DRUG SUMMARY TABLE: CHAPTER 35 Pharmacology of Bacterial and Mycobacterial Infections: Cell Wall Synthesis

DRUG CLINICAL APPLICATIONS SERIOUS & COMMON ADVERSE EFFECTS CONTRAINDICATIONS THERAPEUTIC CONSIDERATIONS
INHIBITORS OF MUREIN MONOMER SYNTHESIS
Mechanism—See specific drug
Fosfomycin (PO) Urinary tract infections Headache, diarrhea, nausea Hypersensitivity to Phosphoenolpyruvate (PEP) analogue that
caused by E. coli, fosfomycin inhibits bacterial enolpyruvate transferase
Enterococcus faecalis (MurA) by covalent modification of the
enzyme’s active site, thereby inhibiting the
synthesis of UDP-NAM from UDP-NAG.
An intravenous formulation (available only
outside United States) has exhibited
synergism with β-lactams, aminoglycosides,
and fluoroquinolones.
Decreased absorption when co-administered
with drugs that increase gastrointestinal
motility (e.g., metoclopramide).
Cycloserine (PO) M. tuberculosis Seizures Hypersensitivity to Inhibits both alanine racemase and D-Ala-D-
Confusion, dizziness, headache, cycloserine Ala ligase.
somnolence Epilepsy Alcohol, isoniazid, and ethionamide
Depression, anxiety, potentiate cycloserine toxicity.
psychosis Pyridoxine may prevent cycloserine-induced
Severe renal peripheral neuropathy.
insufficiency Cycloserine inhibits hepatic metabolism of
Alcohol abuse phenytoin.
Bacitracin (PO and Cutaneous and eye Nephrotoxicity if systemic absorption Hypersensitivity to Inhibits dephosphorylation of bactoprenol
topical use only) infections (topical only) occurs bacitracin diphosphate.
Superficial bacterial Contact dermatitis (topical use only)
infection of skin
INHIBITORS OF MUREIN POLYMER SYNTHESIS
Mechanism—Bind to the D-Ala-D-Ala terminus of the murein monomer unit and inhibit peptidoglycan glycosyltransferase (PGT), thereby preventing addition of
murein units to the growing polymer chain
Vancomycin (IV; PO for Shared indications: Anaphylaxis (shared adverse effect); Shared Increased nephrotoxicity when administered
C. difficile infection  Methicillin- nephrotoxicity (vancomycin and contraindication: with aminoglycosides.
only) resistant S. aureus telavancin only); Clostridium difficile  Hypersensitivity Red man syndrome can be avoided by
Telavancin (IV) infections (IV) diarrhea (vancomycin, dalbavancin, and to drug slowing infusion rate or preadministering
Dalbavancin (IV)  Serious skin oritavancin only); cardiac arrest, Oritavancin only: antihistamines.
Oritavancin (IV) infections involving hypotension, bone marrow suppression,  Unfractionated Resistance to vancomycin most commonly
staphylococci and ototoxicity (vancomycin only); prolonged heparin sodium arises through acquisition of DNA encoding
streptococci (IV) QT interval, bleeding risk, osteomyelitis use within 48 enzymes that catalyze formation of D-Ala-D-
Vancomycin and (oritavancin only) hours lactate.
telavancin only: Gastrointestinal upset Telavancin has slightly greater
 Nosocomial nephrotoxicity than vancomycin.
pneumonia Telavancin and oritavancin may result in
including false increases in coagulation tests.
ventilator-
associated
pneumonia
Vancomycin only:
 C. difficile
enterocolitis
 Infective
endocarditis and
bacteremia
INHIBITORS OF POLYMER CROSS-LINKING: PENICILLINS
Mechanism—β-Lactams inhibit transpeptidase by forming a covalent (“dead-end”) acyl enzyme intermediate. Penicillins have a five-membered accessory ring
attached to the β-lactam ring.
