PHARMA B: ANTI-MICROBIALS I

DR. JENNIFER T. CO – FEB. 26, 2018

BIOCHEMICAL REACTIONS AS POTENTIAL TARGETS CEPHALOSPHORINS

 Class I - The lower the generation, the better the activity for gram (+)
 Class II - As the generation gets higher, it loses its gram (+) coverage
 FA synthesis and utilization but has an increasing gram (-) coverage
 Class III - Third and fourth generation has no coverage for anaerobes
 Synthesis of peptidoglycan First generation Cefadroxil
- Use for prophylactic surgery Cefazolin
 Protein synthesis
except for colorectal surgery; Cephalexin
 Nucleic acid synthesis
commonly used is Cefazolin Cephalothin
(IV prep) Cephradine
BETA-LACTAM AND OTHER CELL WALL AND MEMBRANE
Cephapirin
ACTIVE ANTIBIOTICS
Cephaloridine
BETA-LACTAMS COMPOUNDS Second generation Cefaclor
Penicillinase-Susceptible - Cefuroxime can cross the BBB Cefamandole
Penicillin
- Cephamycins are indicated for Cefonicid
Narrow Spectrum Penicillin Benzylpenicillin – Pen G anaerobes Cefuroxime
Phenoxymethylpenicillin – - Cefoxitin is the only available Cefprozil
Pen V Cephamycin in the Philippines Loracarbef
Extended-Spectrum Penicillin Aminopenicillin
Ceforanide
- Carboxypenicillins and Amoxicillin
Cephamycins:
Ureidopenicillis are anti- Ampicillin
Cefoxitin
pseudomonal penicillins Esters
Cefotetan
- Disodium Carbenicillin is the  Bacampicillin
Cefmetazole
only available  Pivampicillin
Third generation Cefoperazone
carboxypenicillin in the  Talampicillin
- Anti-pseudomonal activity Cefdinir
market Carboxypenicillins
- No activity for anaerobes Cefditoren pivoxil
- Esters are pro-drug and Carbenicillin
Cefetamet
needs to be hydrolyzed in the Indanyl Carbenicillin
Cefotiam
stomach to released Disodium Carbenicillin
Cefotaxime
Ampicillin  Ticarcillin
Ceftizoxime
 Ternocillin
Cefixime
Ureidopenicillins
Cefodoxime proxetil
Piperacillin
Ceftibuten
Mezlocillin
Moxalactam
Azlocillin
Ceftriaxone
Apacillin
Ceftazidime
Penicillinase-Resistant Penicillin
Anti-Staphylococcal Penicillin
Fourth generation Cefpirome
Methicillin
- Anti-pseudomonal activity Cefepime
Nafcillin
- No activity for anaerobes
Isoxazosyl penicillins
Fifth generation Ceftobriprole
Oxacillin
Active against MRSA Ceftaroline fosamil
Cloxacillin
Dicloxacillin (most active)
MONOBACTAM Azteronam
Flucoxacilllin CARBAPENEMS Imipenem (prototype)
- Strongest antibiotic available Meropenem
Beta Lactamase Inhibitors Clavulanic acid
- Do not have anti-microbial Sulbactam - Ertapenem are not used for Ertapenem
properties. The anti-microbial Tazobactam nosocomial infection; little Doripenem
properties depend on the Avibactam coverage for Pseudomonas &
specific antibiotic combined Acinetobacter
with it GLYCOPEPTIDE ANTIBIOTICS Vancomycin
Teicoplanin
Televancin
Dabavancin
OTHER CELL WALL OR Daptomycin
MEMBRANE ACTIVE AGENTS Fosfomycin
Bacitracin
Cycloserine

Page 1 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018
BETA LACTAM COMPOUNDS
 Cycloserine will inhibit the addition of 2 terminal D-ala
 Bacitracin inhibits dephosphorylation of the lipid carrier
 Vancomycin inhibits elongation of proteins
 B-lactam antibiotics inhibits the transpeptidation
PENICILLIN
CLINICAL LIMITATIONS
 Unstable at acidic pH
 Susceptible to beta lactamases
 Inactivity against gram negative bacilli
BASIC STRUCTURE AND CLASSIFICATION
 6-aminopenicillanic acid
 Parent compound of semisynthetic penicillin
 Thiazolidine ring
 Beta-lactam ring
 Site of action of beta lactamase
 Site of action of amidase
 Site of attachment of secondary amino group (RNH-)
CLASSIFICATION
 Penicillins (e.g. Penicillin G)
 Greatest activity for:
 Gram (+) organism
 Gram (-) cocci
 Non B-lactamase producing anaerobes
 Limited activity against gram (-) rods
 Susceptible to hydrolysis by B-lactamases (easily
hydrolyzed)
 Anti-staphylococcal penicillin (e.g. Nafcillin)
 Resistant to staphylococcal B-lactamases
 Active vs. staphylococcus and streptococcus
 Not active vs. enterococci, anaerobes and gram (-) cocci
and rods
 Extended-spectrum penicillin (e.g. ampicillin, anti-pseudomonal
penicillin)
 Retains anti-bacterial spectrum of penicillin
 Improved activity vs. gram (-) organisms
 Relatively susceptible to hydrolysis by B-lactamases
“Non desistas, Non exieris – Never give up, Never surrender”
PENICILLIN UNITS AND FORMULATIONS
 Penicillin G
 With salt that is either potassium or sodium
 Crystalline sodium penicillin G = 1600 units mg
 1 unit = 0.6 ug: 1 million units of penicillin = 0.6 g
 Dry crystalline form: stable for years at 4’C
 Solutions lose their activity rapidly (e.g., 24 hrs at 20’C)
 Semisynthetic penicillin are prescribed by weight
MECHANISM OF ACTION
 Inhibit bacterial growth by interfering with transpeptidation of
bacterial cell wall synthesis
 Inhibition of transpeptidase enzyme
 Activation of PBPs
 Activation of autolysins (murein hydrolases)
 Bactericidal
 Only effective in actively growing cells
 Given before bacteriostatic agents
RESISTANCE
 Inactivation of antibiotics by beta lactamase: most important
 S. aureus, Haemophilus spp., E. coli, Pseudomonas
aeruginosa, Enterobacter spp.
 Modification of target PBPs
 Staphylococcal resistance to methicillin
 Pneumococcal and enterococcal resistance to penicillin
 Impaired penetration of drug to target PBPs
 Gram negative species due to impermeable outer wall
membrane not present in gram positive
 Presence of an efflux pump
 Gram (-) organisms transport drugs from periplasm back
across the outer membrane
PHARMACOKINETICS
 Absorption
 Vary in resistance to gastric acid and in oral absorption
 Dicloxacillin, Amoxicillin, Ampicillin
 Acid stable, well absorbed
 Nafcillin
 Erratic absorption, not for oral
 Food impairs absorption (except for amoxicillin) so must
be given 1-2 hours before or after meals
 Absorption is complete and rapid after parenteral
administration
 IV preferred to IM due to irritation and local pain
 Highly protein bound penicillin (e.g. Nafcillin) have lower
serum free drug levels in the serum than less protein bound
penicillin (e.g. Pen G, Ampicillin)
 Distribution
 95% protein binding (clinically relevant)
 Widely distributed in body fluids
Page 2 of 19
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 Polar molecules: the concentration within cells is less than  Streptococci

