activity to that of cefaclor, cefprozil and
cefuroxime and a chemical structure similar to that of
cefaclor, it is often included as a member of the ce'pha-
losporin family . The main advantage of loracarbef is its
BID dosing and enhanced H. influenzae activi ty. Thus,
like cefpodoxime (Vantin) , it may be useful in cases where
ENT Journal' December 1994
 When you suspect
the presence of
6-lactamase-
producing organisms
in otiti ia
and sinusitis"
Augmentin:
Now, 9years of
undiminished
efficacy 12

...
Excellent clinical response
rates in otitis media and
sinusitis'
...
Latest' ill vitro
susceptibility': still
impressive -
H. influenzae: 100% and

e
M. catarrhalis: 99.8 % 3
...
Actively destroys
8-lactamase4

• For MJ~ptible !lUain~ of indicatedorganism . AU.l:lllt'lI/;n i~

appropria,einitiallherapy "hen you uspect &-Iaclall"" -producing
organi,rT1.' .

*
t La'N av"ailable annual data: January 10 December 1991.
In vitro "uSlXptibi lit)' ooe, noc rece.ccily imply in \·;l'ocfflcacy.
I~ S("(' hri r MJrnmal') of p(b('rihin~ lnfcrmauon for
ron traindicatiom., warni ngs, pnocautions e nd ad verse reactiort"i
on adjan:nt pa~ .
R rerencec I. , leu He. Wil"", APR. Griineberg RN:
Amox.ici llinlcla\ulanic acid - a review of ib crrlC3C)" in over
38.500 patients from 1979 ,u 1992. J ChLm",hu 19935(21:67·93.
2. Data on file. SmithKline Beecham Pharmaceuticals. J. Data
from the Institutes for Microbiology Research. Franklin. Tenn.
.... leu He: Contribution of beta-lectamasc, to bacterial resistance
and mcchani..ms to inhibit beta-lectame . Am J Mt'd 1985:
79 (suppl 58):2·12.