Penicillin G (IV) Penicillin-sensitive S. Anaphylaxis (shared adverse effect); Hypersensitivity to Anticoagulant effects of warfarin may be
Penicillin benzathine aureus and S. pyogenes, congestive heart failure, electrolyte penicillins potentiated by concomitant penicillin
(IM) oral anaerobes, N. imbalance, coma, seizure (penicillin G administration.
Penicillin V (PO) meningitidis, Clostridia only); Clostridium difficile infection β-Lactamase sensitive.
species (penicillin V only)
Syphilis Rash, fever, injection site reaction,
Yaws gastrointestinal upset, Jarisch-
Leptospirosis
 Prophylaxis of rheumatic Herxheimer reaction when used to treat
fever syphilis
Dental infections
Oxacillin (IV) Skin and soft tissue Anaphylaxis, Clostridium difficile infection Hypersensitivity to β-Lactamase resistant.
Cloxacillin (PO) infections or systemic (cloxacillin, nafcillin, and dicloxacillin penicillins Narrow-spectrum antibacterial activity; used
Dicloxacillin (PO) infection with β- only); nephrotoxicity (dicloxacillin and mainly to treat skin and soft tissue infections
Nafcillin (IV) lactamase-producing, nafcillin only); hepatotoxicity (dicloxacillin or documented methicillin-sensitive S.
methicillin-sensitive S. only); hypokalemia, bone marrow aureus infections.
aureus depression (nafcillin only) Nafcillin is a hepatic CYP3A4 enzyme inducer
Gastrointestinal upset (shared adverse and can decrease plasma concentrations of
effect); rash (oxacillin only) CYP3A4 substrates.
Ampicillin (IV/PO) Ampicillin: Erythema multiforme, Stevens-Johnson Hypersensitivity to Broad-spectrum antibacterial activity.
Amoxicillin (PO)  Invasive syndrome, toxic epidermal necrolysis, penicillins Ampicillin and amoxicillin are β-lactamase
Amoxicillin/clavulanic enterococcal anaphylaxis, Clostridium difficile infection sensitive as single agents; clavulanic acid and
acid (PO) infections (shared adverse effects); agranulocytosis, sulbactam are β-lactamase inhibitors.
Ampicillin/sulbactam  Infectious disease thrombocytopenia (ampicillin only) Positively charged amino group on side
(IV) of the Rash, diarrhea chain enhances diffusion through porin
genitourinary channels of Gram-negative bacteria.
system
 Respiratory tract
infection
Amoxicillin:
 Uncomplicated ear,
nose, and throat
infections
 Component of
combination
therapy for
Helicobacter pylori
infection
 Infectious disease
of the
 genitourinary
system
 Infection of the
skin and
subcutaneous
tissue
 Lower respiratory
tract infection
Amoxicillin/clavulanic
acid and
ampicillin/sulbactam:
 β-Lactamase-
producing
organisms such as
S. aureus, H.
influenzae, E. coli,
Klebsiella,
Acinetobacter,
Enterobacter,
anaerobes
Piperacillin/Tazobactam Primarily used to treat P. Erythema multiforme, Stevens-Johnson Hypersensitivity to Broad-spectrum antibacterial activity but
(IV) aeruginosa infection, syndrome, toxic epidermal necrolysis, penicillins primarily used against P. aeruginosa.
peritonitis, and hospital- Clostridium difficile infection, anaphylaxis Generally β-lactamase sensitive.
acquired pneumonia due Rash, gastrointestinal upset
to resistant Gram-
negative organisms
INHIBITORS OF POLYMER CROSS-LINKING: CEPHALOSPORINS
Mechanism—β-Lactams inhibit transpeptidase by forming a covalent (“dead-end”) acyl enzyme intermediate. Cephalosporins have a six-membered accessory ring
attached to the β-lactam ring.
Cefazolin (IV) Proteus mirabilis, E. coli, Stevens-Johnson syndrome, Clostridium Hypersensitivity to First-generation cephalosporins.