that in ECF  Can be used to prevent group B strep in babies
 Delay absorption preparations  Meningococci
 Benzathine and Procaine Penicillin: prolonged blood  Enterococci
and tissue concentrations  Penicillin susceptible pneumococci
 Benzathin Pen: for syphilis  Non-B lactamase producing staphylococci
 Procaine Pen: for neurosyphillis  T. pallidum and other spirochetes
 Concentrations in most tissue equal those in serum  Clostridium, actinomyces, other gram (+) rods
 Poor penetration into the eye, prostate and CNS (except in  Non-B lactamase producing gram (-) anaerobes
meningitis)  Pen V (oral form): minor infections
 Metabolism  Poor bioavailability  need for frequent dosing (QID)
 Liver  Narrow spectrum
 Metabolites: penicillanic acid, penicillenic acid  Benzathine pen and Procaine pen  IM; prolonged drug
 Antigenic determinants: penicillamine, penicilloic acid, levels
penicilloyl derivatives  causes hypersensitivity  Penicillin resistant to staphylococcal beta-lactamase
reactions  Includes: Methicillin, Nafcillin, Isoxazoyl penicillin
 Excretion  Semisynthetic penicillins for B-lactamse producing
 Kidneys (GFR: 10%; tubular secretion: 90%) staphylococcus
 Sputum and milk: 3-15%  Penicillin-susceptible strains of streptococci and
 Nafcillin: biliary excretion pneumococci
 Oxacillin, dicloxacillin, cloxacillin: renal and biliary excretion  Penicillin resistant to staphylococcal beta-lactamase isoxazolyls
 Clearance less efficient for newborns  Cloxacilin, oxacillin, dicloyococcusxacillin
 Probenecid: raises levels  Mild to moderate localized staphylococcal infections
 Prevents the tubular secretion of the drug (skin infections, cellulitis)
 Half-life  Acid-stable, reasonable bioavailability, food affects
 Pen G: 30 mins absorption
 Ampicillin and extended spectrum Penicillin: 1 hr  Oxacillin, Nafcillin
 In the presence of renal insufficiency or renal failure, it will  Severe systemic staphylococcus infections (TSS)
increase the half-life of the drug to 10 hours  IV infusion
 Adjust dose based on creatinine clearance  Extended spectrum aminopenicillins
 Creatinine clearance of <30: give the drug q12 or q24  Includes: ampicillin, amoxicillin
 If dose is not adjusted, potential adverse effects may  Most abused anitbiotics
be experienced  Most active oral B-lactams for penicillin resistant
pneumococci
PREPARATIONS  UTI, sinusitis, otitis, LRTI
PARENTERAL  Amoxicillin: better oral absorption
Short acting Aqueous Pen G potassium (1.7 mEq K)  Ampicillin
Aqueous Pen G sodium (2.4 mEq Na)  Shigellosis
Long acting Procaine Pen G  IV: for pen-susceptible anaerobes, enterococci, L.
Benzathine Pen monocytogenes, B-lactamase negative strains of gram
- Mean duration of activity: 28 days
(-) organisms
-
 Many gram (-) produce B-lactamase and are
ORAL PREPARATION Pen G sodium
resistant to ampicillin (e.g. organisms causing UTI,
Pen G potassium
typhoid, meningitis)
 Not active against:
CLINICAL USES
 Klebsiella, Enterobacter, pseudomonas,
 Penicillin
citrobacter, serratia, indole-positive proteus,
 Effective dose range between 4 and 24 million units per
other gram (-) in hospital acquired infections
day, given IV in 4-6 divided dose
 Extended spectrum aminopenicillins, carboxypenicillins,
 Pen G (IV form)
ureidopenicillins plus B-lactamase inhibitors
 Most commonly used in non B-lactamase producing
 Includes: Clavulanic acid, Sulbactam, Tazobactam
organisms

Page 3 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 B-lactamase inhibitors GUIDELINES FOR DOSING OF SOME COMMONLY USED

 No inherent anti-microbial properties PENICILLINS
 Resemble B lactam molecules
 Inactivate beta lactamases
 Synergistic with other beta lactam compounds
 Most active against Ambler class A (plasmid encoded)
beta lactamases
 Not good inhibitors of class C (chromosomally
encoded) beta lactamases
 Antibacterial spectrum of activity is determined by the
companion penicillin
 Clavulanic acid: amoxicillin, ticarcillin
 Sulbactam: ampicillin, cefoperazone
 Tazobactam: piperacillin
 Amebactam: ceftazidime
 Beta lactamase producing strains of S. aureus and of
gram (-) bacteria
 Empirical therapy for infections caused by awide range
of potential pathogens in immunocompromised
patients
 Treatment of mixed aerobic and anaerobic infections

