Antibiotics, General

Definitions

Bacteriostatic
Inhibit bacterial growth, dependent on host defenses to kill bacteria
Bactericidal
Kills susceptible bacteria without host defenses

Principles

  • Selective toxicity
    • Attach structures that are present in bacteria but not in mammals
    • Attach enzyme systems that differ between bacteria and the host
  • Increased efficacy
  • Increased cost
  • MIC = minimum inhibitory concentration
    • The minimum concentration of an antibiotic required to inhibit growth of a bacterium
  • MBC = minimum bactericidal concentration
    • The minimum concentration of an antibiotic required to kill a bacterium
  • Both are dependent on the bug and the drug
  • Bacteriostatic antibiotic
    • The MBC is > 16-fold higher than the MIC
      • Staph.aureus & Clindamycin
        • MIC = 0.5 mg/L
        • MBC = 16 mg/L
  • Bactericidal antibiotic
    • The MBC is usually within 1-2 dilutions of the MIC
      • Staph.aureus & Cloxacillin
        • MIC = 0.25 mg/L
        • MBC = 0.5 mg/L
    • Greater than 3 x log reduction in viable bacteria at 24 hours following exposure
  • In-vitro antibacterial susceptibility testing does not always correlate with in vivo response
  • In-vitro activity of antiviral and antifungal agents has no established clinical correlation
  • Not all agents in the same class possess similar or identical antimicrobial activity
  • Initial susceptibility may be altered quickly by induction of resistance mechanisms
  • Pharmacodynamics
    • Time-dependent killing
    • Concentration-dependent killing
    • Post-antibiotic effect
  • Pharmacokinetics
  • Host Factors
    • Altered metabolic or excretory pathways
      • Renal failure
        • Aminoglycosides
        • Vancomycin
      • Hepatic dysfunction
        • Chloramphenicol – “Gray Baby Syndrome”
        • Isoniazid – Age-related hepatotoxicity
        • Rifampin & Macrolides – CyP450 effects
  • Spectrum of Activity
    • Broad
      • Good for empiric therapy
      • “Jack of all trades, Master of None”
      • May foster antibiotic resistance
    • Narrow
      • Ideal when possible
      • May decrease resistance pressure
  • Initial or Empiric vs. Definitive Therapy
    • Definitive therapy usually requires microbiologic data to aid selection of the appropriate antibiotic
    • In >50% of cases therapy is empiric
  • Combination Therapy
    • Potential advantages
      • May slow emergence of resistance
      • Increase bactericidal activity “Synergy”
      • Reduced dose of potentially toxic agents
    • Disadvantages
      • Potential for drug interactions
      • Increased cost
      • Possible antagonism
    • Conditions that always or often require combination therapy
      • Tuberculosis
      • Enterococcal infections in specific sites i.e. infective endocarditis
      • Pseudomonas aeruginosa
      • Febrile neutropenia
      • Cryptococcal meninigitis
      • HIV infection
  • Aminoglycosides have a post-antibiotic effect that delays recovery and regrowth of bacteria
  • Rifampin interacts with almost all known drugs
  • If a patient is allergic to penicillin, cephalosporins are indicated
  • “Eagle Effect”
    • If bacterial growth has reached its plateau phase within the host, certain antibiotics such as penicillins loose their bactericidal effects
  • Mechanisms of action
  • Inhibition of bacterial cell wall synthesis
    • Penicillins, cephalosporins
  • Compromise microbial cell membrane
    • Polymyxin ,amphotericin B
  • Inhibition of bacterial protein synthesis
    • Tetracycline
  • Synthesis of altered bacterial proteins
    • Gentamicin
  • Altered synthesis or metabolism of nucleic acids
    • Ciprofloxacin
  • Antimetabolites
    • Trimethoprim/sulfamethoxazole (co-trimoxazole)
  • Nucleic acid analogs
    • Acyclovir for viruses
  • Delivery of drug to site of action
    • Blood-brain barrier
      • Polarity of drug?
      • Does it cross the BBB
    • Extent of protein binding
      • Diffusion may be hampered
      • Active concentration is unbound drug
    • Renal function
      • Many antibiotics are eliminated by the kidney
    • Liver function
      • a number of antibiotics are eliminated by the liver
    • Route of administration
      • IV : bioavailability is assured
      • Oral : convenience
        • Bioavailability can vary
        • Chelation of tetracycline by divalent ions
    • Host specific factors
      • Age: renal and hepatic function differences in young and elderly
      • Genetic factors:
        • Some antibiotics will induce hemolysis in glucose-6-phosphate dehydrogenase deficient pts
      • Pregnancy
        • Exposure of fetus to drugs
        • Δ pharmacokinetics: larger volume of distribution
  • Safety in pregnancy
    • Known to be safe:
      • penicillins and cephalosporins
      • erythromycin base
      • spectinomycin
    • Likely safe, but used with caution:
      • aminoglycosides
        • ototoxicity to fetus
        • renal toxicity to mom
      • INH, rifampin and EMB
        • liver toxicity to mom
        • CNS toxicity to fetus
      • sulfonamides
        • crystalluria to mon
        • kernicterus to fetus
    • Know to notbe safe:
      • metronidazole
        • neuropathy to mom
        • teratogenic to fetus
      • erythromycin salts
        • liver toxicity to mom
      • chloramphenicol
        • marrow suppression/failure to mom
        • Gray syndrome to fetus
      • quinolones
        • GI issues with mom
        • arthropathy to fetus

