page sections

introduction
cell wall inhibitors
protein synthesis inhibitors
DNA synthesis inhibitors
metabolic pathway inhibitors
anti-mycobacterials
history of antibiotic development
antibiotic allergy
resources and references

Antibacterial Drugs

last authored: Feb 2010, David LaPierre
last reviewed:

Introduction

antibiotic sensitivity and resistance
image courtesy of CDC

There are many drugs available to treat bacterial infections, with different drug types best suited for treating specific infections.

The first determination is whether or not the patient has a bacterial infection. If clincial suspicion is low, and if the patient's condition is stable, deferring or avoiding the use of antibiotics until diagnosis is made is very important to prevent antibiotic resistance. However, if a patient's condition is serious, or in infections where bacterial pathogens are likely (UTI, pneumonia, etc), emperic therapy can also be used.

Factors which influence antiobiotic choice include bacteriostatic vs bacteriocidal action, the need for concentration-dependent (infequent, high doses), or time-dependent (more regular dosing) action.

On occasion, the patient does not improve after starting antibiotic therapy. Reasons for treatment failure to consider include:

wrong diagnosis
inadequate activity at site of infection
antibiotic resistance
impaired immune function
undrained source of infections

The following describes the various classes of antiobiotics and their members.

Cell Wall Inhibitors

penicillins
cephalosporins
carbapenems
glycopeptides

Penicillins bind to penicillin binding proteins (PBPs) with bacteria, leading to distorted cell walls and lysis.

drugs	coverage	indications	adverse effects
benzyl penicillin penicillin G (IV) penicillin V (PO)	gram-positives oral anaerobes Streptococcus Meningiococcus Treponema Clostridium NOT Staphylococcus Enterococcus Bacteroides	mild-to-moderate infections: strep pharyngitis rheumatic fever streptococcal skin and soft tissue infections actinomycosis	immediate allergy: anaphylaxis, urticaria delayed allergy (IgG): urticaria, rash, serum sickness dose-related toxicity: seizures, electropyte problems, bleeding diarrhea
aminopenicillin ampicillin (IV) amoxicillin (PO)	same as penicillin E coli E. faecalis Listeria NOT E. faecium	meningitis endocarditis AOM pharyngitis sinusitis AE-COPD H pylori Lyme disease RTI UTI often used in combination with gentamycin (gram -ve) and clavulin (for a boost)	rash common, especially with EBV infection
isoxozoyl penicillin cloxacillin methicillin nafcillin oxacillin	same as penicillin Staphylococcus		no dose adjustment with renal failure do not take with food can cause anaphylactic shock in .05% of people pseudomembranous colitis
ureidopenicillin piperacillin ticaracillin	same as penicillin GNB, including Pseudomonas		can cause hypokalemia
lactamase inhibitors amoxicillin-clavinulate piperacillin-tazobactam	same as penicillin Staphylococcus H. influenzae Bacteriodes	RTI sinusitis AOM skin/soft tissue infections UTI
carboxypenicillin carbenicillin	same as penicillin extended GN coverage

Beta-lactam resistance has evolved in a number of ways. These include:

production of beta-lactamase
altered PBP (S. pneumoniae)
new PBP (MRSA)
altered permeability (not as important)

Cephalosporins bind to penicillin binding proteins (PBPs) and prevent cross-linking of peptidoglycans, leading to distorted cell walls and lysis. They are beta-lactams.

inhibits PBPs, preventing cell wall synthesis
more resistant to beta-lactamase than penicillins

drugs	coverage	indications	adverse effects
1st generation cephalexin (PO) cefazolin (Ancef)	gram-positives +++ NOT Enterococcus gram negatives E coli Klebsiella Proteus	skin/soft tissue infections surgery prophylaxis simple mixed infections does not cross BBB	15% penicillin allergy cross-reactivity nephrotoxicity
2nd generation cefuroxime (Ceftin) cefprozil (Cefzil) cefoxitin	gram positives ++ gram negatives ++ anaerobes Hemophilus (cefuroxime)	soft tissue infection pneumonia
3rd generation cefixime (PO) ceftriaxone (IV) (Rocephin) cefotaxime ceftazidime	gram positive +++ Staphylococcus Streptococcus gram negative + Pseudomonas (ceftazidime)	RTI gonorrhea meningitis (crosses BBB) septicemia abdominal infections ceftriaxone for highly resistant S. peumo Lyme disease febrile neutropenia	once-daily dosing can cause biliary sludging. do not use in jaundiced baby half excreted in liver, half in kidney
4th generation cefepime (IV)	gram positive +++ gram negative +++ Pseudomonas	emperic therapy for febrile neutropenia

Carbapenems bind to penicillin binding proteins (PBPs) and prevent cross-linking of peptidoglycans, leading to distorted cell walls and lysis.

drugs

coverage

indications

adverse effects

imipenem

gram-positives

NOT

Enterococcus
MRSA
Stenotrophomonas
Listeria

gram-negatives

Pseudomonas
Enterobacter
anaerobes

GNB with extended beta-lactamases
polymicrobial infections
intraabdominal abscesses

low risk of penicillin allergy cross-reactivity
seizures

meropenem

Other agents include ertepenem and dorapenem.