ADVERSE REACTIONS
 Hypersensitivity reactions (mild/severe)
 Anaphylactic shock
 Serum sickness (urticaria, fever, joint swelling,
angioneurotic edema, intense pruritis, respiratory
embarrassment)
 Skin rashes, oral lesions, fever, interstitial nephritis
 Eosinophilia, hemolytic anemia and other hematologic
disturbances, vasculitis
 Seizure following rapid IV administration
 Accidental injection to the sciatic nerve  intense pain and
nerve dysfunction persisting for weeks
 Chronic use  superinfection, hepatitis
CEPHALOSPORIN
 GI upset (nausea, vomiting, diarrhea)
 Chemically, MOA and toxicity similar to penicillin
SPECIFIC TOXICITY  More stable than penicillin with broader spectrum of activity
Procaine Pen G Pulmonary embolism  Not active against enterococci and L. monocytogenes
Acute psychotic reactions
Oxacillin Hepatitis BASIC STRUCTURE
Nafcillin Neutropenia  7-aminocephalosporanic: parent compound
Methicillin Interstitial nephritis  Attachment of various R1 and R2 groups
Disodium Carbenicillin Hypernatremia  R2 makes the compound stable in dilute acid and highly
High dose Pen G Na penicillinase resistant
Pen G K Hyperkalemia with high doses  Soluble in water and relatively stable to pH and temperature
Pen G Na Jarisch Herxheimer reaction changes
with high doses in secondary  C7 modifications alter antibacterial activity
syphilis  C3 substitutes change metabolism and kinetic properties
Carbenicillin Bleeding diathesis
Ticarcillin
ADVERSE EFFECTS
Ampicillin Pseudomembranous colitis
 Allergy: anaphylaxis, fever, skin rashes
(abdominal pain & diarrhea)
 Local irritation and thrombophlebitis

Page 4 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 Renal toxicity: interstitial nephritis and tubular necrosis  Anaerobes (good coverage)
 Hypoprothrombinemia and bleeding disorders
 Severe disulfiram-like reactions PHARMACOKINETICS
 Interfere with platelet function and has induced severe bleeding  Oral (Cefaclor, Cefuroxime axetil, Cefrozil, Loracarbef)
(Moxalactam)  Parenteral (Cefoxitin, Cefotetan, Cefuroxime Na, Cefonicid,
 Superinfection Cefamandole)
 Marked difference in half-life, protein binding and interval
FIRST GENERATION CEPHALOSPORINS between doses
 Dose adjustment binding is required in renal failure
 Active against
 Cefuroxime: only 2nd gen that can cross BBB but not usually
 Gram (+) cocci: pneumococci, streptococci, staphylococci
given for CNS infections
 E. coli, K. pneumonia, P. mirabilis (little activity)
 Anaerobes (peptococcus, peptostreptococcus)
CLINICAL USES
 Not active against
 Sinusitis, otitis, CAP
 MRS of staphylococci
 Peritonitis, diverticulitis
 P. aeruginosa
 PID – especially Cefoxitin
 Indole positive proteus
 Enterobacter, S. marcescens, Citrobacter and Acinetobacter
 Anaerobes (B. fragilis) THIRD GENERATION CEPHALOSPORINS
 Expanded gram negative coverage except Cefoperazone
PHARMACOKINETICS  Active against
 Oral (Cephalexin, Cephradine, Cefadroxil)  Citrobacter
 Urine concentration is usually very high  Serratia marcescens
 Most tissue level are variable and lower than the serum  Providencia
 Excretion is mainly by GFR and TS into the urine  B-lactamase producing strains of Haemophilus
 Adjustment is needed in renal impairment  Neisseria
 Parenteral (Cefazolin)  B. fragilis
 Given IV/IM  Not active against
 Peak level: 90-120 ug/mL  Enterobacter
 Dose: 0.5-2g IV every 8 hrs  Cefixime and Ceftibuten have less activity against pneumococci
 Excretion is via the kidney and have poor activity against S. aureus than Cefpodoxime
 Dose adjustment in impaired renal function
PHARMACOKINETICS
CLINICAL USE  Penetrate body fluids and tissues well except Cefoperazone,
 UTI, minor staphylococcal lesions, cellulitis or soft tissue abscess Cefixime, Ceftibuten and Cefpodoxime proxetil
 Surgical prophylaxis  Oral (Ceftibuten, Cefixime, Cefdinir, Cefpodoxime proxetil)
 Persons with staph or strep infection with history of penicillin  Parenteral (Cefoperazone Na, Cefotaxime, Ceftixozime,
hypersensitivity Ceftazidime proxetil, Ceftriaxone)
 Alternative to anti-staph penicillin for patients allergic to  Half-lives and dosing vary greatly
penicillin  Excretion of Cefoperazone and Ceftriaxone is mainly through
the biliary tract
SECOND GENERATION CEPHALOSPORINS  Others are excreted through renal

 Extended gram (-) coverage: Klebsiella

CLINICAL USE
 Less active against gram (+) bacteria than 1st gen
 First line drugs for treatment of:
 Not active against
 Gonorrhea = Ceftriaxone, alternative can be Cefixime
 Enterococci
 Meningitis caused by pneumococci
 Pseudomonas
 Meningococci
 Cefamandole, cefuroxime, cefonicid, ceforanide, cefaclor
 H. influenza
 H. influenza
 Susceptible enteric gram negative rods (but not L.
 Not for Serratia and B. fragilis
monocytogenes)
 Cephamycins
 Empirical therapy serious infections cause by penicillin resistant
 B. fragilis and some Serratia
strains of pneumococci
 Not for H. influenza

Page 5 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 Empirical therapy sepsis of unknown cause in both the  Interfere with platelet function and has induced severe bleeding
immunocompetent and immunocompromised patients (Moxalactam)
 Neutropenic, febrile, immunocompromised patient  Superinfection
(chemotherapy patients)  Fungal infection especially vulvovaginal candidiasis

FOURTH GENERATION CEPHALOSPORINS MONOBACTAM (AZTREONAM)

 Active against:  Monocyclic beta lactam ring
 P. aeruginosa  Resistant to beta lactamase
 Enterobacteriaceae  Not active against:
 S. aureus  Gram (+) bacteria
 S. pneumonia  Anaerobes
 Haemophilus
 Neisseria PHARMACOKINETICS
 Given IV
PHARMACOKINETICS  Half-life: 1-2 hrs (greatly prolonged in renal failure)
 Penetrates well into CSF
 Cleared by the kidneys CLINICAL USES
 Pneumonia
CLINICAL USE  Meningitis
 Used for CNS infections  Sepsis
 Penicillin resistant strains of streptococci
 Enterobacter infections ADVERSE EFFECTS
 Skin rashes
CEPHALOSPORINS ACTIVE AGAINST MRSA  Elevated serum aminotransferases