Taxonomy

Cell Wall Agents

Beta lactams

  • Largest and oldest class of true antibiotics in current use
    • Penicillins
    • Cephalosporins
    • Carbapenems
    • Monobactams
    • Beta-lactamase inhibitors
  • Interfere with cell wall synthesis via penicillin-binding proteins (PBPs)
  • Bactericidal
  • Mechanisms of bacterial resistance
    • Modifying enzymes – β-lactamases
    • Modified target site – methicillin-resistance
    • Decreased entry into cell via altered porins
  • Pharmacokinetics:
    • Excretion
      • Most are renally excreted
        • Glomerular filtration
        • Anionic secretion in proximal tubule
      • Biliary/fecal excretion
        • Cloxacillin
        • Ceftriaxone
        • Piperacillin
  • Toxicity
    • IgE mediated reactions – allergy
    • Seizures

Penicillin organism coverage

  • Penicillin clinical uses:
    • Endocarditis
    • Meningitis
    • Brain abscess
    • Respiratory tract infections
    • Skin and soft tissue infections
    • Infections in pregnancy
    • Miscellaneous infections
      • Syphilis
      • Listeria monocytogenes
      • Enterococcal infections
      • Animal bites
        • Pasturella multocida
        • Capnocytophaga canimorus

Cephalosporin organism coverage

  • Cephalosporin clinical uses:
    • Respiratory tract infections
    • Nosocomial infections
    • Urinary tract infections
    • Surgical prophylaxis
    • Infections in pregnancy
    • Alternative to penicillins in some penicillin-allergic patients

Carbapenems

  • Three available in Canada
    • Imipenem-cilastatin
    • Meropenem
    • Ertapenem
      • Doesn’t cover Pseudomonas aeruginosa
  • Very broad spectrum agents
  • Remember what they DON’T cover
    • Methicillin-resistant staphylococci
    • Organisms without cell walls
      • Mycoplasma, Chlamydia
    • Stenotrophomonas maltophilia, B. cepacia
    • Mycobacterium tuberculosis

Beta-lactamase Inhibitors

  • Block mainly plasmid-mediated β-lactamases
  • Clavulinic acid combined with;
    • Amoxicillin (Clavulin®)
    • Ticarcillin (Timentin®)
  • Sulbactam is combined with;
    • Ampicillin (Unasyn®) U.S. only
  • Tazobactam is combined with;
    • Piperacillin (Tazocin®)

Vancomycin

  • A glycopeptide
  • Aerobic gram-positive cocci and bacilli
    • Staphylococci incl. methicillin-resistant strains
    • Streptococci and Enterococci
    • Bacillus species
  • Anaerobic gram-positive cocci and bacilli
    • Peptostreptococci species
    • Clostridium species
  • Inhibits cell wall synthesis at early stage
  • Bactericidal
  • Resistance:
    • Bypass of D-ala-D-ala pentapeptide intermediate
    • 4 types VanA, B, C1,C2
  • Excretion
    • Solely renal
  • Toxicity
    • Direct release of mast cells/basophils histamine
      • Red Man syndrome
    • Neutropenia
    • Ototoxicity
  • Clinical uses:
    • Alternative to β-lactams in penicillin-allergic patients
    • Vascular line-associated infections
    • MRSA infections
    • Prosthetic material infections
    • Clostridium difficile-associated diarrhea (oral only)

Lipoglycopeptides

  • Daptomycin
    • Lipopeptide
  • Dalbavancin
    • Lipoglycopeptide
    • T1/2 = 160 hours

Protein Synthesis Inhibitors

Aminoglycosides

  • Inhibit protein synthesis (30S ribosome)
  • Bactericidal
  • Post antibiotic effect (PAE)
  • Resistance
    • Modifying enzymes
    • Impaired entry
    • Active efflux
  • Commonly used
    • Gentamicin
    • Tobramycin
    • Netilimicin
    • Streptomycin
  • Reserved for resistant infections
    • Amikacin
  • Excretion
    • Renal
  • Toxicity
    • Nephrotoxicity
    • Ototoxicity
  • Antimicrobial activity
    • Aerobic gram-negative bacilli
    • Synergistic with β-lactams against Staphylococci and Enterococci
    • Additive with β-lactams against Streptococci and Listeria
    • Mycobacterial infections
  • Clinical usage:
    • Sepsis syndrome
    • UTIs
    • Nosocomial infections
    • Tuberculosis
    • Synergistic coverage in:
      • Endocarditis
      • Enterococcal bacteremia
      • Severe staphylococcal infections
      • Pseudomonas aeruginosa