Glycopeptides bind to D-ala in nascent cell wall peptides, preventing cross-linking during peptidoglycan formation. Glycopeptide resistance can be a problem in S. aureus and Enterococcus. It occurs via an altered target: D-lac in place of D-ala.

vancomycin

Renally dosed; AUC/MIC-dependent killing.

coverage

indications

adverse effects

gram-positives

MRSA
coag negative Staph
penicillin resistant S. pneumonea
C. difficile (PO)

not:

Enterococcus
VRE

severe, life-threatening gram-positive infections

endocarditis
osteomyelitis
pneumonia
septicemia
soft-tissue infections
enterocolitis

antibiotic-associated pseudomembranous colitis caused by C. difficle (oral administration)

careful monitoring of vancomycin levels is required when used along with neurotoxic and nephrotoxic agents
excreted rapidly through kidney; decreased renal clearance can cause levels to rise rapidly

Red man syndrome (histamine, hypotension)
nephrotoxicity
ototoxicity
neutropenia, thrombocytopenia

exaggerated hypotension, including shock and occasionally cardiac arrest, can occur following rapid bolus administration
toxic serum levels can occur when given IV

teicoplanin

gram-positives, including MRSA
NOT most VRE

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Protein Synthesis Inhibitors

These target the bacterial ribosome (70S vs 80S).

macrolides
aminoglycosides
lincosamides
tetracyclines
other

Macrolides have a broad spectrum of activity. They are bacteriostatic, with time dependent killing.

These bind the 50S subunit.

erythromycin

coverage

indications

adverse effects

Gram positive

Streptococcus
S. aureus
Chlamydophila pneumoniae
Mycoplasma pneumoniae

NOT

Enterococcus
MRSA

Gram negative

N. meningitidis
N. gonorrhoeae
B. pertussis
C. jejuni
L. pneumophilia

community-acquired pneumonia (atypical coverage)
pertussis
Legionnaires disease
diptheria

second line

Strep throat

nausea (acts as a motilin agonist)
phelbitis
acute cholestatic hepatitis (rare)
transient hearing loss
antibiotic associated diarrhea
prolonged QT
inactivates cytochrome P450, impairing hepatic metabolism (ie warfarin)

clarithromycin (Biaxin)

coverage

indications

adverse effects

same

once daily drug

RTI, skin infections, mycobacteria, H.pylori

azithromycin (Zithromax)

coverage

indications

adverse effects

same
Chlamydia trachomatis
T. gondii
H. influenza

first line for chlamydia

may also be used for:

pharyngitis
tonsilitis
AOM
AE-COPD
community-acquired pneumonia
skin infections
campylobacter

long half-life, leading to long subtherapeutic levels and increased risk of selection for resistance

penetrates tissues well, with [tissue] : [serum] 100x
half life of over 3 d (due to tissue reserve) leads to once daily dosing
decreased drug interactions cf erythromycin
limited metabolism
mostly bile

Aminoglycosides

Aminoglycosides are excellent for gram-negatives. They are bactericidal, killing in a concentration-dependent manner. Irreversibly bind 30S subunit. Do not work against anaerobes, as they require oxygen-dependent influx.

Drugs include: gentamycin, tobramycin, amikacin, neomycin, streptomycin.

coverage

indications

adverse effects/comments

gram negative

Pseudomonas (tobra)
Proteus
Serratia
E coli
Klebsiella

UTI and pyelonephritis
in combination with beta lactam
endocarditis
neonatal pneumonia
Pseudomonas
febrile neutropenia

ototoxicity (requiring monitoring)
nephrotoxicity
resistance : enzymatic, reduced uptake
poor tissue penetration (CSF, abscess, airways)

Once daily dosing is more effective and less nephrotoxic and ototoxic. Connventional dosing is done with pregnancy, ascites, cystic fibrosis, burns, and renal failure.

