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:

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.

Can use:

 

 

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:

General mechanisms of resistance:

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:

 

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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