ClSmi,bKlme Beecham. 1994

0 ., SmlfhKl m 8 Beecham
.;JU Phannaceuticals
PtI~PA11101
 A UGMENTIN '"amoxicillin!clavulanata potassium
BRiEf SUMMARY. FOR RJU PRESCRIBING INFORMATION.SEE PACKAGE
INSERT.
IndicationsendUsage:Augmentin isindicatedinthetreatmentofinfections caused by
susceptible strainsofthedesignated osyanisms inthecoOOitions listedbelow:
(01.., Respi,.tDty TooInfections cased I1i Il-lactamase-producing strains 01 Hemo-
p'iilus infllH!1llae and Moraxella(BtarilamellaJ catarrhali. OrinsMedia cased I1i OTTO, NOORILY
Il-laetamase-pmdoo"Jstainsof Hemop\ilusinfllH!1llae andMDtaxelia(/JlarIlamellaJ
catarrhalis. Sinusiliscausod I1i Il-!aetamase-producing strains ofHemop\ilus infllJl!fll2e
and A10taxella(/JlarIlameIIaJ caranhalis. Skin arrJ Skin Sl1l.<tIte Infections cased I1i
ll-!aetamase-pmdoo"Jstrains of SraiJrtf= alHeUS. E CDli and Klebsiellaspp.
lkinary Tl2Ctlnfections cased I1i Il-lactamase-pmdoo"J strains 01E CDli Klebsiella
Sw.and fnt_ sw I'.I1ile AugmentinisUllicatedonly for tl'eanl i60ns listed this organism is involved. However, the Medical Letter
above. infections caused byampicillirl-susceptible organisms are also amenable to
Augmentintreatment duetoitsamoxicillin <a1lent l1'erelore. mixed infections caused concludes that Loracarbef will simply provide another
I1i ampicillin-SIJStl!llbOle o-ganisms and Il-lactamase-producing lJ9'I1isms suSCfptibie
toAugmentin shouW mt requiretl'eadditioo 01aoother antibio6c alternative, although expensive, for the treatment of respi-
Bacteriologicalstudies todetemlire tl'ecausa.... o-ganisms and tl'eir s"""llbllility to
Augmentinshouldbe~ormed together with art{ indcatedsurgicallJOCfdures.Tbe!af1j ratory, urinary tract, and skin infections. For acute
may beinstiMed IIior toobtaini"J tl'e resul~ franbacteriological and SUSCfjlUoility
studies todetemlire tl'ecausa"" organisms and tl'eit$USCfpti.lity toAugmentinv.hen pharyngitis, penicillin remains the drug of choice. For skin
tl'ere isreason tobelieve tl'einfectionmay irMllwany oftl'eIl-!aetamase-pmdocing
lJ9'I1isms listed alme.lJr<e results arekooMl. adjust tl'eraf1j. if appropriate. or soft tissue infections, loracarbef offers no distinct ad-
Contraindications:Patients with a historyof allergicreactions to aIrf penicillin; 01'
patientswitha hiS1JXY 01AugmentiJ>associated cholestatic~und ice/be pa ti c dys1urcti0Ct vantage over other less expen sive alternatives."
WARNINGS:SERIIXJS AND OCCASIONAllY fATAl HYPERSENSITM1Y IANAf\iYlAC-
TIC) REACTIONS HAI,1O BEEN REPORTED INPATIENTS ON PENIClWN THERAPY. THESE
REACTIONS ARE MORELIKElY TO OCCUR ININOMOUAlS WITH A HISTORY OF
PENICIWN HYPERSENSITM1Y AND/ORAHISTORY OfSENSITM1Y TO MUlTIPlE
AllERGENS. THERE HAI,1O BEEN REPORTS OfINOMOUAlS WITH AHISTORY Of
Third Generation Cephalosporins
PENICIWN HYPERSENSITM1Y 'MiDHAI,1O EXPERIENCED SEVERE REACTIONS'MiEN
TREATEDWITH CEPHAlOSPORINS. BEfOREINITIATINGTHERAPY WITH AUGMENTIN.
The third gen eration cephalospor ins (cefotaxime,
CAREfULINQUIRY SHOUlDBE MADECONCERNING PRE'i10US HYPERSENSITM1Y
REACTIONSTO PENICIWNS.CEPHAlOSPORINSQROTHER AllERGENS.IfAN AllERGIC
ceftizoxime, ceftriaxone, ceftazidime, cefoperazone,
REACTION OCCURS. AUGMENTINSHOUlD BE DISCONTINUED AND THEAPPROPRIATE
THERAPY INSTffiJTEO.SERIOUS ANAPHYlACTIC REACTIONS REOUIRE IMMEDI·
moxalactam, cefixime and cefpodoxime proxetil ) repre-
ATE EMERGENCY TIREATMENT WITH EPINEPHRINE. OXYGEN. IfiTRAVENDUS
STERDIDS AND AIRWAY MANAGEMENT.INCWOING INTUBATION. SHOUlD
sent the result of continu ed efforts to improve gram (-)
AlSO BE ADMINISTERED AS INDICATED. Psoudomembranous colitishasbeen
reported with nearty all antibacterial agents.including AlIgmentin, andhas coverage. These agents demon strate an increased stability
ranged in severity from mild to life-threatening. Therefure. it is important to
considerthis diagnosisinpatientswhopresent withdiarmeasuhsequenttothe to B-Lactamases produced by many gram (-) bacteria and
administration ofantibaeterialagents.Treatment 'Nittiantibacterial agents altersthe
normal flora 01thecolonand may permit overgrowlh 01 dostridia. StudiesUllicate thet several provide excellent CSF penetration (ceftazidime,
