MICRO PHARM Flashcards
Ribavirin
Mechanism:
- Inhibits synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate dehydrogenase.
- It is a nucleoside analog that can act on both RNA and DNA viruses. Can act on both RNA and DNA viruses but is mechanism of action in DNA viruses remains unclear.
Clinical Use:
- Hepatitis C, RSV infection, and viral hemorrhagic fever (e.g., Lassa fever, Hantavirus infection).
- For hepatitis C, it is always used in combination with other medications such as simeprevir or PEG-interferon-α.
Adverse Effects:
Nausea, irritability, hemolytic anemia, and severe teratogenicity.
Carbapenems Clinical Use
IV imipenem (combined with cilastatin)
IV meropenem
IV ertapenem
IV doripenem
Imipenem is always given with cilastatin, which inhibits human dehydropeptidase I (a renal tubular enzyme that breaks down imipenem).
Meropenem is stable to dehydropeptidase I.
- Last-resort drugs (used only in life-threatening infections or after other antibiotics have failed) because of the significant adverse effects
- Broad-spectrum antibiotics with intrinsic beta-lactamase resistance
- Gram-positive cocci (except for MRSA and Enterococcus faecalis, which are intrinsically resistant)
- Gram-negative rods, including Pseudomonas aeruginosa (except ertapenem which has limited activity against Pseudomonas)
- Anaerobes
Azithromycin Mechanism
Macrolide IV or oral form Poor CNS penetration poor Route of elimination → biliary All macrolides (except azithromycin) have a short half-life.
Mechanism:
Bind to 23S ribosomal RNA molecule of the 50S subunit → blockage of translocation → inhibition of bacterial protein synthesis (bacteriostatic effect)
Tetracyclines
Oral or IV minocycline and tetracycline
Oral doxycycline and demeclocycline
CNS penetration → poor
Route of elimination: renal
Doxycycline → only gastrointestinal elimination (doxycycline is the only tetracycline that is not contraindicated in patients with renal failure)
Oral tetracyclines should not be taken with substances that contain large amounts of Ca2+, Mg2+, or Fe2+ (e.g., milk, antacids, iron supplements, respectively) because divalent cations inhibit the intestinal absorption of tetracyclines.
Mechanism:
Bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome acceptor site → inhibition of bacterial protein synthesis (bacteriostatic effect)
Clinical Use:
Bacteria that lack a cell wall (e.g, Mycoplasma pneumoniae, Ureaplasma)
Intracellular bacteria, such as Rickettsia, Chlamydia, or Anaplasma (tetracyclines accumulate intracellularly and are, therefore, effective against intracellular pathogens)
Borrelia burgdorferi
Ehrlichia, Vibrio cholerae, Francisella tularensis
Cutibacterium acnes (topical tetracycline is used to treat acne)
Community-acquired MRSA (doxycycline)
Adverse Effects:
Hepatotoxicity
Deposition in bones and teeth → inhibition of bone growth (in children) and discoloration of teeth
Damage to mucous membranes (e.g., esophagitis, GI upset)
Photosensitivity (drug or metabolite in the skin absorbs UV radiation → photochemical reaction → formation of free radicals → damage to cellular components → inflammation (sunburn-like))
Demeclocycline can cause nephrogenic diabetes insipidus
Degraded tetracyclines are associated with Fanconi syndrome.
Rarely: pseudotumor cerebri
Contraindications: Children < 8 years of age (except doxycycline) Pregnant women (except doxycycline) Patients with renal failure (except doxycycline) Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
Plasmid-encoded transport pumps increase efflux out of the bacterial cell and decrease uptake of tetracyclines.
Macrolides
Oral or IV → erythromycin, azithromycin, clarithromycin
CNS penetration → poor
Route of elimination → biliary
All macrolides (except azithromycin) have a short half-life.
Mechanism:
Bind to 23S ribosomal RNA molecule of the 50S subunit → blockage of translocation → inhibition of bacterial protein synthesis (bacteriostatic effect)
Clinical Use:
Atypical pneumonia caused by Mycoplasma pneumonia, Legionella pneumophila, Chlamydophila pneumoniae
Bordetella pertussis
STIs caused by Chlamydia
Gram-positive cocci (especially for the treatment of streptococcal infection in patients who are allergic to penicillin)
Neisseria spp.
Second-line prophylaxis for N. meningitidis
Dual therapy with ceftriaxone for N. gonorrhoeae (azithromycin)
Mycobacterium avium (prophylaxis: azithromycin; treatment: azithromycin, clarithromycin)
H. pylori (clarithromycin is the part of triple therapy)
Ureaplasma urealyticum
Babesia spp. (azithromycin in combination with atovaquone)
Erythromycin is used off-label for the treatment of gastroparesis because it increases GI motility.
Adverse Effects: Increased intestinal motility → GI upset QT-interval prolongation, arrhythmia Acute cholestatic hepatitis Eosinophilia Rash
Drug Interactions:
Erythromycin enhances the effect of oral anticoagulants (e.g., warfarin).
Erythromycin and clarithromycin increase theophylline serum concentrations due to CYP3A4 inhibition (cytochrome P450 inhibitors)
Contraindications:
Erythromycin estolate and clarithromycin are contraindicated in pregnant women (potentially hazardous to the fetus).
Azithromycin and clarithromycin are contraindicated in patients with hepatic failure (erythromycin should be used cautiously).
Cautious use of clarithromycin in patients with renal failure
Mechanisms of Resistance:
Methylation of the binding site of 23S rRNA prevents the macrolide from binding to rRNA.
Antipseudomonal penicillins
Piperacillin, ticarcillin, and carbenicillin.