 Ceftaroline fosamil: prodrug of the active metabolite

ceftaroline CARBAPENEMS
 Increased binding to PBP 2a which mediates MR (methicillin  Broad spectrum antibiotics
resistance) in staph  Active against
 Active against:  Gram (-) rods
 Enterococci  Gram (+) organisms and anaerobes
 Gram (-) organisms except ESBL  Resistant against
 Currently approved for the treatment of skin and soft tissue  E. faecium
infections and CAP  MRSA
 C. difficile
ADVERSE EFFECTS  B. cepacia
 Allergy (anaphylaxis, fever, skin rashes) : most common  Stenotrophomonas maltophilia
 Local irritation and thrombophlebitis  Resistant to most beta lactamases but not carbapenemases or
 Renal toxicity (interstitial nephritis and tubular necrosis) metallo-beta-lactamases
 Hypoprothrombinemia and bleeding disorders
 Encountered in: ADVERSE EFFECTS
 Cephalosporin containing methylthiotetrazole:  Nausea, vomiting, diarrhea, skin rashes and reactions at the
 Moxalactam infusion sites
 Cefoperazone  Seizure in renal failure (imipenem)
 Cefotetan  Allergy in patients allergic to penicillin
 Cefmetazole
 Cefamandole IMIPENEM
 Non-methylthiotetrazole cephalosporin  Inactivated by dehydropeptidase in renal tubules
 Ceftriaxone  Administered together with cilastatin
 Severe disulfiram-like reactions  Penetrates body tissues and fluids well, including CSF
 Occurs when taken with alcohol  Dose: 0.25-0.5g IV every 6-8h
 Can also occur with Metronidazole  Half-life: 1 hr

Page 6 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

MEROPENEM  Alternative regimen for treatment of endocarditis

 Meningitis: combined with cefotaxime, ceftriaxone or rifampicin
 Slightly greater activity against gram (-) aerobes and slight less
against gram (+)
ADVERSE REACTIONS
 Not degraded by renal dehydropeptidases
 Phlebitis, chills, fever, ototoxicity and nephrotoxicity
 Dose: 1g IV q 8 hrs
 “Red man” or “red neck” syndrome
 Avoided if given as IV infusion
ERTAPENEM
 Spectrum of activity includes: all anaerobes and many gram
TEICOPLANIN
(-) bacilli with exception of P. aeruginosa and Acinetobacter
 Mechanism of action and antibacterial spectrum: similar to
 Not used for nosocomial or hospital acquired infections
vancomycin
 Indicated for:
 Complicated intra-abdominal infections
PHARMACOKINETICS
 Complicated skin and skin structure infections
 IM or IV
 CAP
 Long half-life (45 – 70 hours)
 Complicated UTI
 Acute pelvic infections
TELAVANCIN
 Dose: 1g IV or IM OD
 Not available worldwide, only in some European countries
 Semisynthetic lipoglycopeptide derived from vancomycin
GLYCOPEPTIDE ANTIBIOTICS
 Active against
VANCOMYCIN
 Gram- positive bacteria including strains less susceptible to
 Antibiotic produced by Streptococcus orientalis and vancomycin
Amycolatopsis orientalis  Mechanism of action
 Similar to vancomycin
MECHANISM OF ACTION  Disrupts the bacterial cell membrane potential and
 Inhibit transglycosylase preventing further elongation of PG and increases membrane potential and increases membrane
cross linking  weakening of PG and cell wall permeability
 Half-life: 8hrs
BASIS OF RESISTANCE  Clinical use:
 Modification of the D-ala-D-ala binding site of PG building  Treatment of complicated skin and soft tissue infections at
blocks  terminal D-ala replaced by D-lactate a dose of 10 mg/kg IV daily
 Potentially teratogenic
ANTIBACTERIAL ACTIVITY
 Staphylococci (including those producing beta lactamase and
DALBAVANCIN
those resistant to nafcillin and methicillin)
 Semisynthetic lipoglycopeptide derived from teicoplanin
 Synergistic with gentamicin and streptomycin against E. faecium
 Mechanism of action
and E. faecalis strains
 Similar to vancomycin and teicoplanin but has improved
 Bactericidal
activity against many gram (+) bacteria including MRSA
PHARMACOKINETICS and vancomycin-intermediate S aureus.
 Oral: poorly absorbed from the intestinal tract  Not active against
 Water soluble and quite stable  Most strains of vancomycin-resistant enterococci
 Parental doses must be administered intravenously  Half-life: 6-11 days (once a week)
 Distributed widely
 Excretion by GFR – 90% OTHER CELL WALL- OR MEMBRANE-ACTIVE AGENTS
 (Anephric – half-life 6 – 10 hrs) DAPTOMYCIN
 Cyclic lipopeptide fermentation products of Streptomyces
CLINICAL USES roseosporus
 Antibiotic-associated enterocolitis/pseudomembranous colitis  Activity similar to vancomycin
caused by C. difficile  Active against:
 Given through oral route  Vancomycin-resistant strains of enterococci and of S.
 Main indication for parenteral vancomycin is sepsis or
aureus
endocarditis caused by MRS

Page 7 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 Mechanism of action ADVERSE REACTION

 Binds and depolarizes cell membrane  K* efflux  cell  Markedly nephrotoxic (proteinuria, hematuria, nitrogen
death retention)
 Effective alternative to vancomycin  Hypersensitivity
 Cleared renally
 Antagonistic action with pulmonary surfactant CLINICAL USE
 Not given to premature babies receiving surfactant  Mixed bacterial flora in surface lesions of the skin, wounds or on
 Causes myopathy, allergic pneumonitis mucous membranes
 Monitor creatinine phosphokinase because of myopathy  Irrigation of joints, wounds or the pleural cavity

