Overview of antibiotic therapy

Antibiotics are employed against bacterial as well as some parasitic infections. They have either a bacteriostatic or a bactericidal effect and can be effective against a small group of bacteria (narrow-spectrum) or a wide range of pathogens (broad-spectrum). Most antibiotics work by inhibiting cell wall synthesis, protein synthesis, or nucleic acid synthesis in bacteria. Common side effects include allergies and cross-reacting hypersensitivities, as well as nephrotoxic and hepatotoxic effects. Many antibiotics are contraindicated in certain patient groups (e.g., children, pregnant or lactating women). In the case of severe infections, early initiation of one or more antibiotics without waiting for a microbiological confirmation is indicated (empirical antibiotic therapy), with the aim of targeting the most likely pathogen(s). Because of widespread use of antibiotics (often misuse!), antibiotic-resistant pathogens have emerged (e.g., MRSA, Pseudomonas).

• A large group of antibiotics that includes penicillins, carbapenems, aztreonam, and cephalosporins
• Mechanism of action
  • Inhibit cell wall synthesis by blocking peptidoglycan crosslinking
    • The beta-lactam structure mimics the D-ala-D-ala residue of bacterial peptidoglycan
    • Irreversibly binds to penicillin-binding proteins (transpeptidases responsible for peptidoglycan crosslinking); , stalling the catalytic reaction because the beta-lactam cannot be cleaved
    • Bacterial death as a result of an inability to synthesize new cell wall during replication
  • Activate autolytic enzymes
  • Beta-lactam antibiotics are bactericidal
• CNS penetration: only when meninges are inflamed
  • Exceptions: ceftriaxone and aztreonam always have good CNS penetration
• Route of elimination
  • Primarily renal
  • Exceptions
    • Primarily biliary: nafcillin
    • Both renal and biliary: other anti-staphylococcal penicillins (e.g., oxacillin, dicloxacillin), ceftriaxone
• General adverse effects
  • Penicillin allergy (hypersensitivity reactions)
  • Jarisch-Herxheimer reaction (e.g., when treating syphilis)

Beta-lactamase inhibitors

• Beta-lactamases, which are usually produced by gram-negative and anaerobic organisms, can split the beta-lactam ring and render certain beta-lactam antibiotics ineffective.
• Beta-lactamase inhibitors increase the spectrum of antibiotic activity.
• Drugs
  • Clavulanic acid (combined with amoxicillin = co-amoxiclav)
  • Sulbactam (combined with ampicillin)
  • Tazobactam (combined with piperacillin)

Beta-lactamase inhibitors (CAST): Clavulanic Acid, Sulbactam, Tazobactam

• Drugs: Oral or IV vancomycin
• Mechanism of action
  • Inhibits cell wall synthesis by binding the terminal D-ala-D-ala moiety of cell-wall precursor peptides, therefore only effective against gram-positive bacteria.
  • Vancomycin; is bactericidal.
• CNS penetration: only when meninges are inflamed
• Route of elimination: renal
• Clinical use: especially effective against multidrug-resistant organisms
  • Broad-spectrum coverage against gram-positive bacteria only
  • Methicillin-resistant Staphylococcus aureus (MRSA)
  • S. epidermidis
  • Enterococci
  • Clostridium difficile
• Adverse effects
  • Nephrotoxicity
  • Ototoxicity/vestibular toxicity
  • Rapid infusions are associated with anaphylactoid reactions; ("red man syndrome" or "red neck syndrome")
  • Thrombophlebitis
  • Neutropenia
• Contraindications
  • Pregnancy (relative contraindication)

References:^[1]

• Drugs: fosfomycin
• Mechanism of action
  • Inhibits cell wall synthesis by inhibiting the formation of N-acetylmuramic acid (a component of bacterial cell wall)
  • Bactericidal
• CNS penetration: only when meninges are inflamed
• Route of elimination: renal elimination
• Clinical use: : women with uncomplicated urinary tract infections (e.g., cystitis)
• Adverse effects: mild electrolyte imbalances (e.g., hypernatremia, hypokalemia), diarrhea

• Drugs: daptomycin
• Mechanism of action
  • Incorporation of potassium ion-channels into the cell membrane of pathogens, leading to rapid membrane depolarization
    • → Inhibition of intracellular synthesis of DNA, RNA, and proteins.
  • Bactericidal
• CNS penetration: poor
• Route of elimination: renal
• Clinical use
  • Gram-positive aerobes
    • However, daptomycin only has limited efficacy against Enterococci.
  • MRSA (except for pneumonia as it is bound and inactivated by surfactant)
  • Vancomycin-resistant Enterococci (VRE)
• Adverse effects
  • Reversible myopathy
  • Rhabdomyolysis
  • Allergic pneumonitis