Mechanism:
D-Ala-D-Ala structural analog.
Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Extended spectrum.
Penicillinase sensitive; use with β-lactamase inhibitors.
Clinical Use:
Pseudomonas spp. and gram ⊝ rods.
Adverse Reaction:
Hypersensitivity reactions.
Fidaxomicin
Macrocyclic antibiotic (related to macrolides)
Mechanism:
Inhibits the sigma subunit of RNA polymerase, leading to protein synthesis impairment and cell death (bactericidal activity against C difficile)
Clinical Use:
First-line therapy for initial episodes of C. difficile infection (WBC < 15,000)
Acyclovir
Mechanism:
Guanosine analogs.
Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells –> few adverse effects.
Triphosphate formed by cellular enzymes.
Preferentially inhibit viral DNA polymerase by chain termination.
Clinical Use:
HSV and VZV. Weak activity against EBV.
No activity against CMV.
Used for HSV- induced mucocutaneous and genital lesions as well as for encephalitis.
Prophylaxis in immunocompromised patients.
Only affects actively replicating viruses and has no effect on latent infections of HSV and VZV.
Valacyclovir, a prodrug of acyclovir, has better oral bioavailability.
For herpes zoster, use famciclovir.
Adverse Effects: Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated Thrombotic thrombocytopenic purpura Gastrointestinal symptoms (e.g., nausea) ↑ Transaminases
Mechanism of Resistance:
Mutated viral thymidine kinase.
Famciclovir
Mechanism:
Prodrug of penciclovir
Guanosine analog
Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells –> few adverse effects.
Triphosphate formed by cellular enzymes.
Preferentially inhibit viral DNA polymerase by chain termination.
Clinical Use:
HSV and VZV. Weak activity against EBV.
No activity against CMV.
Used for HSV- induced mucocutaneous and genital lesions as well as for encephalitis.
Prophylaxis in immunocompromised patients.
No effect on latent forms of HSV and VZV.
For herpes zoster, use famciclovir.
Adverse Effects: Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated. Thrombotic thrombocytopenic purpura Gastrointestinal symptoms (e.g., nausea) ↑ Transaminases
Mechanism of Resistance:
Mutated viral thymidine kinase.
Sofosbuvir
Mechanism:
NS5B inhibitor
Inhibition of NS5B (a RNA-dependent RNA polymerase) → chain termination and disruption of RNA synthesis → prevention of HCV replication
Clinical Use:
Used in combination with velpatasvir or ledipasvir for the treatment of chronic hepatitis C infection.
Adverse Effects: Fatigue, headache, nausea. Insomnia Pruritus Asthenia It is contraindicated in severe renal insufficiency.
Glycylcyclines
Tigecycline is only agent in this class
Mechanism:
Tetracycline derivative.
Binds to 30S, inhibiting protein synthesis.
Generally bacteriostatic.
Biliary elimination
Should not be taken with milk, antacids, or iron supplements because divalent cations inhibit the absorption of glycylcyclines in the intestines.
Clinical use:
Gram-positive aerobes (not effective against S. viridans or Enterococci; limited efficacy against MSSA)
Gram ⊝
MRSA
VRE
Anaerobes (broad spectrum)
Partially effective against gram-negative aerobes (no effect against Proteus species)
Gram-intermediate bacteria: Borrelia, Mycoplasma, Rickettsia, Chlamydia
Infections requiring deep tissue penetration.
Adverse Effects: GI upset (nausea, vomiting) Hepatotoxicity Deposition in bones and teeth Photosensitivity
Tigecycline
Glycylcycline class
Mechanism:
Tetracycline derivative.
Binds to 30S, inhibiting protein synthesis.
Generally bacteriostatic.
Biliary elimination
Should not be taken with milk, antacids, or iron supplements because divalent cations inhibit the absorption of glycylcyclines in the intestines.
Clinical use:
Gram-positive aerobes (not effective against S. viridans or Enterococci; limited efficacy against MSSA)
Gram ⊝
MRSA
VRE
Anaerobes (broad spectrum)
Partially effective against gram-negative aerobes (no effect against Proteus species)
Gram-intermediate bacteria: Borrelia, Mycoplasma, Rickettsia, Chlamydia
Infections requiring deep tissue penetration.
Adverse Effects: GI upset (nausea, vomiting) Hepatotoxicity Deposition in bones and teeth Photosensitivity
Albendazole
Mechanism:
Inhibit microtubule polymerization resulting in decreased glucose uptake and glycogen synthesis, degeneration of mitochondria and endoplasmic reticulum and lysosomal release
Clinical Use: Ascariasis Enterobiasis Trichuriasis Strongyloidiasis Hookworm infection Cysticercosis Trichinellosis Toxocariasis
Adverse Effects: Headache GI upset (especially in short term use) Increased liver enzymes Rash, urticaria Hair loss Agranulocytosis
Penicillin G
IV (crystalline) and IM (benzathine) form
Prototype β-lactam antibiotics.
Probenecid blocks the rebel tubular excretion (sometimes used to increase their serum levels or prolong their half life)
Often coadministered with aminoglycosides to aid their entry into the cell
Mechanism:
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases).
Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Clinical Use:
Mostly used for gram ⊕ organisms (S pneumoniae, S pyogenes, Actinomyces, C. perfringens, S. agalactiae). Also used for gram ⊝ cocci (mainly N meningitidis) and spirochetes (mainly T pallidum).
Pasteurella
Rheumatic fever prophylaxis
Bactericidal for gram ⊕ cocci, gram ⊕ rods, gram ⊝ cocci, and spirochetes.