CLINICAL USES CYCLOSERINE

 Skin and soft tissue infections MECHANISM OF ACTION
 Bacteremia  Structural analog of D-ala and inhibits the incorporation of D-
 Endocarditis ala into the PG polypeptide by inhibiting alanine racemase
which converts L-ala to D-alanyl-D-alanine ligase
FOSFOMYCIN TROMETAMOL  Inhibits the addition of the 2 terminal D-ala
 Active against
 Gram (+) and gram (-) PHARMACOKINETICS
 Synergism with beta-lactams, aminoglycosides and  Water soluble and unstable in acidic pH
fluoroquinolones  Excreted in active form in the urine
 Widely distributed in the tissues
MECHANISM OF ACTION
 Inhibits enolpyruvate transferase by blocking the cysteine ANTIBACTERIAL ACTIVITY
residue of the active site and blocking the addition of PEP to  Gram negative bacteria
UDP-N-AGA  Mycobacteria
 Second line treatment for tuberculosis (MDR TB or XDR TB)
RESISTANCE
 Inadequate transport of drug into the cell ADVERSE EFFECTS
 Serious dose-related CNS toxicity: headache, tremors, seizures,
PHARMACOKINETICS acute psychosis
 Oral formulation of 3 gms
 Excreted in the kidneys PROTEIN SYNTHESIS INHIBITORS
 Taken early in the morning with an empty stomach (AMINOGLYGOSIDES, STREPTOMYCIN, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN, CHLORAMPHENICOL,
CLINICAL USE STREPTOGRAMINS AND OXAZOLIDINONES)
 Uncomplicated UTI in women (pregnant and non-pregnant)
 Can be used during pregnancy 30 S INHIBITORS AMINOGLYCOSIDES
- Streptomycin: prototype  Streptomycin
drug  Gentamicin
BACITRACIN
 Neomycin
 Active against  Tobramycin
 Gram (+) bacteria  Kanamycin
 Sisomicin
MECHANISM OF ACTION  Amikacin
 Interferes with dephosphorylation in the cycling of lipid carrier  Netilmicin
that transfers PG subunits to the growing cells  Paromomycin
 Hygromycin B
PHARMACOKINETICS
TETRACYCLINES
 Limited to topical ointment combined with polymixin B or
 Short-acting (6-8h)
neomycin
 Chlortetracycline
 Poorly absorbed, excreted by glomerular filtration
 Tetracycline
 Oxytetracycline

Page 8 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 Intermediate-Acting (10- MECHANISM OF ACTION

50 S INHIBITORS
- Streptogramins and Line-
zolid is used for resistant
gram (+) infection and
vancomycin resistance
-  Telithromycin
12h)  Irreversible inhibitors of protein synthesis (30S ribosomal
 Demeclocyline subunit)
 Methacycline  Induce misreading of mRNA  incorrect AA
 Long-acting  Causes break up of polysomes into nonfunctional monosomes
 Doxycycline (6-18h)  Requires oxygen uptake
 Minocycline (6-18h)  Bactericidal
 Tigecycline (36h –
longest half-life)
RESISTANCE
SPECTINOMYCIN  Enzyme inactivation
MACROLIDES  Impaired entry of the drug due to cell-mutation or deletion
 Erythromycin: prototype  Receptor protein maybe deleted or altered due to mutation
 Clarithromycin
 Azithromycin ACTIVITY
 Dirithromycin  Gram-negative enteric bacteria
 Tuberculosis
 Not active against
CHLORAMPHENICOL  Anaerobes

CLINDAMYCIN
PHARMACOKINETICS AND ONCE-DAILY DOSING
STREPTOGRAMINS  Poorly absorbed from intact GIT except when there’s ulceration
 Entire oral dose excreted in the feces after oral administration
OXAZOLADINONE – Linezolid  Highly polar compounds that do not enter cells readily but
penetrate inflamed meninges (20%)
GENERAL MODE OF ACTION OF PROTEIN SYNTHESIS  Water soluble, stable in solution, more active at alkaline than at
INHIBITORS acid pH
 Attachment of the transfer RNA to the A site: inhibited by  Synergistic with beta lactams and vancomycin
Tetracyline  Administered intravenously as a 30-60 minutes infusion
 Interpretation of the codon anti-codon complex: inhibited by  Concentration not high in most tissues even after parenteral
Aminoglycosides, Gentamycin, Amikacin administration
 Transpeptidation process: inhibited by Chloramphenicol  Except: renal cortex, bile (50%), pleural or synovial fluid (50-
 Translocation: inhibited by Erythromycin, Chloramphenicol, 90%)
Spectinomycin, Fusidic acid  Excretion: Glomerular filtration
 Directly proportional to creatinine clearance
AMINOGLYCOSIDES  Feces (neomycin, paramomycin)
OLDER AMINOGLYCOSIDES NEWER AMINOGLYCOSIDES  Half-life of in serum is 2-3 hours
Streptomycin Gentamycin  Increasing to 24-48 hours in patients with significant
Kanamycin Tobramycin impairement of renal function
Neomycin  Concentration-dependent killing activity  given in bolus
Amikacin  Post-antibiotic effect
Netilmicin  Administered single-daily dosing
Sisomicin  As effective and often less toxic
Paromycin  Determination of serum concentration is probably
Hygromycin B
unnecessary
 Achieves greater post-antibiotic effect
STRUCTURES
 Bactericidal
 Hexose ring contains either streptidine (streptomycin) or 2-
deoxystreptamine (other aminoglycosides)
ADVERSE EFFECTS
 Amino sugars
 Among elderly, dehydrated patients, those with renal or hearing
 Glycosidic linkage
impairment, and treatment > 5days:
 Nephrotoxicity
 Ototoxicity: auditory and vestibular
 Neuromuscular blockade  respiratory paralysis

Page 9 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 CNS  headache, tremors, lethargy, numbness, seizures  Complicated urinary tract infection
 Blurred vision, rash, urticarial, fever, pain at injection site  Septicemia
 Diarrhea, nausea/vomiting (paromomycin)  Peritonitis and other severe intra-abdominal infections
 Severe pelvic inflammatory disease
SPECIFIC TOXICITY  Endocarditis
Ototoxic Neomycin  Mycobacterium infection
Kanamycin  Neonatal sepsis
Amikacin  Ocular infections and Otitis extema (topical)
Vestibulotoxic Streptomycin
Gentamycin
STREPTOMYCIN
Nephrotoxic Neomycin
Gentamycin CLINICAL USE
Tobramycin  Mycobacterial infection – second line of tra=eatment
Respiratory paralysis Neomycin  Plague, tularemia, brucellosis
 Enterococcal endocarditid (with penicillin)
RISK FACTORS FOR OTOTOXICITY
 Advanced age ADVERSE EFFECT
 Noise exposure  Vertigo and loss of balance frequency and severity of this
 Pre-existing disorders of hearing and balance disturbance are proportionate to the age of the patient, the
 Hypovolemia blood levels of the drug and the duration of administration
 Bacteremia  Fever, skin rash, pain at the injection site
 Liver and renal dysfunction
 Concomitant ototoxic drugs (amphotericin B, cephalosporins, GENTAMYCIN
polymixin B, bacitracin, vancomycin) ANTIBACTERIAL ACTIVITY
 Active against
RISK FACTORS FOR NEPHROTOXICITY  Gram negative organism
 Use of diuretics
 Radiographic contrast exposure CLINICAL USE
 Effective circulating volume depletion  IM or IV administration mainly in severe infection (sepsis and
 Use of ACE inhibitors pneumonia)
 Use of NSAIDs  Strep viridans or Enterococcal endocarditis (+Pen G)
 Use of other nephrotoxic medications  Staph endocarditis (+Nafcillin)
 Concomitant use of amphotericin (Fungizone IV)  Synergistic with beta-lactams against
 Use of cisplatin (Platinol)  Pseudomonas, Proteus, Enterobacter, Klebsiella, Serratia
and other gram (-) rods
CONTRAINDICATIONS/EXTREME CAUTION  Topical for infected burns, wounds and skin lesion, IV catheter
 Tinnitus, vertigo, high frequency hearing loss infections
 Reduced renal function  Intrathecal route for meningitis
 Dehydration  Nephrotoxic and ototoxic
 Pregnancy or lactation  Cheapest of all the aminoglycosides
 Infants, elderly