atoxinproduced byClostridium difflCileisooe ~ cause of-antibioticassociated
colitis.· Aftertl'edi,glllSis01pseudomemillaoouscolitishas been established.tl'erapeu-
ma ry
ceftriaxone and cefotaxime). Third generation cepha-
ticmeasures shouldbeinitiated.Mildcases01pseudomernbraoo colitisusua l~ respool
todrug cflSCOlltinuationalore.lnmoderate to5eI1!re cases. cons~eratioo shouldbegr..n losporins are highly active against Neisseria gonorrhoe ae
tomanag"""" withfluids and electroljtes. protein s u ~ ementa tion andtreatmentwith
anantibi)cterial drug d inica l~ effectMl against C difficile colitis. Use Augmentin cau- and gram (-) bacilli includin g H. influenza and most of the
tioos~ inpa ti en ~ with eviderce 01 hepatic ~ fur<ti0Ct Hepatic toxicityassociatedwith
Augmentin use isusua l~ reversible On rareoccasions. deathe have been reported Iless Enterobacteriaceae. Some are also activeagainst pseudomo-
than 1 death reported perestimated4 millionpresaiptions v.OOdwidel. These have
g erera l ~ been cases associated with sari""uRleffvi"J diseasesorcamnitant medica- nas (ceftazidime and cefoperazone) with ceftazidime pos-
tions lsee CONTRANOICATIONS and AMRSE REACTIONS-lNefl
Preca utiD ns:G e n era ~ I'.I1i ~ Augmen tin lXlS""" tl'e cha _ ""' toxici ty of tl'e sessing the greatest antipseudomonal activity, including
penicillingroup ofantlbiotics. periorfc assessment 01 organ Sl'1'lTl hmions. ir<luding
renal.hepaticand hernatqxlieticfurdion. isaiMsa~ e dlling prolonged tl'eraf1j. so me strains resis tant to the aminog lycosi des and
Ahighpen;entage 01 pa t i ~ with """"""eosiswill receive ampicilfm develop askin
rash. Thus. ampicillin class antibiotics should oot beadministered to pa t i en ~ with
""""",I eosi< The IXlSSiMtyof superinlections with IIIjtOlic orbacterial pathogens
antipseudomonal penicillin s.
shouI d be kept in rniOO
nas orCarrJidal. tl'edrug sIllu~
du ring theravl · ~superin l ections
bediscontinued and/orappropriatetl'eraf1j instituted.
OCCUl l usual ~ i rMlivi "J PseIXiamo­ Like the second generati on cephalosporins, the third
Drog Interactions: ProIJenetlj decreases therenal tubular secretion ofarroxicillin.
Cor<urrent use with Augmentin may resuh in ircreased and prolonged blood levels01
generation agents are generall y less active against the gram
aroorollin.The txmJITent aOOlinistration of al ~ ri nol and ampicillinircreases substan-
tiallytheincidence of rashes inpatients receivirYJ roth drugs as comparedtopatients
(+) organisms and anaerobic organisms than the first
receiviIY:I a ~ ci l i n alone. ItisootknlJo,om vJletherthispotentiationofampicillinrashes is
duetoa n~rinol ortheh;-peruricemiap-esent inthese patients.Therearenodata with generation cephalosporins. Only moxalactam has activity
Augmentin andallopurinol adm in i ~ ared corcunently.
A"JI7l"Itinshouldootbeco-administered with Antabuse' ldisuifiram}. against Bacteroidesfragili s comparable to that of cefoxitin.
Carcinogenesis.Mutagenasis..lmpairmentoffertility: lOOij-term studiesinanimals
have not been performed toevaluatecarcinogenicOfmutagenicpotential. All other third generation cephalosporins generall y have
Pregnancy (category 8~ Reproductionstudieshave beenperformed inmiceand ratsat
doses uptoten(1 0)times the human dose and haverevealednoevideru of impaired less activity.' Against the gram (+) cocci, the third genera-
fertility orharm tothefetusdue toAugmentin. Thereare, however,no adequateand wall-
controlled studies inpregnant'NOmen.Becaus&animalreproduction studiesarenotalways tion cephalosporins offer no clinical advantages over the
predictive ofhumanresponse,usethis drugduring pregnancy onlyifclearlyneeded.
laborandDelivery:Oralampicillinclassantibiotics aregenerally ~rly absorbed during first generation cephalosporins except in the case of men-
lalxlr. Studiesinguinea pigs have shoYm that intravenous administration of ampicillin
decreased theuterinetone.frequency ofcontractions,height ofcontractions andduration ingitis when CSF penetration is important. Moxalactam
ofcontractions.Hmvever,itisnot krJov.m whether theuse ofAugmentininhumansduring
law ordelivery hasimmediate ordelayed adverseeffects onthefebJS, prolongs the and ceftazidim e are the least active parental third genera-