β-lactamase sensitive.
Adverse Effects:
Hypersensitivity reactions, direct Coombs ⊕ hemolytic anemia (binds to bacterial breakdown products that form haptens thus forming anti-IgG), drug-induced interstitial nephritis, cutaneous small vasculitis
Resistance:
β-lactamase cleaves the β-lactam ring.
Mutations in penicillin-binding proteins.
Penicillin V
Oral form
Prototype β-lactam antibiotics.
Probenecid blocks the rebel tubular excretion (sometimes used to increase their serum levels or prolong their half life)
Often coadministered with aminoglycosides to aid their entry into the cell
Mechanism:
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases).
Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Clinical Use:
Mostly used for gram ⊕ organisms (S pneumoniae, S pyogenes, Actinomyces, C. perfringens, S. agalactiae). Also used for gram ⊝ cocci (mainly N meningitidis) and spirochetes (mainly T pallidum).
Pasteurella
Rheumatic fever prophylaxis
Bactericidal for gram ⊕ cocci, gram ⊕ rods, gram ⊝ cocci, and spirochetes.
β-lactamase sensitive.
Adverse Effects:
Hypersensitivity reactions, direct Coombs ⊕ hemolytic anemia (binds to bacterial breakdown products that form haptens thus forming anti-IgG), drug-induced interstitial nephritis, cutaneous small vasculitis
Resistance:
β-lactamase cleaves the β-lactam ring.
Mutations in penicillin-binding proteins.
Amoxicillin
Oral or IV
Combined with clavulanate
The molecular structure is similar to penicillin and therefore susceptible to degradation by β-lactamase (β-lactamase sensitive).
Oral bioavailability of amoxicillin is greater than that of ampicillin
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases).
Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Clinical use:
Broader spectrum of activity than penicillin (extended-spectrum penicillin)
Gram-positive aerobes
Gram-negative rods (not effective against Enterobacter spp.)
Prophylaxis against encapsulated bacteria in asplenic patients and before dental procedures in patients with high risk for endocarditis
Otitis media and sinusitis caused by S. pneumonia, Moraxella and H influenzae
Most effective against:
H. pylori, H. influenzae, Enterococci, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, Spirochetes (Lyme disease in pregnant and children)
Adverse effects: Diarrhea Pseudomembranous colitis Hypersensitivity reactions Drug-induced rash (in patients with mononucleosis) Possibly acute interstitial nephritis
Mechanisms of resistance:
Cleavage of the β-lactam ring by penicillinases
Ampicillin
IV or IM form
With or without sulbactam
The molecular structure is similar to penicillin and therefore susceptible to degradation by β-lactamase (β-lactamase sensitive).
Oral bioavailability of ampicillin is lesser than that of amoxicillin
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases).
Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Clinical use:
Broader spectrum of activity than penicillin (extended-spectrum penicillin)
Gram-positive aerobes
Gram-negative rods (not effective against Enterobacter spp.)
IV is good for aspiration pneumonia
Otitis media and sinusitis caused by S. pneumonia, Moraxella and H influenzae
Most effective against:
H. pylori, H. influenzae, Enterococci, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, Spirochetes (Lyme disease in pregnant and children)
Adverse effects: Diarrhea Pseudomembranous colitis Hypersensitivity reactions Drug-induced rash (in patients with mononucleosis) Possibly acute interstitial nephritis
Mechanisms of resistance:
Cleavage of the β-lactam ring by penicillinases
Dicloxacillin
Mechanism:
Same as penicillin.
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Penicillinase resistant because bulky R group (e.g., isoxazolyl), which prevent bacterial β-lactamase from hydrolyzing the β-lactam ring
Clinical Use:
Narrow spectrum
Gram-positive aerobes, especially S. aureus (non-MRSA)
Penicillinase-resistant penicillins are not effective against Streptococcus viridans, Enterococci, or Listeria.
IV for systemic S aureus endocarditis and osteomelitis
Adverse Effect:
Interstitial nephritis (esp. associated with methicillin use)
Hypersensitivity reactions
Mechanism of Resistance:
Alteration of PBP binding site → reduced affinity → pathogen is not bound or inactivated by β-lactam (an altered PBP target site is one of the main virulence factors of MRSA)
Nafcillin
Mechanism:
Same as penicillin.
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Penicillinase resistant because bulky R group (e.g., isoxazolyl), which prevent bacterial β-lactamase from hydrolyzing the β-lactam ring
Clinical Use:
Narrow spectrum
Gram-positive aerobes, especially S. aureus (non-MRSA)
Penicillinase-resistant penicillins are not effective against Streptococcus viridans, Enterococci, or Listeria.
IV for systemic S aureus endocarditis and osteomelitis
Adverse Effect:
Interstitial nephritis (esp. associated with methicillin use)
Hypersensitivity reactions
Mechanism of Resistance:
Alteration of PBP binding site → reduced affinity → pathogen is not bound or inactivated by β-lactam (an altered PBP target site is one of the main virulence factors of MRSA)
Oxacillin
Mechanism:
Same as penicillin.
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Penicillinase resistant because bulky R group (e.g., isoxazolyl), which prevent bacterial β-lactamase from hydrolyzing the β-lactam ring
Clinical Use:
Narrow spectrum
Gram-positive aerobes, especially S. aureus (non-MRSA)
Penicillinase-resistant penicillins are not effective against Streptococcus viridans, Enterococci, or Listeria.