Streptomycin

used in conjunction with other agents in the treatment of M tuberculosis
also has activity against M leprae, Y pestis, and others

lincosamides

irreversibly binds the 50S subunit, inhibiting protein initiation

clindamycin

coverage

indications

adverse effects and notes

gram positives

Streptococcus
Staph (some MRSA)
B fragilis
anaerobes

Not

Enterococcus
not C. difficile

anaerobic infections, usually with anti-GN

aspiration neumonias
necrotizing pneumonias
intra-abdominal
diabetic/ischemic feet
necrotizing infections: prevents toxin synthesis

nausea
pseudo-membranous colitis
contra-indicated in pregnancy

penetrates most tissues, but not CSF
metabolized in liver
excreted in both urine and stool

Tetracyclines

Members include tetracycline, doxycycline, minocycline. Main mechanism of resistance is efflux.

coverage

indications

adverse effects

gram positives

B anthracis
C perfringens
C tetani
L monocytogenes
some strains of Staphylococcus and Streptococcus

common gram negatives

B pertussis
Brucella
Campylobacter,
H influenzae
N meningitis
V cholerae
Y pestis

atypicals (excellent)

Chlamydia
Mycoplasma
Rickettsiae
Treponema

B. burgdorferi

anaerobes
malaria prophylaxis

poor:

Pseudomonas
C. difficile

acne
Chlamydia
Rickettsial infections
brucellosis
bartonellosis
PID
malaria prophylaxis

GI upset
hepatotoxicity
Fanconi's syndrome
photosensitivity
teratogenic
yellow teeth and stunted growth in children

tigecycline.

glycylcycline. derivative of monicycline.

IV; poor oral bioavailability.

coverage

indications

adverse effects

gram positives

common gram negatives
MRSA
VRE
NO activity against Pseudomonas

skin and soft-tissue
intra-abdominal infections

nausea and vomiting (very common)
may discolor teeth

daptomycin (where should this go?)

cyclic lipopeptide. Bactericidal; concentration-dependent killing. Irreversibly binds to bacterial cell membrane, forming a pore that leads to rapid depolarization through K efflux

coverage

indications

adverse effects

Corynebacterium jeikeium

Enterococcis

Staphylococcus epidermidis

Other

chloramphenicol

inhibits protein synthesis by binding the 50S ribosomal subunit

coverage

indications

adverse effects

GP
GN
anaerobes
Rickettsia, Chlamydia, Mycoplasma

Typhoid fever

serious infections when suitable alternatives not available

aplastic anemia
grey baby syndrome

oxazolidinone - inhibits initiaition of bacterial protein synthesis. Alternative to vancomycin for MRSA and VRE.

coverage	indications	adverse effects
GP, including VRE and MRSA	VRE, MRSA as outpatient	hypertension myelosuppression optic neuropathy peripheral neuropathy with prolonged use tyramine food

daptomycin

will be good for penetrating biofilms

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DNA Synthesis Inhibitors

fluoroquinolones
other

Fluroquinolones

Fluoroquinolones act on DNA gyrase and topoisomerase IV, causing permanent DNA double-stranded breaks and bacterial death.

They demonstrate concentration dependent killing. Bad for children, as DNA is important to them.

Resistance can occur with DNA gyrase mutations, cellular membrane efflux, and decreased porins.

They have excellent bioavialability, though concentration is lower in the CSF. They are predominantly renally excreted, causing concentration in urine, but requiring dose adjustment.

ciprofloxacin, norfloxacin, ofloxacin

coverage

indications

adverse effects/comments

gram positives -

gram negatives +++

Pseudomonas

use only when necessary to prevent resistance

respiratory tract infections
bone and joint infections
infectious diarrhea
intra-abdominal infections + metronidazole
mixed skin and soft tissue infection
pyelonephritis, UTI (2nd line)
prostatitis
febrile neutropenia
cystic fibrosis

limited use in pregnancy, nursing, and children <18
C. difficile infection
H/A, dizziness, nausea
allergy
seizures
prolonged QT
teratogenic
drug interactions
arthralgias 1%
decreased absorption when taken with cations

levofloxacin, moxifloxacin

coverage

indications

adverse effects/comments

gram positives ++

gram negatives +++

atypicals
anaerobes

same as above
community-acquired pneumonia

same as above

Other

metronidazole (Flagyl)

Leads to free radical release, damaging DNA and other macromolecules. First needs to be reduced. Good oral viability.