TOBRAMYCIN
DRUG INTERACTIONS
 Ototoxic drugs  Antibacterial activity and kinetics similar to gentamycin except:
 Potentiate nephrotoxicity (loop diuretics, vancomycin,  Gentamycin is more active vs Serratia
amphotericin)  Tobramycin is slightly more active vs Pseudomonas
 General anesthetics or neuromuscular blockers (succinylcholine,  Less nephrotoxic and ototoxic
curare)  Enterococcus faecalis susceptible
 Antiemetics: mask vestibular ototoxicity  Enterococcus faecium resistant
 Nephrotoxic and ototoxic
CLINICAL USES
 Serious, life-threatening gram-negative infection
 Complicated skin, bone or soft tissue infection

Page 10 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

AMIKACIN  Oral administration: preparation for elective bowel surgery/

hepatic coma
 Semisynthetic derivative of kanamycin
 Resistant to many enzymes that inactivates gentamicin and
ADVERSE EFFECTS
tobramycin
 Significant nephrotoxicity and ototoxicity
 Strains of MDR M. tuberculosis including streptomycin-resistant
 Curare-like neuromuscular blockade and respiratory arrest
strains are usually susceptible to amikacin
 Severe allergic reactions- prolonged application of neomycin-
 Active against
containing ointments to skin and eyes
 Gram (-) organisms: Proteus, Pseudomonas, Enterobacter
and Serratia
 Nephrotoxic and ototoxic HYGROMYCIN B
MECHANISM OF ACTION
NETILMICIN  Inhibits the protein synthesis at the translocation step by
interfering with the 70S ribosome causing misreading of the
 Addition of an ethyl group to the 1-amino position of the 2-
mRNA
deoxystreptamine ring protects the molecule from enzymatic
degradation
USES
 Active against
 Can be used as a selective antibiotic in molecular genetics and
 Some gentamicin-resistant and tobramycin-resistant
in cell culture experiments to inhibit the growth of prokaryotic
bacteria
(bacteria) and eukaryotic microorganisms (yeasts) as well as
 Largely interchangeable with gentamicin or tobramycin but is
mammalian cells
no longer available in the US
 Effective on most bacteria, fungi and higher eukaryotes
 Used when there is resistance to Gentamicin

KANAMYCIN/NEOMYCIN/PARAMOMYCIN
 Neomycin: given as a bowel preparation agent for colorectal
surgery

ANTIMICROBIAL ACTIVITY & RESISTANCE

 Active against
 Gram positive and negative organisms
 Some Mycobacteria
 Not active against
 Pseudomonas
 Streptococci
 Mechanisms of action and resistance are the same as with other
aminoglycosides
 Cross-resistance between kanamycin and neomycin is complete

PHARMACOKINETICS
 Poorly absorbed from the gastrointestinal tract
 Intestinal flora suppressed or modified after oral administration
 Excreted in the feces
 Excretion of any absorbed drug mainly through glomerular
filtration into the urine

CLINICAL USE
 Paromomycin
 Shown to be effective against visceral leishmaniasis when
given parenterally
 Topical administration: infected surfaces or injected into the
joints, pleural cavity, tissue spaces or abscess cavities with
infection

Page 11 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

TETRACYCLINE
MECHANISM OF ACTION
 Binds to 30s ribosomal RNA at the site that directly blocks
binding of AA-charged tRNA to the acceptor site at the
ribosomal mRNA complex  preventing addition of AA to
growing peptide

RESISTANCE
 Decrease intracellular accumulation due to either impaired
influx or increase efflux by active transport
 Ribosome protection probably due to production of proteins
that interferes with tetracycline binding to ribosomes
 Enzymatic deactivation

PHARMACOKINETICS
 Absorption
 Chelates divalent ions such as calcium, magnesium, iron,
aluminum/ dairy products, alkaline pH and antacid
 Except doxycycline and minocycline

Chlortetracycline 30%
Tetracycline, Oxytetracycline 60-70%
Demeclocycline, Methacyline
Doxycycline, Minocycline 95-100%

 Protein bound in 40-80%

SPECTINOMYCIN  Highly protein bound: doxycycline and minocycline
PROPERTIES  Acid stable except chlortetracycline
 An aminocyclitol antibiotic structurally related to  Oral/parenteral
aminoglycosides  Distributed widely to tissues and body fluids except for CSF
 Lack sugar and glycosidic bonds  High concentrations of minocycline in tears and saliva  useful
 Dispense as dihydrochloride pentahydrate (IM) for eradication of the meninogococcal carrier state
 Increase concentration in tears and saliva
ANTIBACTERIAL ACTIVITY  Cross placenta and excreted in milk
 Active against  Excretion: urine and bile
 Gram positive and negative organisms  Doxycycline and tigecycline eliminated by nonrenal mechanisms
 require no dosage adjustment in renal failure
CLINICAL USE
 An alternative treatment for gonorrhea for penicillin allergic ANTIBACTERIAL ACTIVITY
patients and for resistant strains to other drugs  Bacteriostatic for:
 Gram positive and gram negative bacteria
ADVERSE REACTION  Anaerobes
 Pain at the injection site (local irritation or pain)  Rickettsia
 Fever  Chlamydia
 Nausea  Mycoplasma
 Nephrotoxic  Protozoa (e.g. amoeba, malaria)
 Anemia  Prophylaxis for chloroquine resistant malaria (Doxycycline)

CLINICAL USE
 Mycoplasma pneumonia, chlamydia, rickettsia, and some
spirochetes
 Gastric and duodenal ulcer caused by Helicobacter pylori
 Non-resistant vibrio, plague, tularemia and brucellosis,