duration Df .bor.
orira eases tl'elikeliOOod tl'et 10_ del ",,~ orother obstetrical
interventionorresuscitationof thenev.tomwillbenecessary.
Nursing Mothers:Ampicillinclass antibiotics areexcretedinthemilk; therefore,caution
tion cephalosporins against S. aureus and coagula se nega-
slxJuldbeexercised when Augmentin isadministeredtoa nursing woman.
AlIve"" Reactions:Augmentinisg "" ral ~ well tolerated.!bemajority 01side effom
tiv e staphy lococc i. Mo xalactam, ceft azidime and
obseo"" indinical trials were rniW and transient<3%01patientsdiscontinued theraf1j
because ofthem.The roost frequently reported adverseeffomweredianhea/loose stools,
cefoperazone are also less active against streptococci and
19'Ji>1nausea 13%1. skin rashes and urticaria 13'Ji>1.lIlrniti"J(1 %)and '"'linitis(1 %J!be
overall ir<idence of side effom. and in particular dian1lea. ircreased withtl'ehigler
pneumoc occi. Parenteral cefotaxime, ceftizox ime and
reconnmled dose.Other lessfrequently r"l'Jf1edreactions ir<lude:abdominaldiscom-
Iort. f1atuleoce and headache.
ceftriaxone demon strate excellent activity against S.
!befollowi"J adversereections have been reported for alTllicillinclass antibiotics:
Diarrtlea. nausea, vomiting. indigestioo. gastritis. stomatitis. glossitis. black 1lair{
pnew noniae, S. pyogenes and S. agalactiae. 2
!O"JUe.enteroeolitis. mocoartaneous canddOsis andpseudoroomlxaoous colitisOnsetol
pseudoroomlxaoous colitis S)'IlIl!OOlS may oa:ur dlling oraft" antllliotic treatment lsee Although many of the third generation antimicrobials
WARNINGSI. Slin rashes. pruritus. toticaria. a"Jioederna. serum s ickness ·l~e reections
lurticaria orskin rash aetlJl'Il'nied I1i artlritis. a t1lua~~. mya lg ~ . and lrequently fever!.
are quite similar, a brief description of each agent is
erytl'ema multiforme l rare~ Stevens.Jcmson S)TXIroniel and an occasional case 01 extoli-
a.... dermatitis lir<iud"l toxic ep ~ermaI necro1)1isJThese reections may becontrolled warranted to highlight some of these clinica lly important
withantihista rninesand .ilnecessa~ .S'r'fernic_
0CC1J. tl'edrug shouldbediscontiooed.unlesstl'eopinion oftl'eliTYsiciandictates other·
ro ids .l'il'oneve rsoch reactions
features.
wise.Sen"" and occasionallatellrtpersensitivitylanalir1lactic)reections canoctUrwith
oral penicillin lseeWARNtNGS).Amoderaterise inASTISGOn and/or AlTISGl'Tlhasbeerl
ootedinpa ti ~ treatedwithal11licillinclassantJoiotics lxJt tl'es~n ificarce oftl'ese
fiooif'ijsisunkrowTl.Hepatic dysfuoctioo. ioclOOingirr:reases inserum transaminasesfAST Cefotaxime (Claforan)
and/or Aln. serum rnlirubinand/or alkalinephosphatase. hasbeen infrequently reported
with Augmentin. The histologicfrndi"JsonI"",biopsy have consisted01predominantly Cefotaxime was the prototype third generation cepha-
cholestatic. oopatocellular. ormixed chotestatic-!lepatocellularcha"Jes. The onset of
signs/S)mptorns 01hepaticdysfurction may OCClJrduring or5eI1!raiweeks aft" theraf1j has losporin to be marketed in the United States. It demon-
beendiscontinued.The hepatic~ fu rcti on . v.ilich may be"""e. is u sua l ~ " ", ~ ib le .
Onrareoccasions. deathshave been reponed(less than1deathrepolled perestimated strates excell ent acti vit y aga inst S. pn eu111oniae, S.
agala ctia e and S. pyogenes. It also demon strates "good
4 million prescriptions worldwidel. These have g e neral~ beencases a ssoc ~ ted with
serious underlyingdiseases orCOOCOO1itantmedications.Interstitial nephritisand hemabJria
have been reported rarely. Anemia, thrombocytopenia. thrombocytopenic purpura.
eosinophilia. leukopeniaand agranulocytosis have been reportedduring therapy with activity against staphylococci, however, it demon strates
penicillins.Thesereactions areusually reversible ondiscontinuationof therapy and are
believed tobehype~ens i tMty phenomena. Aslightthrombocytosiswasnotedinless than
1%ofthe patientstreatedwith Augmentin. Reversible tr,-peractivity, agitation. anxiety.
no clinical advantage over the first generation cepha-
insomnia.confusion,behavioraldlanges,and/ordillinesshave beenrep:lrtedrarely. losporins except in the event of meningitis.
BRS-AG:l6