IV for systemic S aureus endocarditis and osteomelitis
Adverse Effect:
Interstitial nephritis (esp. associated with methicillin use)
Hypersensitivity reactions
Mechanism of Resistance:
Alteration of PBP binding site → reduced affinity → pathogen is not bound or inactivated by β-lactam (an altered PBP target site is one of the main virulence factors of MRSA)
Floxacillin
Mechanism:
Same as penicillin.
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Penicillinase resistant because bulky R group (e.g., isoxazolyl), which prevent bacterial β-lactamase from hydrolyzing the β-lactam ring
Clinical Use:
Narrow spectrum
Gram-positive aerobes, especially S. aureus (non-MRSA)
Penicillinase-resistant penicillins are not effective against Streptococcus viridans, Enterococci, or Listeria.
IV for systemic S aureus endocarditis and osteomelitis
Adverse Effect:
Interstitial nephritis (esp. associated with methicillin use)
Hypersensitivity reactions
Mechanism of Resistance:
Alteration of PBP binding site → reduced affinity → pathogen is not bound or inactivated by β-lactam (an altered PBP target site is one of the main virulence factors of MRSA)
Methicillin
NO LONGER USED DUE TO HIGH ADVERSE EFFECTS
Mechanism:
Same as penicillin.
D-Ala-D-Ala structural analog. Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Penicillinase resistant because bulky R group (e.g., isoxazolyl), which prevent bacterial β-lactamase from hydrolyzing the β-lactam ring
Clinical Use:
Narrow spectrum
Gram-positive aerobes, especially S. aureus (non-MRSA)
Penicillinase-resistant penicillins are not effective against Streptococcus viridans, Enterococci, or Listeria.
IV for systemic S aureus endocarditis and osteomelitis
Adverse Effect:
Interstitial nephritis (esp. associated with methicillin use)
Hypersensitivity reactions
Mechanism of Resistance:
Alteration of PBP binding site → reduced affinity → pathogen is not bound or inactivated by β-lactam (an altered PBP target site is one of the main virulence factors of MRSA)
Mention Aminopenicillins (Penicillinase-Sensitive Penicillins)
Oral or IV: amoxicillin (combined with clavulanate )
IV or IM: ampicillin (with or without sulbactam)
Mention Antipseudomonal Penicillins
IV piperacillin (combined with tazobactam)
IV mezlocillin
IV ticarcillin
IV carbenicillin
Mention Penicillinase-Resistant Penicillins
Nafcillin Dicloxacillin Oxacillin Floxacillin Methicillin
Piperacillin
Antipseudomonal penicillins
IV form
Combined with tazobactam
Mechanism:
D-Ala-D-Ala structural analog.
Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Extended spectrum.
Penicillinase sensitive; use with β-lactamase inhibitors.
Clinical Use:
Pseudomonas spp. and gram ⊝ rods.
Also effective against anaerobes (e.g., Bacteroides fragilis)
Gram-positive aerobes (not effective against S. viridans)
Adverse Reaction:
Hypersensitivity reactions.
Mezlocillin
Antipseudomonal penicillins
IV form
Mechanism:
D-Ala-D-Ala structural analog.
Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Extended spectrum.
Penicillinase sensitive; use with β-lactamase inhibitors.
Clinical Use:
Pseudomonas spp. and gram ⊝ rods.
Also effective against anaerobes (e.g., Bacteroides fragilis)
Gram-positive aerobes (not effective against S. viridans)
Adverse Reaction:
Hypersensitivity reactions.
Ticarcillin
Antipseudomonal penicillins
IV form
Mechanism:
D-Ala-D-Ala structural analog.
Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Extended spectrum.
Penicillinase sensitive; use with β-lactamase inhibitors.
Clinical Use:
Pseudomonas spp. and gram ⊝ rods.
Also effective against anaerobes (e.g., Bacteroides fragilis)
Gram-positive aerobes (not effective against S. viridans)
Adverse Reaction:
Hypersensitivity reactions.
Carbenicillin
Antipseudomonal penicillins
IV form
Mechanism:
D-Ala-D-Ala structural analog.
Bind penicillin-binding proteins (transpeptidases). Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
Extended spectrum.
Penicillinase sensitive; use with β-lactamase inhibitors.
Clinical Use:
Pseudomonas spp. and gram ⊝ rods.
Also effective against anaerobes (e.g., Bacteroides fragilis)
Gram-positive aerobes (not effective against S. viridans)
Adverse Reaction:
Hypersensitivity reactions.
Mention Streptogramins
Quinupristin
Dalfopristin
Quinupristin
Streptogramin
Synergistic effect with Dalfopristin
Route of elimination → biliary and renal
Mechanism:
Inhibits the late phase of protein synthesis
Binds to 50S subunit → elongation of polypeptide is prevented → release of incomplete chains
Bacteriostatic when used separately, but bactericidal when used in combination with Dalfopristin
Clinical use: Skin and skin structure infection with: -S. aureus (methicillin-susceptible and resistant) -S. pyogenes -Vancomycin-resistant E. faecium (VRE) -Not effective against E. faecalis
Adverse effects: Inhibits CYP3A4 Nausea, vomiting Diarrhea Headache Arthralgia, myalgia Thrombophlebitis Rash, pruritus Pseudomembranous colitis
Mechanisms of resistance:
Modification of bacterial ribosome binding site
Enzyme-mediated methylation (cross resistance with clindamycin and macrolides)
Efflux pumps
Dalfopristin
Streptogramin
Synergistic effect with Quinupristin
Route of elimination → biliary and renal
Mechanism:
Inhibits the early phase of protein synthesis
Binds to 23S portion of 50S subunit → change of conformation → enhanced binding of quinupristin
Inhibits peptidyl transferase
Bacteriostatic when used separately, but bactericidal when used in combination with Quinupristin
Clinical use: Skin and skin structure infection with: -S. aureus (methicillin-susceptible and resistant) -S. pyogenes -Vancomycin-resistant E. faecium (VRE) -Not effective against E. faecalis
Adverse effects: Inhibits CYP3A4 Nausea, vomiting Diarrhea Headache Arthralgia, myalgia Thrombophlebitis Rash, pruritus Pseudomembranous colitis
Mechanisms of resistance:
Modification of bacterial ribosome binding site
Enzyme-mediated methylation (crossresistance with clindamycin and macrolides)
Efflux pumps
Mention 1st generation cephalosporins
Oral → cephalexin
IV, IM → cefazolin
Mention 2nd generation cephalosporins
Cefaclor Cefuroxime Cefoxitin Cefotetan Cefprozil
Mention 3rd generation cephalosporins
Cefixime Cefpodoxime Cefotaxime Ceftazidime Ceftriaxone Cefdinir Cefoperazone
Mention 4th generation cephalosporins
IV → cefepime
Mention 5th generation cephalosporins
IV → ceftaroline
Cephalexin
1st generation cephalosporin
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae.