Cephalexin (PO) Klebsiella pneumoniae difficile infection, anaphylaxis (shared cephalosporins Relatively good Gram-positive coverage
Cefadroxil (PO) Skin and soft tissue adverse effects); hepatotoxicity (cefazolin (Staphylococcus species and Streptococcus
infections and cefadroxil only); renal toxicity species).
 Surgical prophylaxis
Cefuroxime (IV) Shared indication:
Cefotetan (IV)  H. influenzae
Cefoxitin (IV) Cefotetan and cefoxitin
only:
 Enterobacter
species, Neisseria
species, P.
mirabilis, E. coli, K.
pneumoniae
Cefotaxime (IV) Cefotaxime only:
Cefpodoxime (PO)  H. influenzae
Ceftriaxone (IV/IM) Ceftriaxone only:
Cefoperazone (IV/IM)  N. gonorrhoeae,
Ceftazidime (IV) Borrelia
burgdorferi, H.
influenzae, most
Enterobacteriaceae
Ceftazidime only:
 P. aeruginosa
(cephalexin only); leukopenia, Sensitive to many β-lactamases.
encephalopathy, seizure (cefazolin only);
thrombocytopenia (cefadroxil only)
Gastrointestinal upset (shared adverse
effect); rash (cefazolin only)
Stevens-Johnson syndrome, toxic Hypersensitivity to Second-generation cephalosporins.
epidermal necrolysis, anaphylaxis, cephalosporins Relatively broader Gram-negative coverage
Clostridium difficile infection (shared than first-generation cephalosporins.
adverse effects); seizure (cefotetan and More β-lactamase resistant than first-
cefoxitin only); hemolytic anemia generation cephalosporins.
(cefotetan only) Cefuroxime is primarily used in community-
acquired pneumonia.
Cefotetan and cefoxitin are primarily used in
intra-abdominal and pelvic infections and for
surgical prophylaxis.
Cardiac arrhythmia, erythema Shared Third-generation cephalosporins.
multiforme, Stevens-Johnson syndrome, contraindication: Highest CNS penetration of the
toxic epidermal necrolysis, anaphylaxis,  Hypersensitivity cephalosporins.
Clostridium difficile infection (shared to Resistant to many β-lactamases.
adverse effects); granulocytopenic cephalosporins Highly active against Enterobacteriaceae but
disorder (cefotaxime only); hemolytic Ceftriaxone only: less active against Gram-positive organisms
anemia, kernicterus of newborn, renal  Concurrent than are first-generation cephalosporins.
failure, lung toxicity (ceftriaxone only); administration
gastrointestinal hemorrhage of calcium-
(cefoperazone only); asterixis, coma, containing IV
encephalopathy, myoclonus, seizure solutions in
(ceftazidime only) neonates, due
Injection site pain (IV formulations only); to risk of fatal
rash, gastrointestinal upset salt
precipitation in
lung and kidneys
 Hyperbilirubine
mic neonates,
 due to increased
risk of
kernicterus
Cefepime (IV) Enterobacteriaceae, Stevens-Johnson syndrome, toxic Hypersensitivity to Fourth-generation cephalosporin.
Neisseria, H. influenzae, epidermal necrolysis, Clostridium difficile cephalosporins Resistant to many β-lactamases.
P. aeruginosa, Gram- infection, anaphylaxis, encephalopathy,
positive organisms myoclonus, seizure
Ceftaroline (IV) Methicillin-resistant S. Same as cefazolin, except ceftaroline may Hypersensitivity to Fifth-generation cephalosporin.
aureus infections, cause drug-induced hemolytic anemia cephalosporins (rarely Ceftobiprole is a fifth-generation
vancomycin-resistant S. and may cause significant leukopenia or cross-react with cephalosporin in late-stage clinical trials with
aureus infections, S. neutropenia penicillins) a similar spectrum of action.
pneumoniae, Moraxella
catarrhalis, Haemophilus
influenzae
INHIBITORS OF POLYMER CROSS-LINKING: MONOBACTAMS/CARBAPENEMS
Mechanism—β-Lactams inhibit transpeptidase by forming a covalent (“dead-end”) acyl enzyme intermediate.