910 ENT Journal · December 1994

 CEPHALOSPORI N ANTIBIOTICS
Cefotaxime contain s an active metabolit e which is 4-8
times less active than cefotaxime but more active than
cefazolin and cefoxitin again st mo st anaerobic gram (-)
bacteria. Cefotaxime has only fair act ivity against
Ba cteriod es frag ilis.
Appl ication s for cefo taxime includ e meningiti s and,
among the third generation ceph alosporins, the greatest
clini cal experience has been obtained with this agent. It is
useful in the treatment of gram (-) enteric bacilli menin gitis
and meningiti s secondary to H. influ enza type B, including
B-Lactamase producing strains. Indeed , most prefe r a third
generation cephalosporin for treatment of these infections
over ampicillin and chloramphenicol. Cefotaxime is also
indicated for emperic treatment of meningitis in infants
and young children and for the treatment of neonatal
meningitis in combination with ampicillin. It is not indi-
cated for pseudom onas meningitis. Other serious gram (-)
bacillary infections can be treated with cefotaxime, as an
effective alternative to aminoglycosides, and for certain
serious infections such as Klebsiella pneumonia and uncom-
plicated as well as disseminated gonococcal infections.
Ceftizoxime (Cefizox)
Ceftizoxime is essenti ally identical to cefotaxime except
that it possesses a longer half-life and is not metabolized.
Clinical experience how ever is limited, but appears prom-
ising. It is currently approved for meningitis due to H.
influenza and look s promising for other forms of men ingi-
tis. Likewise it can also be used for treatment of gon orrhea.
Ceftriaxone (Rocephin)
Ceft riaxone has a similar mechani sm ofaction, spectrum
and resistant properties to cefotaxime except that it demon -
strate s outstanding activity against Neisseria gonorrh oeae
including chromosom al-mediated resist ant N eisseria
gono rrhoe ae, tetracycline-resistantNeisseria gon orrh oeae,
and penicillin-resistant Neisseria gonorrhoe ae. Ceftri axone
has an ex tremely long half-li fe of 6-9 hours and demo n-
strates the best third generation cephalosporin activity
agai nst staphylococc i. Additionally, ceftriaxo ne demon-
strates exquisite activity against H. influ enza with an MIC
of .015mcg/ml and is also active against strep A, B and
pneumococci.
Becau se ceftriaxone is highly protein bound it can dis-
place bilirubin from albumin binding sites and some re-
commend caution when used in jaundi ced or prem ature
infants. I I Ceftriaxone has also been associated with forma-
tion of biliary sludge in the gallbladder leading to symp-
toms ofcholecys titis, which are reversible.v'<" Ceftriaxone
can be used in severe renal imp airment without dosage
adju stment if the total dose is maintained to less than 2
grams/day.
Ceftriaxone has the same applications as cefotaxime
plus it is the drug of choice for uncomplicated gonococcal
Volume 73, Numb er 12
infections. It is also the preferred drug for disseminated
gonococc al infections in adults and children, neonatal gono-
coccal infections , chancroid and Lyme disease with serious
neurologic, cardiov ascul ar or joint abnorrnalities.v'v "
Ceftriazone also represents an excellent monotherapy agent
for the treatment of bacterial meningitis in infants and young
children and in combination with ampicillin for neonatal
meningitis.v"
Ceftazidime (Fortaz. Tazicef. Tazidime)
Ceftazidime dem onstrates the best activity aga inst
pseudomona s of the third generation ceph alosporin s and
obtains a high CSF concentration in the presence of inflam -
mation. Alon g with moxalactam, ceftazidime is the least
active third generation cephalosporin agai nst the S. au reus
and coagulase (-) staphylococci. Ceftazidime contains no
MTT side chain and is not associa ted with bleedi ng and
disulfiram-type reactions.
The primary adva ntage of ceftazidime over the other
third ge neration cephalospor ins is its activity aga inst
pseudom on as . It is m ore acti ve in vitr o than
amino glycosides, carbenicillin and piperacillin, including
resistant strains. It is superior to cefoperazone in its
activity to pseudomonas, CSF penetration, lack of the
MIT side chain and its labelin g for children.
Indications for ceftazidime include hospital-acqu ired
gram (-) infections when pseudomonas is suspected, men-
ingiti s due to pseud omonas, cys tic fibros is patient s with
acute pulmonary exace rbations and treatment of the febrile
neutropen ic patient whe n used in combination with
aminoglycosides.'
Cefoperazone (Cefobid)
Cefoperazone is considered the least active of the third
generation cephalosporin s against the Ent erobacteri aceae.2
Cefoperazone is also not reco mmended for meningitis due
to its variable penetration of the CSF and it is not labeled
for use in children, infants and neonates.' Cefoper azone
dem onstr ates moderate activity aga inst Pseudomonas
aeruginosa, however is considera bly less active than
ceftaz idime. It has poor activity against S. aureus and
Bacteri odes fragilis and is less active against the strepto-
cocci and pneumococci. Additionally, cefop erazone con -
tains an MTT group and therefore can be associated with
bleeding and disulfiram-typ e reactions.
The main advantage of cefoperazone is its longer half-
life result ing in a b.i.d. dosing.
Moxalactam (Moxam)
Moxalactam, although classified as a third generation
cephalosporin, is technically not a penicillin , cephalosporin
or cephamycin. Moxalactam is very similar to cefotaxime
except that moxalactam has been assoc iated with serious
bleedin g disorders secondary to the MIT group as well as
911
 ana, NOORILY