Macrolides

  • Commonly used:
    • Erythromycin
      • Base
      • Salts
        • Ethylsuccinate (EES®)
        • Estolate (Ilosone®)
    • Clarithromycin
    • Azithromycin
    • Telithromycin
  • Inhibit protein synthesis (50S ribosome)
  • Bacteriostatic
  • Resistance
    • Altered ribosomal target site (erm genes)
      • MLSB phenotype
    • Efflux (mef genes)
      • M phenotype
  • Excretion
    • Biliary/Fecal
  • Toxicity
    • GI distress
    • Rashes
    • Cholestatic jaundice
    • Drug interactions
  • Organism activity:
    • Gram-positive cocci
    • Respiratory gram-negatives
      • Hemophilus species
      • Neisseria species
    • Mycoplasma and Chlamydia species
    • Legionella species
    • Helicobacter pylori
    • Non-tuberculous mycobacteria
  • Clinical uses:
    • Respiratory tract infections esp. Community-acquired pneumonia
    • Sexually Transmitted Diseases
    • Alternative to β-lactams in penicillin-allergic patients
    • Mycobacterial infections
    • Peptic ulcer disease (Helicobacter pylori)

Clindamycin

  • A lincosamide
  • Activity
    • Most aerobic gram-positive cocci
    • Anaerobes including;
      • Peptostreptococci
      • Bacteroides species
      • Some Clostridium species (but not C. difficile)
  • Inhibits protein synthesis
  • Bacteriostatic
  • Resistance
    • Alteration of target site (MLSB phenotype)
  • Excretion
    • Fecal/Biliary
  • Toxicity
    • Rashes
    • Clostridium difficile-associated diarrhea
      • IV admin. 5-10%
      • PO admin. 10-20%
  • Clinical uses:
    • Alternative to β-lactams in gram-positive infections
    • Intra-abdominal/pelvic infections
    • Aspiration (anaerobic) pneumonia
    • Odontogenic (dental) infections
    • Cellulitis and diabetic foot infections
    • Toxoplasmosis

Tetracyclines

  • Original “broad-spectrum” oral agents
  • Overuse has lead to widespread resistance especially in gram-positive cocci
    • Doxycycline and tetracycline most frequently used
    • Tigecycline-1st new tetracycline since 1960’s
      • Active against MRSA, many enteric GNB, anaerobes
  • Inhibit protein synthesis (30S)
  • Bacteriostatic
  • Resistance
    • Multiple
    • Altered target site
    • Increased efflux
  • Excretion
    • Renal for tetracycline
    • Hepatobiliary for doxycycline
  • Toxicity
    • Rashes
    • Photosensitivity
    • GI distress
    • Bone and teeth discolouration
  • Clinical uses:
    • Older tetracyclines
      • Sexually Transmitted Diseases
      • Acute Exacerbations of COPD
      • Rickettsial infections i.e. RMSF, Typhus

Acne

  • Protozoal infections
    • Malaria
    • Dientamoeba fragilis
  • Tigecycline
    • Hospital-acquired infections
    • Intra-abdominal infections
    • Skin & soft tissue infections caused by MRSA

Chloramphenicol

  • Inhibits protein synthesis (50S)
  • Bacteriostatic or bactericidal depending on organism
  • Resistance
    • Inactivation by C-acetyltransferase
  • Excretion
    • Renal excretion of hepatic metabolites
  • Toxicity
    • Severe bone marrow suppression
      • Dose-dependent and idiosyncratic (irreversible)
    • Gray Baby syndrome in neonates
    • Optic neuritis
  • Clinical uses:
    • Rarely used in developed world
    • Meningitis
    • Brain abscess
    • Mixed aerobic/anaerobic infections
    • Enteric fever

Streptogramins

  • Synercid® (quinupristin-dalfopristin)
    • Inhibit protein synthesis similar to macrolides
  • Active against chiefly gram-positives
    • Used for treatment of MRSA and VRE (E. faecium only) infections
  • IV only
  • Adverse effects
    • Infusion-related thrombophlebitis
    • Arthralgias

Oxazolidinones

  • Linezolid
  • Inhibit protein synthesis at initiation of translation
  • Very broad activity against gram-positive organisms including MRSA and VRE
  • High oral bioavailability (99-100%)
  • Adverse effects
    • Myelosuppression
    • Tongue discolouration
    • Weak reversible Monoamine oxidase inhibition