• Drugs
  • IV or IM polymyxin B
  • IV or IM polymyxin E (colistin)
• Mechanism of action
  • A cationic detergent molecule the disrupts cell wall membranes
  • Binds to and inactivates endotoxins
  • Bactericidal
• CNS penetration: poor
• Route of elimination: mostly renal
• Clinical use
  • Topical antibiotics
  • Systemically against severe gram-negative infections including Pseudomonas, Acinetobacter; , and species of Enterobacteriacea
  • Polymyxins are not effective against gram-positive organisms
• Adverse effects (severe)
  • Nephrotoxicity
  • Neurotoxicity
  • Urticaria, eosinophilia, and/or anaphylactoid reactions
• Contraindications
  • Renal failure (relative contraindication)

• Drugs
  • IM or IV gentamicin
  • IV or IM amikacin
  • IV or IM tobramycin
  • IV or IM streptomycin
  • Oral neomycin
• Mechanism of action
  • Inhibits bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome
  • Damage to the cell wall
  • Bactericidal
  • Synergistic effect when combined with beta-lactam antibiotics; : Beta-lactams inhibit cell wall synthesis → facilitate entry of aminoglycoside drugs into the cytoplasm
• CNS penetration: poor
• Route of elimination: renal
• Clinical use
  • Severe gram-negative bacilli infections
  • Not effective against anaerobes
  • Neomycin, which is not absorbed systemically, is administered orally to prepare the gut for bowel surgery.
  • Streptomycin: Mycobacterium tuberculosis, M. avium-intracellulare
• Adverse effects
  • Nephrotoxicity
  • Ototoxicity and vestibulotoxicity (impaired hearing and balance)
  • Neuromuscular blockade
• Contraindications
  • Myasthenia gravis, botulism
  • Renal failure (relative contraindication)
  • Pregnancy (relative contraindication)
    • Streptomycin is absolutely contraindicated during pregnancy
• Mechanism of antibiotics resistance: Secreted bacterial enzymes inactivate the antibiotics through acetylation, phosphorylation, or adenylation.

Mean GNATScaNNOT kill anaerobes. (AMINoglycosides; Gentamycin, Neomycin, Amikacin, Tobramycin, Streptomycin; Nephrotoxicity, Neuromuscular blockade, Ototoxicity, Teratogenic)
References:^[1][2]

• Drugs
  • Oral or IV tetracycline
  • Oral doxycycline
  • Oral demeclocycline
  • Oral or IV minocycline
• Mechanism of action
  • Inhibits bacterial protein synthesis by blocking incoming aminoacyl-tRNA from binding to the ribosome acceptor site.
  • Bacteriostatic
• CNS penetration: poor
• Route of elimination
  • Renal elimination
  • Doxycycline: only GI elimination
• Clinical use
  • Atypical bacteria such as Borrelia, Mycoplasma, Rickettsia, Anaplasma, Ehrlichia, Chlamydia, Ureaplasma, Vibrio cholerae
  • Acne
• Adverse effects
  • Hepatotoxicity
  • Deposition in bones and teeth → discoloration of teeth and inhibition of bone growth in children
  • Damage to mucous membranes (e.g., esophagitis)
  • Photosensitivity: UV light is absorbed by the drug, which releases energy to the surrounding area and damages exposed areas
  • Degraded tetracyclines associated with Fanconi syndrome
• Contraindications
  • Children < 8 years
  • Pregnancy
  • Breastfeeding women
  • Renal failure (except doxycycline)
  • Hepatic failure (relative contraindication)

References:^[1][3]

• Drugs: tigecycline
• Mechanism of action
  • A glycylcycline that inhibits bacterial protein synthesis by blocking peptidyl transferase at the 30S subunit
  • Bacteriostatic
• CNS penetration: poor
• Route of elimination: mostly biliary
• Clinical use
  • Gram-positive aerobes
  • MRSA
  • Anaerobes
  • Partially effective against gram-negative aerobes
  • Atypical bacteria: Borrelia, Mycoplasma, Rickettsia, Chlamydia
• Adverse effects
  • GI upset
  • Hepatotoxicity
  • Deposition in bones and teeth
  • Damage to mucous membranes (these antibiotics should be taken with a lot of water)
  • Photosensitivity
• Contraindications
  • Pregnancy
  • Hepatic failure (relative contraindication)
  • Should be used with caution for children < 8 years and lactating women

References:^[4][5][6]