Table 2. Summary of the Most Clinically Useful Cephalosporin Antibiotics.

First Generation:
Cefazolin (Kefzol, Ancef) Preferred 1st generation parenteral agent
Cephalexin (Kefle x, Keftab) Preferred 1st generation oral agent

Second Generation:
Cefuroxime (Zinacef, Ceftin) Penetrates CSF
Cefo xitan (Mefo xin) Best Cephalosporin vs. B. trag.
Cefprozil (Cefzil) Oral 2nd generation agents available in suspen-
Loracarbef (Lorabid) sion with improved H. influenza activity

Th ird Generation:
Ceftazidime (Forta x, Tazicef, Best antipseudomonal cephalosporin
Tazidime)
Ce ftria xone (Rocephin) Best choice for meningitis , complicated Lyme
disease, and oral gonorrhea. Use with caution in
jaundiced or premature infants.

Ceftriaxone (Rocephin) Penetrates CSF

Cefotaxime (Claforan)
Ceftazidime (Fortaz, Tazicef,
Tazidime)

Cefpodoxime (Vantin) Best 3rd generation oral agent vs . H. influenza

and gram (+) organisms.

(Note: None of the above contain an MTT side chain).

carboxyl substitution at the RI posttion. These bleeding
co mplications have included fatalities and occ ur in approxi-
mately 2.5% of patient s receiving the antibiotic for more than
7 days.2.2o.21 Most of the bleedin g complications have been
indeed serious ones . Additionally, superi nfec tions with
enterococci have been more frequent with Moxalactam than
any of the other third generation cephalospori ns." This may
be due to the very poor activity of moxa lactam against these
orga nisms . Due to the numerous complications and the
superior altematives moxa lacta m is no longer indicated.
Cefixime (Suprax). Cefpodo xime proxetil (Vantin)
Th e only orally administered third ge neration cepha-
losporins marketed in the Unite d States are cefixime, and
more recently, cefpodoxi rrie proxetil. Th ese age nts have
excellent activity agai nst the entero bacteriace ae, H. infl u-
enza , Moraxella catarrhalis, N. meningitides, and N.
gonorrhoeae.
Cefixime is more active against S. pneumoniae, S.
pyogenes, and S. aga lactiae than other ora l cep halospor-
ins . However, S. aureus, and coagulase negati ve stap hylo-
cocci are resistant to cefixime, thus severely limit ing its
applications for many otolaryngologic infections.' Poten-
tial applica tions for cefixime have been primarily for otitis
media and strep pharyngitis, however freq uent side effec ts
are associated with cefixime including diarrhea in 16%,
loose stools in 5% and nausea in 7%.2,22.24 Th ere have also
been repor ts of docum ent ed pse udo me mbrano us coli tis
with cefixime.' One study ha s shown cefixime to be better
than amoxicillin for B-Iactam pro ducing H. influenza but
less effective for S. pneumo nia . Addi tionally, nine patients
dem onstrated resis tant S.aureus cultured from the middl e
ear whereas none of those pa tien ts in the amox icillin gro up
subsequently grew Siaureus from the mid dle ear space."
It therefore appears that cefixime offers no adva ntage for
the treatm ent of otitis medi a or strep pharyngitis over other
less expensive antimicrobials.
Cefpodoxime proxetil, like ce fixi me, has excelle nt H
influ enzae activi ty. However, it also possesses better gram
(+) activi ty. Due to these properties and avai lability in a
suspension form, it has becom e a popul ar drug for treat-
men t of recalcitran t pedi atr ic sinusi tis amo ng some clin i-
cians. Like all othe r ora l cephalosporins, cefpodoxime
proxetil has no anaerobic ac tivity. As with cefixime, there
have been documented repo rts of pseudomembra nous colitis
wi t h cefpo dox ime a nd o ne dea th a ttrib uted to
pseudom embranous co litis and dissemi nated intravascular
coagulation."
Summary
Although a large number of cep halos pori n antimicrobi-
als are avai lable, one ca n quick ly dis till these down to a few