Page 12 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 Entamoeba histolytica, P. falciparum MACROLIDES

 Eradication of meningococcal carrier state
ERYTHROMYCIN
 Acne, exacerbation of bronchitis, lyme disease, relapsing fever,
CHEMISTRY
leptospirosis and some non-tuberculous mycobacterial
 14 or 16 atom lactone ring
infections
 2 deoxy sugars (Desosamine and Cladinose)

DRUG INTERACTION
OLD GENERATION NEW GENERATION
 Carbamazepine, phenytoin, barbiturates and chronic alcohol
Erythromycin: prototype Rosaramycin
ingestion – shorten half-life of Doxycline
Oleandomycin, Roxithromycin
 Demeclocycline inhibits ADH actions in the renal tubules Troleandomycin Clarithromycin: given for 5 days
Spiramycin Azithromycin: given for 3 days
ADVERSE REACTIONS Josamycin Dirithromycin
 Gastrointestinal disturbance (nausea, vomiting, diarrhea)
 Bony structures and teeth (fluorescence discoloration and MECHANISM OF ACTION
enamel dysplasia, chelation with calcium  Prevent translocation of peptidyl tRNA from the acceptor site to
 HPS/ hepatotoxic donor site
 Nephrotoxic – renal tubular acidosis and other renal injury
resulting to nitrogen retention RESISTANCE
 Local tissue toxicity (venous thrombosis, painful local irritation)  Reduced permeability of cell membrane or active efflux
 Photosensitization  Production of esterases leading to hydrolysis
 Other drugs: tetracycline, fluoroquinolones, sulfonamides (enterobacteriaceae)
 Vestibular reaction (dizziness, vertigo, nausea and vomiting)  Ribososmal protection by mutation or by macrolide-inducible
or constitutive methylase
TIGECYCLINE
PHARMACOKINETICS
 Glycylcycline, semisynthetic derivative of minocycline
 Destroyed by acid and enhanced by alkaline pH
 Active against
 Oral preparation: lauryl salt propionyl ester (estolate), stearates,
 Coagulase-negative staph and S. aureus (methicillin-
esters, ethylsuccinate, base
resistant, vancomycin-intermediate, and vancomycin-
 Estolate should not be given to pregnant patients 
resistant strain)
hepatotoxicity
 Gram (+) rods
 Parenteral preparation: Erythromycin lactobionate
 Enterobacteriaceae
 Excretion: bile, feces (main), urine (5%)
 MDR strains of Acinetobacter sp.
 Well distributed except to the brain and CSF
 Gram (+) and gram (-) anaerobes
 Crosses the placenta
 Atypical agents (rickettsia, chlamydia and legionella, rapidly
 Taken up by the PMN and macrophages
growing mycobacteria)
 Proteus and P. aeruginosa are intrinsically resistant
ANTIBACTERIAL ACTIVITY
 IV formulation given at a loading dose of 100mg, then 50mg
 Gram positive organisms
q12 hrs
 Pneumococci, strep, staph, corynebacteria
 With excellent tissue and intracellular penetration
 Mycoplasma
 Elimination – biliary
 Legionella
CLINICAL USES  C. trachomatis
 FDA-approved for treatment skin and skin-structure infection  Helicobacter
and intraabdominal infection  M. kansasii, M. scrofulaceum
 MDR nosocomial pathogens (MRSA, ESBL producing gram (-)  Gram negative organisms
agents, Acinetobacter sp)  Neisseria, Rickettsia, T. pallidum, Campylobacter spp.

CLINICAL USE
TOXICITY
 Corynebacterial infection (diphtheria, sepsis and erythrasma)
 Same as tetracycline
 Chlamydia infection and CAP: most clinically significant use
 Most common is nausea, and occasionally vomiting
 Alternative in penicillin allergic patients with staph., strep,
pneumococci infections
 Prophylaxis against endocarditis

Page 13 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

 Preoperative preparation for bowel surgery (colorectal)  Al OH and Mg OH delay absorption and reduce peak serum
concentration
ADVERSE REACTIONS  Does not inhibit the microsomal enzyme
 Gastrointestinal disturbances (anorexia, nausea, vomiting,
diarrhea) – most common cause for discontinuation KETOLIDES
 Liver toxicity (acute cholestatic hepatitis – fever, jaundice and
 14 atom lactone ring, differing from E by substitution of 3-keto
impaired liver function)
group for the neutral sugar 1-cladinose
 Telithromycin: approved for use
DRUG INTERACTION
 Active in vitro against
 Increase serum concentration of theophylline, oral
 S. pyogenes, S. pneumoniae, S. aureus
anticoagulants, cyclosporine, methylprednisolone and
 H. influenza, Moraxella catarrhalis, Mycoplasma
antihistamine, digoxin
 Legionella spp., Chlamydia spp.
 H. pylori, N. gonorrhea
CLARITHROMYCIN  B. fragilis, T. gondii and non-tuberculous mycobacteria
CHEMISTRY  Many macrolide-resistant strains are susceptible to ketolides
 R1 and R2 = CH3: derived by the addition of methyl group  Structural modification renders them poor subrates to
efflux pump-mediated resistance
PHARMACOKINETICS  Higher binding to ribosomes
 Improved acid stability and oral absorption  Oral bioavailability: 57%
 Penetrates most tissue well, penetrates well into phagocytes  Dose of 800mg OD
 Metabolized in the liver (hydrxoclarithromycin)  Metabolized in the liver
 Excretion: urine  Eliminated thru biliary and urinary
 Dose 250mg – 500mg BID (HL 6hrs or more)  Reversible inhibitor of the CYP3A4 enzyme system and may
slightly prolong the QT interval
ANTIBACTERIAL ACTIVITY
 Similar to erythromycin CLINICAL USE
 More active against M avium complex, M. leprae, T. gondii  Respiratory tract infections
 CAP
DRUG INTERACTION  Acute exacerbation of chronic bronchitis
 Similar to erythromycin  Sinusitis
 Streptococcal pharyngitis
ADVANTAGES
 Less GI intolerance and frequency of dosing
TOXICITY: rare
 Hepatitis
AZITHROMYCIN  Liver failure
CHEMISTRY
 15 atom lactone CLINDAMYCIN
 Methylated nitrogen into the lactone ring
 Chlorine substituted derivative of lincomycin
 Bacteriostatic
PHARMACOKINETICS
 Penetrates most tissues (except CSF) and phagocytic cells
MECHANISM OF ACTION
 Half-life of 2-4 days
 Prevent translocation of peptidyl tRNA from acceptor to donor
 Rapidly absorbed and well tolerated orally
site