• Drugs
  • Oral or IV erythromycin
  • Oral or IV azithromycin
  • Oral clarithromycin
• Mechanism of action
  • Inhibits bacterial protein synthesis by blocking translocation; binds to the 23S ribosomal RNA molecule of the 50S subunit
  • Bacteriostatic
• CNS penetration: poor
• Route of elimination: biliary
• Clinical use
  • Atypical pneumonia
    • Mycoplasma pneumonia
    • Legionella pneumophila
    • Chlamydophila pneumoniae
  • Upper respiratory infections
  • STIs caused by Chlamydia (including chancroid)
  • Gram-positive cocci
  • Bordetella pertussis
  • Neisseria
  • Erythromycin: gastroparesis (e.g., resulting from diabetes mellitus)
  • Mycobacterium Azithromycin: treatment and prophylaxis of avium complex infection
• Adverse effects
  • Increased intestinal motility; → GI discomfort
  • QT-interval prolongation
  • Acute cholestatic hepatitis
  • Eosinophilia
  • Rash
  • CYP3A4 inhibition
• Contraindications
  • Pregnancy
  • Erythromycin is relatively contraindicated in hepatic failure.

References:^[1]

• Drugs: clindamycin
• Mechanism of action
  • Inhibits bacterial protein synthesis by binding the 50S subunit of the bacterial ribosome and inhibiting peptide translocation
  • Bacteriostatic
• CNS penetration: poor
• Route of elimination: both renal and biliary
• Clinical use
  • Anaerobes (e.g., Clostridium, Bacteroides)
    • Aspiration pneumonia
    • Lung abscesses
  • Partially effective against gram-positive aerobes (MRSA)
  • Babesiosis
• Adverse effects
  • GI upset
  • Pseudomembranous colitis
  • Fever
  • Cross-resistance with macrolides
• Contraindications
  • Pregnancy (relative contraindication)

Clindamycin is indicated for anaerobes above the diaphragm and metronidazole treats anaerobes below it!

• Drugs: linezolid
• Mechanism of action
  • Inhibition of bacterial protein synthesis by binding at the 50S subunit of the bacterial ribosome
  • Bacteriostatic
  • Additionally bactericidal only against streptococci
• CNS penetration: good
• Route of elimination: both biliary and renal elimination
• Clinical use: gram-positive resistant bacteria (VRE, MRSA)
• Adverse effects
  • Bone marrow suppression (especially thrombocytopenia)
  • Peripheral neuropathy
  • GI upset
  • Serotonin syndrome
• Contraindications
  • Concurrent use with monoamine oxidase inhibitors (MAOI) and selective serotonin reuptake inhibitors (SSRIs)

• Drugs: chloramphenicol
• Mechanism of action
  • Inhibits bacterial protein synthesis by blocking peptidyl transferase at the 50S subunit
  • Bacteriostatic
• CNS penetration: good
• Route of elimination: renal elimination
• Clinical use
  • Meningitis caused by H. influenzae, N. meningitidis, and/or S. pneumonia
  • Rickettsia (Rocky Mountain spotted fever)
• Adverse effects
  • Dose-dependent bone-marrow suppression: anemia, leukopenia, thrombocytopenia
  • Aplastic anemia
  • Gray baby syndrome (in infants ): cyanosis, vomiting, flaccidity, hypothermia, shock
• Contraindications
  • Infancy
  • Last trimester of pregnancy
  • Hepatic failure (relative contraindication)

References:^[1]

• Drugs
  • Oral: norfloxacin, moxifloxacin, gemifloxacin
  • Oral or IV ciprofloxacin, ofloxacin, levofloxacin
• Mechanism of action
  • Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV
  • Bactericidal
• CNS penetration: good
• Route of elimination
  • Primarily renal
  • Moxifloxacin undergoes biliary excretion
  • Absorption is reduced when coadministered with polyvalent cations (e.g. magnesium, calcium, or iron)
• Clinical use
  • • Gram-negative bacilli causing urinary and GI infections
    • Genital pathogens Neisseria gonorrhoeae, Chlamydia trachomatis, Ureaplasma urealyticum
    • Ciprofloxacin is effective against Pseudomonas
  • • Pneumonia
    • Certain forms of atypical pneumonia (e.g., Legionella, Mycoplasma, and Chlamydophila pneumoniae)
    • Also effective against anaerobes
    • Gemifloxacin is highly potent against penicillin-resistant pneumococci.
• Adverse effects
  • In children: potential damage to growing cartilage; reversible arthropathy
  • Muscle ache; , tendinitis; , tendon rupture (especially the Achilles tendon)
  • Hyperglycemia/hypoglycemia
  • Peripheral neuropathy
  • Can lower the seizure threshold
  • QT prolongation
  • Photosensitivity
  • GI upset
• Contraindications
  • < 18 years
  • Pregnancy
  • Breastfeeding women
  • Epilepsy, stroke, CNS lesions/inflammation
  • QT prolongation
  • Renal failure (relative contraindication)
  • Hepatic failure (relative contraindication)