1st generation—PEcK.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefazolin
1st generation cephalosporin
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae.
Perioperative wound infection prophylaxis (covers S. aureus)
1st generation—PEcK.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefaclor
2nd generation cephalosporin
Oral form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae, H. influenzae
Klebsiella aerogenes (previously known as Enterobacter aerogenes), Neisseria, Serratia marcescens
2nd generation—HENS PEcK.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefuroxime
2nd generation cephalosporin
Oral form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae, H. influenzae
Klebsiella aerogenes (previously known as Enterobacter aerogenes), Neisseria, Serratia marcescens
2nd generation—HENS PEcK.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefoxitin
2nd generation cephalosporin
IV form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae, H. influenzae
Klebsiella aerogenes (previously known as Enterobacter aerogenes), Neisseria, Serratia marcescens
2nd generation—HENS PEcK.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefotetan
2nd generation cephalosporin
IV form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae, H. influenzae
Klebsiella aerogenes (previously known as Enterobacter aerogenes), Neisseria, Serratia marcescens
2nd generation—HENS PEcK.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefprozil
2nd generation cephalosporin
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊕ cocci, Proteus mirabilis, E coli, Klebsiella pneumoniae, H. influenzae
Klebsiella aerogenes (previously known as Enterobacter aerogenes), Neisseria, Serratia marcescens
2nd generation—HENS PEcK.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefixime
3rd generation cephalosporin
Oral form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Least active among all cephalosporins against Gram ⊕ cocci
Serious gram ⊝ infections resistant to other β-lactams.
Perioperative wound infection prophylaxis (covers S. aureus)
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefpodoxime
3rd generation cephalosporin
Oral form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Least active among all cephalosporins against Gram ⊕ cocci
Serious gram ⊝ infections resistant to other β-lactams.
Perioperative wound infection prophylaxis (covers S. aureus)
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefotaxime
3rd generation cephalosporin
IV form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Least active among all cephalosporins against Gram ⊕ cocci
Serious gram ⊝ infections resistant to other β-lactams.
Perioperative wound infection prophylaxis (covers S. aureus)
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Ceftazidime
3rd generation cephalosporin
IV form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Least active among all cephalosporins against Gram ⊕ cocci
Serious gram ⊝ infections resistant to other β-lactams.
Perioperative wound infection prophylaxis (covers S. aureus)
Pseudomonas
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Ceftriaxone
3rd generation cephalosporin
IM and IV form
Excreted in bile
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Serious gram ⊝ infections resistant to other β-lactams.
Can cross blood-brain barrier.
Perioperative wound infection prophylaxis (covers S. aureus)
Ceftriaxone—meningitis, gonorrhea, disseminated Lyme disease.
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefdinir
3rd generation cephalosporin
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Least active among all cephalosporins against Gram ⊕ cocci
Serious gram ⊝ infections resistant to other β-lactams.
Perioperative wound infection prophylaxis (covers S. aureus)
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefoperazone
3rd generation cephalosporin
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Least active among all cephalosporins against Gram ⊕ cocci
Serious gram ⊝ infections resistant to other β-lactams.
Pseudomonas
Organisms typically not covered by 1st–4th generation cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Cefepime
4th generation cephalosporin
IV form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Gram ⊝ organisms, with increase activity against Pseudomonas and gram ⊕ organisms.
Penetrate CNS (so can be used in meningitis)
Broad spectrum
Used for severe life-threatening infections (including nosocomial)
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
Ceftaroline
5th generation cephalosporin
IV form
Mechanism:
β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal.
Clinical Use:
Broad gram ⊕ and gram ⊝ organism coverage
Unlike 1st–4th generation cephalosporins, ceftaroline covers Listeria, MRSA, and Enterococcus faecalis— does not cover Pseudomonas and atypicals (Chlamydia, Mycoplasma, Legionella)
Adverse Effects:
Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency which increase the risk of bleeding. Low rate of cross- reactivity even in penicillin-allergic patients.
Increase nephrotoxicity of aminoglycosides.
Neurotoxicity (can lower seizure threshold)
Mechanism of resistance:
Inactivated by cephalosporinases (a type of β-lactamase).
Structural change in penicillin-binding proteins (transpeptidases).
β-lactamase Inhibitors
Clavulanate (combined with amoxicillin)
Avibactam (combined with ceftazidime)
Sulbactam (combined with ampicillin)
Tazobactam (combined with piperacillin)
Prevent the destruction of β-lactam antibiotics by β-lactamases and increase the spectrum of the antibiotic activity.