ANTIBACTERIAL ACTIVITY
RESISTANCE
 Less active than erythromycin and clarithromycin against Staph
 Modification of ribosomal acceptor site
and Strep but slightly more active vs H. influenza
 Production of enzyme
 Modification of receptor by a constitutively expressed
CLINICAL USE
methylase
 Chlamydia urethritis and cervicitis
 Community acquired pneumonia

DRUG INTERACTION

Page 14 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

PHARMACOKINETICS
 Highly protein bound – 90%  Parenteral
 Half-life 2.5 hrs  Chloramphenicol succinate – highly water soluble
 Metabolized by the liver  Widely distributed in all tissues and body fluids
 Excretion: liver, bile and urine  Serum concentration is equal to the concentration in CNS and
 Penetrates well into the most tissues except brain and CSF CSF
 Penetrates well into abscesses: ideal medication to be given  Inactivated in the liver either by conjugation with glucuronic
for abscesses acid and reduction to inactive amines
 Excretion: kidneys, bile and feces
ANTIBACTERIAL ACTIVITY
 Active against ANTIBACTERIAL ACTIVITY
 Streptococci and staphylococci  Bacteriostatic
 Pneumococci  Aerobic and anaerobic gram-positive
 Gram (+) organism  Aerobic and anaerobic gram-negative organism
 Bacteroides and other anaerobes  Rickettsia
 Not active against  Bactericidal
 Enterococci  H. influenza
 Gram (-) aerobic organism  N. meningitides
 C. difficile  Some strains of Bacteriodes
 Not active against
CLINICAL USE  Chlamydia
 Severe anaerobic infections, penetrating wounds of abdomen
and GUT CLINICAL USE
 Female genital tract infections (septic abortion, pelvic abscess,  Serious Rickettsial infection in children (<8 years) with
PID) contraindication for tetracycline treatment
 Aspiration pneumonia  Alternative to beta lactam for treatment of meningitis
 Lung abscess  Alternative in major penicillin HPS reaction
 Prophylaxis of endocarditis  Eye infection
 Alternative to TMP-SMZ for P. carinii infection
 TMP-SMZ: trimethoprim-sulfamethoxazole ADVERSE REACTION
 AIDS related toxoplasmosis of the brain  Gastrointestinal disturbances (nausea, vomiting, diarrhea, oral
candidiasis)
ADVERSE REACTIONS  Bone marrow disturbances (suppress RBC production, aplastic
 GIT disturbance (antibiotic associated colitis) anemia)
 Liver toxicity, skin rash and neutropenia  Gray Baby syndrome (vomiting, flaccidity, hypothermia, gray
color, shock and collapse)  not given to pregnant women
CHLORAMPHENICOL
 Not commonly used due to its adverse effects DRUG INTERACTION
 Using this drug is a marker of bad medical practice in the US  Increase half-life and serum concentration of the following:
 Phenytoin, Tolbutamide, Chlorpropamide, Warfarin
MECHANISM OF ACTION  Antagonist to the following:
 Binds reversibly to 50s subunit of bacterial ribosome   Penicillin, aminoglycoside
inhibiting peptidyltransferase step of protein synthesis
STREPTOGRAMINS
RESISTANCE  Combination of:
 Production of chloramphenicol acetyltransferase-plasmid  Quinupristin (B)
encoded enzyme  Dalfopristin (A)

PHARMACOKINETICS MECHANISM OF ACTION

 Oral: chloramphenicol palmitate  Similar to macrolides and clindamycis
 Crystalline form
 Rapidly and completely absorbed
 Soluble in alcohol but poorly stable in water

Page 15 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

RESISTANCE CLINICAL USE

 Modification of the Quinupristin binding site
 Enzymatic inactivation of Dalfopristin or efflux
STRUCTURE:
 B:A (30:70 ratio)
ANTIBACTERIAL ACTIVITY
 Bactericidal for most organism except Enterococcus faecium
which is killed slowly
 Active againts
 Gram positive cocci including MDR strains of Streptococci
 Penicillin Resistant strains of S. pneumonia
 Methicillin-susceptible and resistant strains of staph.
 Vancomycin resistant E. faecium
 HAP, CAP
 Complicated and uncomplicated skin and soft tissue infections
caused by susceptible gram-positive bacteria
 Off-label uses include: treatment of multidrug-resistant
tuberculosis and Nocardia infections
ADVERSE EFFECT
 Hematologic – reversible and mild
 Thrombocytopenia  2 weeks
 Neutropenia – common in patients with BM depression
 Optic, peripheral neuropathy, lactic acidosis – prolonged use

PHARMACOKINETICS
 IV
 Rapidly metabolized (HL 0.85) and 0.7 hours)
 Excretion: Fecal route (75%) and (20%)
 Significantly inhibit CYP 3A4 which metabolize warfarin,
diazepam, astemizole, ternafedine, cisapride and cyclosporine

CLINICAL USE
 Infection caused by vancomycin-resistant strains of E. faecium,
 Bacteremia or RTI caused by MRS of staph or streptococci
 Penicillin-susceptible and resistant strains of S. pneumoniae

ADVERSE REACTION
 Infusion related events (pain and arthralgia-myalgia)

OXAZOLADINONES (Linezolid)
MECHANISM OF ACTION
 Inhibits protein synthesis by preventing formation of the
ribosome complex that initiates protein synthesis
 Its uniques binding site, located on 23S ribosomal RNA of the
50S subunit, results in no cross-resistance with other drug
classes

RESISTANCE
 Mutation of the linezolid binding site on 23S ribosomal RNA

PHARMACOKINETICS
 High oral bioavailability (100%)
 Half-life of 4 to 6 hours
 Metabolism by oxidation
 Neither an inducer nor an inhibitor of cytochrome P450
enzymes

ANTIBACTERIAL ANTIVITY
 Active against
 Gram (+) organisms (Staph, Strep, Enterococci)
 Gram positive anaerobes
 Gram positive rods (Corynebacteria and L. monocytogenes)

Page 16 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

Page 17 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

Page 18 of 19
“Non desistas, Non exieris – Never give up, Never surrender”
PHARMA B | ANTI-MIRCOBIALS I
DR. JENNIFER T. CO – FEB. 26, 2018

Page 19 of 19
“Non desistas, Non exieris – Never give up, Never surrender”