Aztreonam (IV) Gram-negative bacteria Clostridium difficile infection, Hypersensitivity to A monobactam.
Used in penicillin-allergic gastrointestinal hemorrhage, aztreonam No Gram-positive activity.
patients neutropenia, ototoxicity, nephrotoxicity
Imipenem/cilastatin Gram-positive and Gram- Anaphylaxis (imipenem/cilastatin, Shared Cilastatin inhibits renal dehydropeptidase I,
(IV/IM) negative bacteria except meropenem, and doripenem only); contraindication: which would otherwise inactivate imipenem.
Meropenem (IV) MRSA, VRE, and Clostridium difficile infection, jaundice  Hypersensitivity Probenecid may increase meropenem levels.
Doripenem (IV) Legionella (ertapenem is (meropenem only); Stevens-Johnson to drug All four agents decrease valproate levels.
Ertapenem (IV/IM) not active against syndrome, toxic epidermal necrolysis, Imipenem/cilastatin
Pseudomonas or seizure, interstitial pneumonia and ertapenem only:
Acinetobacter) (doripenem only)  Hypersensitivity
Injection site pain (shared adverse to amide local
effect); headache (doripenem only) anesthetics
Imipenem/cilastatin
only:
 Severe shock or
heart block
 Meropenem and
doripenem only:
 Hypersensitivity
to β-lactam
antibiotics
INHIBITORS OF CELL MEMBRANE STABILITY
Mechanism—Daptomycin integrates into membranes of Gram-positive bacteria, leading to formation of pores that cause potassium efflux, membrane
depolarization, and cell death.
Daptomycin (IV) Complicated skin Rhabdomyolysis, eosinophilic pneumonia Hypersensitivity to Daptomycin should be co-administered with
infections Diarrhea, vomiting daptomycin a statin with caution due to risk of
Bacteremia or right-sided myopathy.
endocarditis from S.
aureus
ANTIMYCOBACTERIAL AGENTS
Mechanism—See specific drug
Ethambutol (PO) Mycobacterium species Optic neuritis, blindness, peripheral Known optic neuritis Decreases arabinogalactan synthesis by
neuropathy, neutropenia, Patients unable to inhibiting the arabinosyl transferase that
thrombocytopenia report visual changes, adds arabinose units to the growing
Hyperuricemia, mania, nausea, vomiting such as young children arabinogalactan chain.
Optic neuritis Mycobacteriostatic and used in combination
with other antimycobacterials, including
rifampin and streptomycin.
Pyrazinamide (PO) Mycobacterium species Anemia, hepatotoxicity Hypersensitivity to Pyrazinamide is a prodrug that must be
Nausea, vomiting, hyperuricemia, pyrazinamide converted to its active form pyrazinoic acid,
arthralgia Acute gout which inhibits fatty acid synthetase 1 (FAS1).
Severe hepatic Used in combination with other
dysfunction antimycobacterials, including rifampin and
streptomycin.
Isoniazid (IV/IM/PO) Mycobacterium species Hepatotoxicity (shared adverse effect); Shared Inhibit mycolic acid synthesis by targeting
Ethionamide (PO) neurotoxicity (paresthesias, peripheral contraindications: fatty acid synthetase 2 (FAS2).
neuropathy, ataxia), systemic lupus  Hypersensitivity Can inhibit or induce cytochrome P450
erythematosus, seizure, hematologic to drug enzymes and thus interact with other drugs,
abnormalities, rhabdomyolysis (isoniazid  Active liver such as rifampin, antiseizure medications
only); encephalopathy (ethionamide only) disease (carbamazepine and phenytoin), azole
Gastrointestinal upset (ethionamide only) Isoniazid only: antifungals, and alcohol.
 Concomitant Mycobactericidal and used in combination
use with with other antimycobacterials, including
serotonergic rifampin and streptomycin.
agents Isoniazid neurotoxicity can be prevented by
pyridoxine supplementation.