Can be coadministered with β-lactamase-sensitive penicillins in order to treat β-lactamase-producing organisms
Aztreonam
Monobactam
IV form
Less susceptible to β-lactamases.
Prevents peptidoglycan cross-linking by binding to penicillin- binding protein 3.
Synergistic with aminoglycosides.
No cross-allergenicity with penicillins.
Clinical Use:
Effective against Gram ⊝ rods only, including nosocomial Pseudomonas, H. influenzae, and N. meningitidis
No activity against gram ⊕ rods or anaerobes
Alternative for penicillin-allergic patients (no cross-sensitivity with penicillins) and those with renal insufficiency who cannot tolerate aminoglycosides
Broad-spectrum coverage in combination with vancomycin or clindamycin
Adverse Effects:
Usually nontoxic; occasional GI upset.
Injection reactions
Rash
Vancomycin
Glycopeptide
Oral or IV form
Mechanism:
Bind terminal D-ala-D-ala of cell-wall precursor peptides → inhibition of cell wall synthesis (peptidoglycan formation) → bacterial death (bactericidal effect against most gram-positive bacteria)
Bacteriostatic against C. difficile
CNS penetration → only when there is increased permeability of the meningeal vessels (i.e., with meningeal inflammation)
Route of elimination → renal (via glomerular filtration)
Clinical Use:
Especially effective against multidrug-resistant organisms
Effective against a wide range of gram-positive bacteria only
MRSA
S. epidermidis
Enterococci (if not vancomycin resistant enterococci)
C. difficile (causing pseudomembranous colitis) → administered orally
Penetrate bone so its useful treatment for MRSA osteomyelitis
First line empiric treatment of endocarditis.
Adverse Effects:
Intravenous administration
Nephrotoxicity
Ototoxicity/vestibular toxicity
Thrombophlebitis
Red man syndrome (anaphylactoid reaction caused by rapid infusion of vancomycin; nonspecific mast cell degranulation → rapid release of histamine. Diffuse flushing of the skin, pruritus mainly of the upper body, muscle spasms and pain in the back and chest, possible hypotension and dyspnea. Can be prevented by slowing the rate of infusion and pretreating with antihistamines)
DRESS syndrome (drug reaction (anticonvulsant [hallopurinol] and sulfonamide) leading to eosinophilia and systemic symptoms)
Neutropenia
Dysgeusia and gastrointestinal side effects (e.g., nausea, vomiting, abdominal pain)
Oral administration → predominantly dysgeusia and gastrointestinal side effects
Mechanisms of Resistance:
Modification of amino acid D-Ala-D-Ala to D-Ala-D-Lac → occurs mainly in Enterococcus (e.g., E. faecium, less in E. faecalis)
Beta-lactamase resistant
Ricin
Castor oil toxin
Inhibits eukaryotic 60 subunit
Aminoglycosides
IV or IM gentamicin, amikacin, tobramycin, streptomycin
Oral neomycin, paromomycin
Poor CNS penetration
Route of elimination → renal (via glomerular filtration)
Mechanism:
Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Misreading of mRNA
Blockage of translocation
Synergistic effect when combined with β-lactam antibiotics (β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm)
Clinical Use:
Severe gram-negative rod infections
Not effective against anaerobes (aminoglycosides require oxygen to be absorbed by cells)
Neomycin, which is not absorbed systemically, is administered orally to prepare the gut for bowel surgery.
Streptomycin is used as a second-line treatment for Mycobacterium tuberculosis and M. avium-intracellulare
Paromomycin is not significantly absorbed from the gastrointestinal tract, it is used as a luminal antibiotic in the treatment of hepatic encephalopathy and as a luminal amebicide (by eradicating intestinal cysts). First line treatment for amebiasis or giardiasis during pregnancy.
Gentamycin is the first line treatment of acute pyelonephritis in case of fluoroquinolone allergy or resistance
Adverse Effects:
Nephrotoxicity (proximal tubular injury and acute tubular necrosis visualized histologically as focal tubular epithelial necrosis, often with extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane)
Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in tinnitus, ataxia, vertigo
Neuromuscular blockade (risk increases in the event of hypomagnesemia or myasthenia gravis, and in patients who use calcium channel blockers)
Teratogenicity
Contraindications: Myasthenia gravis Botulism Pregnancy Cautious use in patients with renal dysfunction
Mechanisms of resistance:
Inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes
Paromomycin
Aminoglycoside
Oral form
Poor CNS penetration
Route of elimination → renal (via glomerular filtration)
Mechanism:
Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Misreading of mRNA
Blockage of translocation
Synergistic effect when combined with β-lactam antibiotics (β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm)
Clinical Use:
Because it is not significantly absorbed from the gastrointestinal tract, it is used as a luminal antibiotic in the treatment of hepatic encephalopathy and as a luminal amebicide (by eradicating intestinal cysts).
First line treatment for amebiasis or giardiasis during pregnancy.