DNA Replication

Quinolones

  • Taxonmy:
    • Standard
      • Norfloxacin – UTI agent only
      • Ciprofloxacin
      • Ofloxacin/Levofloxacin
    • Respiratory
      • Gatifloxacin
      • Moxifloxacin
      • Gemifloxacin
    • Broad spectrum
      • Trovafloxacin
  • Inhibit DNA gyrase & topoisomerase IV
  • Bactericidal
  • Post-antibiotic effect
  • Resistance
    • Point mutations in target site genes
      • gyrA and parC
    • Impaired entry
    • Efflux
  • Excretion
    • Renal
  • Toxicity
    • Cartilage growth inhibition
    • QT interval prolongation
    • Photosensitivity/Rashes
    • Hypoglycemia
    • Rare nephrotoxicity and hepatotoxicity
  • Antimicrobial activity:
    • Standard Quinolones (e.g. ciprofloxacin/norfloxacin/levofloxacin)
      • Enteric and Respiratory gram-negative bacilli
      • Pseudomonas species (Ciprofloxacin only)
      • Neisseria species
      • Borderline staphylococcal coverage
    • Respiratory Quinolones (e.g. gemifloxacin/moxifloxacin)
      • Respiratory gram-positive and gram-negatives including penicillin-resistant S. pneumoniae
      • Legionella species
      • Chlamydia and Mycoplasma species
      • Enteric gram-negative bacilli
    • Broad spectrum Quinolones (e.g. trovafloxacin)
      • Most gram-positive cocci/bacilli incl. PRSP and some MRSA
      • Most aerobic gram-negative bacilli including Legionella species
      • Most anaerobes
      • Chlamydia and Mycoplasma species
  • Clinical uses:
    • Standard:
      • Drugs of Choice for:
        • Prostatitis
        • Gram-negative osteomyelitis
        • Uncomplicated gonorrhea
        • Complicated UTIs
      • Useful in:
        • Empiric coverage of bacterial diarrhea
        • Eradication of Hemophilus and Meningococcal carrier states in adults
    • Respiratory
      • Community-acquired pneumonia
      • Other respiratory tract infections in adults
        • Acute exacerbations of chronic obstructive lung disease
        • Sinusitis
      • Studied but not frequently used in:
        • UTI
        • Skin & Soft tissue infections i.e. cellulitis
    • Broad spectrum
      • Trovafloxacin use is severely restricted to use only in life threatening clinical situations
      • Nosocomial infections incl. Hospital-acquired pneumonia
      • Intra-abdominal infection
      • Other serious polymicrobial infections
        • i.e. diabetic foot infections

Co-trimoxazole

  • Taxonomy
    • Trimethoprim
    • Sulfamethoxazole
  • Inhibits sequential steps in folate synthesis
  • Bactericidal
  • Resistance
    • Altered dihydrofolate reductase target site
  • Excretion
    • Renal
  • Toxicity
    • Severe rashes
    • Bone marrow suppression
    • GI side effects
  • Microbial activity
    • Enteric and Respiratory Gram-negative bacilli
    • Staphylococci
    • Listeria
    • Chlamydia species
    • Pneumocystis jiroveci [carinii]
  • Clinical uses:
    • All UTIs
    • Acute exacerbations of COPD
    • Pneumocystis jiroveci pneumonia (PCP)
    • Otitis media in children
    • MRSA infection (occasionally)
    • Prophylaxis
      • PCP
      • Neutropenia
      • UTIs

Metronidazole

  • A nitro-imidazole
  • Activity
    • Anaerobes (gram-negative > gram-positive)
    • Parasites
      • Entamoeba histolytica
      • Giardia lamblia
      • Trichomonas vaginalis
  • DNA damage induced by toxic intermediate metabolites
  • Bactericidal
  • Resistance
    • Rare
    • Decreased uptake into cell
  • Excretion
    • Hepatic metabolism
    • Renal & biliary
  • Toxicity
    • Peripheral neuropathy
    • GI distress
    • Disulfiram-like reaction with alcohol
  • Clinical uses:
    • Intra-abdominal, pelvic and other infections where anaerobes play an important role
    • Brain abscess and other suppurative (pus-producing) CNS infections
    • Intestinal parasitic infestations
    • Clostridium difficile-associated diarrhea

Nitrofurantoin

  • A nitrofuran
  • Mechanism of action unknown
  • Bacteriostatic
  • Resistance
    • Rare
  • Clinical Use
    • Lower tract UTIs
    • Acute therapy & prophylaxis
  • Excretion
    • Renal
    • Tissue and hepatic metabolism
  • Toxicity
    • GI irritation
    • Hypersensitivty reactions
    • Rashes
    • Cytopenias