912 ENT Journal · December 1994

 CEPHAL OSPORIN ANTIBI OTICS
which are most likely to be clinically useful (Table 2). One
should keep in mind that the first generation ceph alospor-
ins tend to have the best gram (+) coverage of all the
cephalosporin antimicrobials and relatively poor gram (-)
activity. Although the first generation agents have similar
antibacterial activity, cefazolin (Kefzol,Ancef) is often the
preferred parenteral drug of this group for treatment of
gram (+) infections as well as surgical proph ylaxis with
cefalexin (Keflex) being the preferred oral first generation
cephalosporin .
Second generation cephalosporins demonstrate improved
gram (-) activity, generally at the expense of gram (+)
coverage. Of the second generation cephalosporins,
cefoxitin (Mefoxin) has the best activity of all the ceph a-
losporin s against bacteroides. Cefotetan (Cefotan) has the
best Ent erob acteriaceae activity and only cefuro xime
(Zinacef, Ceftin) has any CSF penetration.
With developm ent of the third generation cephalas por-
ins, further gram (-) activity coupled with improved CNS
penetration has. been realized. Of the cephalo sporin s,
ceftazidime (Fortaz, Tazicef, Tazidime) is clearly superior
for its antipseudomonal activity. Ceftriaxone (Rocephin)
is the preferred drug for treatment of Lyme disease with
serious neurologic, cardiovascular or joint abno rmalities
as well as for many gonococcal infections.
Likely uses for the third generation cephalosporins fall
into primarily three categories. 1) When the bacteria are
known to be multiply resistant to other, less expensive
antimicrobials and are sensitive to the third generation
cephalosporins. 2) When equally effective, third genera-
tion ceph al osp orin s are usuall y pr eferred to
aminoglycosides to avoid the ototoxicity, nephrotoxicity
and the need to monitor serum levels assoc iated with
aminoglycoside use. 3) The high in vitro activity of third
generation cephalosporins against most gram (-) bacilli
makes these agents more desirable than less expensive
alternatives for certain severe infections (i.e. pneumonia
due to Klebsiella pn eumoniaey.
When considering the selection of a particular third
generation cephalosporin the following should be kept in
mind : I ) ceftaz id ime (Fo rtaz, T az ice f,T azidime),
ceftriaxone (Rocephen), cefotaxime (Claforan) all have
excellent CNS penetration. Therefore compare adverse
reaction profil es, cost and pharmacokinetics, when select-
ing a specific agent. 2) Third generation cephalosporins
should not be used alone for neonatal meningitis since none
of these agents are active vs. L. mo nocytogenes or entero-
cocci. 3) Ceftazidime (Fortaz, Tazicef, Tazidime) is the
preferred third generation cephalosporin vs pseudomonas,
with cefoperazone being a less active alternate however,
4) Enterococcus, Listeria monocytogenes, methicillin-re-
sistant staph aureus and legionella pn eumoph ila are resis-
tant to almo st all cephalosporins.
Volume 73 , Number 12
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