Adverse Effects:
Nephrotoxicity (proximal tubular injury and acute tubular necrosis visualized histologically as focal tubular epithelial necrosis, often with extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane)
Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in tinnitus, ataxia, vertigo
Neuromuscular blockade (risk increases in the event of hypomagnesemia or myasthenia gravis, and in patients who use calcium channel blockers)
Teratogenicity
Contraindications: Myasthenia gravis Botulism Pregnancy Cautious use in patients with renal dysfunction
Mechanisms of resistance:
Inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes
Gentamicin
Aminoglycoside
IV or IM form
Poor CNS penetration
Route of elimination → renal (via glomerular filtration)
Mechanism:
Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Misreading of mRNA
Blockage of translocation
Synergistic effect when combined with β-lactam antibiotics (β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm)
Clinical Use:
Severe gram-negative rod infections
Not effective against anaerobes (aminoglycosides require oxygen to be absorbed by cells)
Gentamycin is the first line treatment of acute pyelonephritis in case of fluoroquinolone allergy or resistance
Adverse Effects:
Nephrotoxicity (proximal tubular injury and acute tubular necrosis visualized histologically as focal tubular epithelial necrosis, often with extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane)
Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in tinnitus, ataxia, vertigo
Neuromuscular blockade (risk increases in the event of hypomagnesemia or myasthenia gravis, and in patients who use calcium channel blockers)
Teratogenicity
Contraindications: Myasthenia gravis Botulism Pregnancy Cautious use in patients with renal dysfunction
Mechanisms of resistance:
Inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes
Amikacin
Aminoglycoside
IV or IM form
Poor CNS penetration
Route of elimination → renal (via glomerular filtration)
Mechanism:
Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Misreading of mRNA
Blockage of translocation
Synergistic effect when combined with β-lactam antibiotics (β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm)
Clinical Use:
Severe gram-negative rod infections
Not effective against anaerobes (aminoglycosides require oxygen to be absorbed by cells)
Adverse Effects:
Nephrotoxicity (proximal tubular injury and acute tubular necrosis visualized histologically as focal tubular epithelial necrosis, often with extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane)
Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in tinnitus, ataxia, vertigo
Neuromuscular blockade (risk increases in the event of hypomagnesemia or myasthenia gravis, and in patients who use calcium channel blockers)
Teratogenicity
Contraindications: Myasthenia gravis Botulism Pregnancy Cautious use in patients with renal dysfunction
Mechanisms of resistance:
Inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes
Tobramycin
Aminoglycoside
IV or IM form
Poor CNS penetration
Route of elimination → renal (via glomerular filtration)
Mechanism:
Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Misreading of mRNA
Blockage of translocation
Synergistic effect when combined with β-lactam antibiotics (β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm)
Clinical Use:
Severe gram-negative rod infections
Not effective against anaerobes (aminoglycosides require oxygen to be absorbed by cells)
Adverse Effects:
Nephrotoxicity (proximal tubular injury and acute tubular necrosis visualized histologically as focal tubular epithelial necrosis, often with extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane)
Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in tinnitus, ataxia, vertigo
Neuromuscular blockade (risk increases in the event of hypomagnesemia or myasthenia gravis, and in patients who use calcium channel blockers)
Teratogenicity
Contraindications: Myasthenia gravis Botulism Pregnancy Cautious use in patients with renal dysfunction
Mechanisms of resistance:
Inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes
Streptomycin
Aminoglycoside
IV or IM form
Poor CNS penetration
Route of elimination → renal (via glomerular filtration)
Mechanism:
Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Misreading of mRNA
Blockage of translocation
Synergistic effect when combined with β-lactam antibiotics (β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm)
Clinical Use:
Severe gram-negative rod infections
Not effective against anaerobes (aminoglycosides require oxygen to be absorbed by cells)
Streptomycin is used as a second-line treatment for Mycobacterium tuberculosis and M. avium-intracellulare
Adverse Effects:
Nephrotoxicity (proximal tubular injury and acute tubular necrosis visualized histologically as focal tubular epithelial necrosis, often with extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane)
Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in tinnitus, ataxia, vertigo
Neuromuscular blockade (risk increases in the event of hypomagnesemia or myasthenia gravis, and in patients who use calcium channel blockers)
Teratogenicity
Contraindications: Myasthenia gravis Botulism Pregnancy Cautious use in patients with renal dysfunction
Mechanisms of resistance:
Inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes
Neomycin
Aminoglycoside
Oral form
Poor CNS penetration
Route of elimination → renal (via glomerular filtration)
Mechanism:
Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Misreading of mRNA
Blockage of translocation
Synergistic effect when combined with β-lactam antibiotics (β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm)
Clinical Use:
Severe gram-negative rod infections
Not effective against anaerobes (aminoglycosides require oxygen to be absorbed by cells)
Neomycin, which is not absorbed systemically, is administered orally to prepare the gut for bowel surgery.
Adverse Effects:
Nephrotoxicity (proximal tubular injury and acute tubular necrosis visualized histologically as focal tubular epithelial necrosis, often with extensive granular casts that obstruct the tubular lumen and lead to rupture of the basement membrane)
Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in tinnitus, ataxia, vertigo
Neuromuscular blockade (risk increases in the event of hypomagnesemia or myasthenia gravis, and in patients who use calcium channel blockers)
Teratogenicity
Contraindications: Myasthenia gravis Botulism Pregnancy Cautious use in patients with renal dysfunction
Mechanisms of resistance:
Inactivation via acetylation, phosphorylation, and/or adenylation by secreted bacterial transferase enzymes
Minocycline
Tetracycline IV and oral form CNS penetration → poor Route of elimination → renal Oral tetracyclines should not be taken with substances that contain large amounts of Ca2+, Mg2+, or Fe2+ (e.g., milk, antacids, iron supplements, respectively) because divalent cations inhibit the intestinal absorption of tetracyclines.