coverage

indications

adverse effects

anaerobes

C difficile
Garnderella vaginalis
oral anerobes
H. pylori
bacteriodes
Entamoeba histolytica
Giardia
Trichomonas vaginalis

poor

aerobic GP and GN

Trichomonas
amebiasis
giardiasis
bacterial vaginosis
serious intra-abdominal infections
anerobic infections
C. difficile colitis
brain abscess

adverse effects with EtOH (antabuse effect)
seizures
peripheral neuropathy
urine discoloration
metallic taste
may be teratogenic and cause tumours
vomiting, diarrhea, dizziness, thrush, vertigo, neutropenia

orally, well-absorbed and is widely distributed in tissues
penetrates CSF and brain
can also be given IV and rectally

potentiates the effects of coumarin-type anticoagulants
phenytoin and phenobarbital may accelerate elimination of metronidazole
cimetidine may decrease plasma clearance of metronidazole
lithium toxicity possible
alcohol (nausea, vomiting)

half-life of 7.5 hours
metabolized in liver
excreted in urine

Rifampin

inhibits RNA polymerase, preventing RNA synthesis. It cannot be used alone due to rapid development of

coverage	indications	adverse effects
GPC N meningitidis H. influenza Mycobacteria	active TB other mycobacterial infections prosthetic endocarditis can	hepatic dysfunction induces cyt P450 orange tears/saliva/urine rapid resistance can develop

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Metabolic Pathway Inhibitors

Trimethoprim/sulfamethoxazole (TMP/SMX) blocks folic acid synthesis at two steps; bacteria cannot obtain folate from their environment and rely on its synthesis to proliferate. Resistance if organism can bypass metabolic requirements. Good CNS penetration

coverage	indications	adverse effects
GP GN: enteric Nocardia Toxoplasma Stenotrophomonas H. influenza Strep. pneumo Neisseria S. aureus Pneumocystis jiroveci	UTR, RTI, GI infections, skin and soft tissue, PCP	frequent mild allergic reactions hepatitis Stevens-Johnson syndrome anemia, hemolysis, leukopenia, hyperkalemia interstitial nephritis BM suppression erythema nodosum erythema multiforme vasculitis not in pregnancy or neonates due to competition for bilirubin

nitrofurantoin (MacroBID, Macrodantin)

coverage

indications

adverse effects

Enterococcus
S. saphrophyticus
E coli

poor against:

Serratia
Proteus
Pseudomonas

lower UTI; not pyelonephritis or bacteremia

cholestasis, hepatitis
hemolysis in G6PD
lung disease with chronic use
urine discoloration

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Antimycobacterials

Always used as combination therapy (minimum three) due to high rates of resistance.

These drugs are given over a long duration, ie 6 months or more.

drugs	coverage	indications	adverse effects
isoniazid	mycobacteria	inhibits formation of the mycobacterial cell wall
rifampin	GPC N meningitidis H. influenza Mycobacteria	active TB, other mycobacterial infections; prosthetic endocarditis	hepatic dysfunction inc P450 orange tears/saliva/urine
ethambutol	mycobacteria
pyrazinamide	mycobacteria
sulfones	M. leprae PCP toxoplasmosis
clofazimine	M. leprae

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History of Antibiotic Development

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SPICE

AmpC inducible; resistant to third-generation cephalosporins.

Serratia
Pseudomonas
Indole positive
Citrobacter
Enterobacter

Can use:

carbapenems
vancomycin
etc

Antibiotic Resistance

Bacterial reistance to antibiotics may be innate (ie with Pseudomonas) or acquired, either through mutation or transformation/congulation of foreign DNA.

Resistance is increased by:

inadequate levels of antibiotic at site of infection
too short a treatment time
elevate numbers of organism
overuse of antibiotics
frequent exposure to the same class of antibiotic

General mechanisms of resistance:

altered permeability
inactivation/destruction of antibiotic
altered drug binding site
new binding sites
drug pumps
bypass of metabolic pathways

Erythromycin can turn on resistance to clindamycin in some bacteria.

An antibiogram is an antiotic susceptibility chart.

Antibiotic Allergy

Many people are not clear regarding allergy.

Immunologically mediated reactions include:

reaction does not resemble the drug's pharmacologic effect
lag time to reaction
reaction may occur with minute doses
symptoms characteristic of allergic reaction (hives, bronchospasm, etc)
reaction resolves after drug is discontinued
reaction is preproduced by agents with similar chemical structures

Penicillin

Approx 10% of patients in one study reported being allergic to penicillin, while 90% of these people are able to tolerate penicillin (Khan et al, 2010).

Up to 20% of the hospitalized population believes they are allergic to penicillin. However, in patients with an anaphylactic response, only 20% are still allergic after 10 years.

Cross-reactivity to cephalosporins, which have a similar penicillin ring, is very controversial. If any concern, use 2nd or 3rd generation cephalosporins.

Resources and References

Khan DA et al. 2010. Drug Allergy. J Allergy Clin Immunol. 125:S126-7.

McLean-Toole A et al. 2011. Practical management of antibiotic allergy in adults. J Clin Pathol. 64:192-199.

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