• Mechanisms of resistance
  • Bacterial mutations can occur in genes that mediate:
    • DNA gyrase and topoisomerase IV enzymes
    • Cell wall permeability
    • Efflux pumps

References:^[7][8]

• Drugs
  • Oral or IV metronidazole
• Mechanism of action
  • Creates free radicals within the cell, which leads to DNA-strand breaks
  • Bactericidal
• CNS penetration: good
• Route of elimination: renal
• Clinical use
  • Certain protozoa (Entamoeba, Giardia histolytica, Trichomonas)
  • Anaerobes (e.g., Clostridium, Bacteroides)
  • Facultative anaerobes
    • Gardnerella vaginalis
    • Helicobacter pylori as part of a triple therapy regimen
  Adverse effects
  • Neurotoxicity (e.g., headache)
  • Disulfiram-like reaction when consumed with alcohol (flushing, tachycardia, hypotension)
    • Nitroimidazoles inhibit acetaldehyde dehydrogenase → accumulation of acetaldehyde → immediate hangover-like symptoms
  • Metallic taste
• Contraindications
  • Breastfeeding women
  • Hepatic failure (relative contraindication)

GET GAP on the Metro! (Giardia, Entamoeba, Trichomonas, Gardnerella, Anaerobes (Clostridium, Bacteroides), H. Pylori → Metronidazole)

Clindamycin is indicated for anaerobes above the diaphragm and metronidazole treats anaerobes below it!
References:^[1][9][10]

• Drugs
  • Oral or IV cotrimoxazole (TMP/SMX) = trimethoprim (TMP) + sulfamethoxazole (SMX)
  • Oral sulfisoxazole
  • Oral sulfadiazine + pyrimethamine
• Mechanism of action
  • Inhibition of bacterial folic acid synthesis
  • TMP inhibits dihydrofolate reductase (DHFR), a key enzyme in purine synthesis
    • DHFR reduces dihydrofolic acid to tetrahydrofolic acid (THF), using NADPH
    • THF can subsequently be converted to methylene-THF
    • Methylene-THF is an important cofactor for thymidylate synthetase, which catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP)
  • Both SMX and TMP are bacteriostatic, but become bactericidal when combined
• CNS penetration: good
• Route of elimination: primarily renal
• Clinical use
  • SMX
    • Gram-positive bacteria
    • Gram-negative bacteria
    • Simple urinary tract infections (UTIs)
    • Nocardia
    • Chlamydia
  • TMP/SMX
    • Shigella
    • Salmonella
    • Recurring UTIs
    • Prophylaxis and treatment of P. jirovecii
    • Prophylaxis of toxoplasmosis
• Adverse effects
  • SMX
    • Aplastic anemia and pancytopenia
    • Hyperkalemia
    • Rash
    • Gastrointestinal distress
    • Photosensitivity
    • Nephrotoxicity (especially tubulointerstitial nephritis)
    • Kernicterus in infancy
    • Triggers hemolytic anemia in G6PD-deficient patients
    • Displaces albumin-binding drugs (e.g., warfarin)
  • TMP: may be alleviated by leucovorin rescue
    • Megaloblastic anemia
    • Leukopenia/granulocytopenia
    • Hyperkalemia, particularly in HIV-positive patients
    • Artificially increased creatinine (despite unchanged GFR)
• Contraindications
  • Last trimester of pregnancy
  • Breastfeeding women

Trimethoprim (TMP) Treats Marrow Poorly.

References:^[1][11][12]

• Drugs: nitrofurantoin
• Mechanism of action
  • Nonspecific binding to bacterial ribosomal proteins → impaired metabolism, impaired protein, DNA, and RNA synthesis
  • Bactericidal
• Route of elimination: : mostly renal
• Clinical use: : treatment of and/or prophylaxis against lower urinary tract infections (e.g., urethritis, cystitis)
• Adverse effects
  • Gastrointestinal side effects
  • Reversible peripheral neuropathy
  • Pulmonary fibrosis
  • Triggers hemolytic anemia in G6PD-deficient patients
• Contraindications
  • Renal injury
  • Breastfeeding women

Compare drugs below with tuberculosis therapy for an overview

The four drugs used as first-line treatment are “RIPE”: Rifampin, Isoniazid, Pyrazinamide, and Ethambutol.