Mechanism:
Bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome acceptor site → inhibition of bacterial protein synthesis (bacteriostatic effect)
Clinical Use:
Bacteria that lack a cell wall (e.g, Mycoplasma pneumoniae, Ureaplasma)
Intracellular bacteria, such as Rickettsia, Chlamydia, or Anaplasma (tetracyclines accumulate intracellularly and are, therefore, effective against intracellular pathogens)
Borrelia burgdorferi
Ehrlichia, Vibrio cholerae, Francisella tularensis
Adverse Effects:
Hepatotoxicity
Deposition in bones and teeth → inhibition of bone growth (in children) and discoloration of teeth
Damage to mucous membranes (e.g., esophagitis, GI upset)
DRESS syndrome
Photosensitivity: drug or metabolite in the skin absorbs UV radiation → photochemical reaction → formation of free radicals → damage to cellular components → inflammation (sunburn-like)
Degraded tetracyclines are associated with Fanconi syndrome.
Pseudotumor cerebri (rarely)
Contraindications: Children < 8 years of age (except doxycycline) Pregnant women (except doxycycline) Patients with renal failure (except doxycycline) Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
Plasmid-encoded transport pumps increase efflux out of the bacterial cell and decrease uptake of tetracyclines.
Doxycycline
Tetracycline
Oral form
CNS penetration: poor
Gastrointestinal elimination (only tetracycline that is not contraindicated in patients with renal failure)
Oral tetracyclines should not be taken with substances that contain large amounts of Ca2+, Mg2+, or Fe2+ (e.g., milk, antacids, iron supplements, respectively) because divalent cations inhibit the intestinal absorption of tetracyclines.
Mechanism:
Bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome acceptor site → inhibition of bacterial protein synthesis (bacteriostatic effect)
Clinical Use:
Bacteria that lack a cell wall (e.g, Mycoplasma pneumoniae, Ureaplasma)
Intracellular bacteria, such as Rickettsia, Chlamydia, or Anaplasma (tetracyclines accumulate intracellularly and are, therefore, effective against intracellular pathogens)
Borrelia burgdorferi
Ehrlichia, Vibrio cholerae, Francisella tularensis
Community-acquired MRSA (doxycycline)
Adverse Effects:
Hepatotoxicity
Deposition in bones and teeth → inhibition of bone growth (in children) and discoloration of teeth
Damage to mucous membranes (e.g., esophagitis, GI upset)
Photosensitivity: drug or metabolite in the skin absorbs UV radiation → photochemical reaction → formation of free radicals → damage to cellular components → inflammation (sunburn-like)
Degraded tetracyclines are associated with Fanconi syndrome.
Pseudotumor cerebri (rarely)
Contraindications: Children < 8 years of age (except doxycycline) Pregnant women (except doxycycline) Patients with renal failure (except doxycycline) Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
Plasmid-encoded transport pumps increase efflux out of the bacterial cell and decrease uptake of tetracyclines.
Chloramphenicol
Mechanism:
Bind 50S subunit → blockage of peptidyltransferase → inhibition of bacterial protein synthesis (bacteriostatic effect)
CNS penetration → good
Route of elimination → renal elimination after hepatic metabolism
Clinical Use:
Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae) and rickettsial diseases (eg, Rocky Mountain spotted fever [Rickettsia rickettsii]).
Limited use due to toxicity but often still used in developing countries because of low cost.
Adverse Effects:
Anemia (dose dependent), aplastic anemia (dose independent; due to bone marrow suppression), gray baby syndrome (in premature infants because they lack liver UDP-glucuronosyltransferase; hyponatremia, cyanosis, vomiting, flaccidity, hypothermia, and shock).
Potent inhibitory effect on cytochrome P450 isoforms CYP2C19 and CYP3A4
Contraindications:
Infancy
Pregnancy
Cautious use in patients with renal and/or hepatic dysfunction
Mechanism of resistance:
Plasmid-encoded acetyltransferase inactivates the drug.
Clindamycin
Mechanism:
Binds to 50S subunit → blockage of peptide translocation (transpeptidation) → inhibition of peptide chain elongation → inhibition of bacterial protein synthesis (bacteriostatic effect)
CNS penetration → poor
Route of elimination → both renal and biliary
Actively transported in macrophages so can have penetration in abscesses
Clinical Use:
Anaerobic infections (eg, Bacteroides spp., Clostridium perfringens) in aspiration pneumonia, lung abscesses, and oral infections.
Also effective against invasive group A streptococcal infection (especially invasive infections)
Partially effective against gram-positive aerobes
Can be used in MRSA infections
Babesia (together with quinine)
Gardnerella vaginalis
Acne
Not effective against Enterococci
Treats anaerobic infections above the diaphragm vs metronidazole (anaerobic infections below diaphragm).
Adverse Effects:
Pseudomembranous colitis (C difficile overgrowth), fever, diarrhea, teratogenicity
Associated with esophagitis due to low pH and irritant effects on the distal esophagus
Contraindications:
In pregnant women during the 1st trimester and breastfeeding women, clindamycin should be used only if benefits outweigh the risks.
Cross-resistance with macrolides
Fosfomycin
Oral and IV form
Mechanism:
Inhibits enolpyruvate transferase (MurA) → no formation of N-acetylmuramic acid (a component of bacterial cell wall) → inhibition of cell wall synthesis → cell death (bactericidal effect)
Route of elimination → renal
Clinical use:
Women with uncomplicated urinary tract infections (e.g., cystitis due to E. coli or E. faecalis)
Adverse Effects:
Mild electrolyte imbalances (e.g., hypernatremia, hypokalemia)
Diarrhea
Contraindications:
Hypersensitivity
Mechanisms of resistance:
MurA mutations
Linezolid
Oxazolidinone
Oral form
Mechanism:
Binds to 23S subunit of 50S bacterial ribosome → inhibition of initiation complex formation → inhibition of bacterial protein synthesis (bacteriostatic effect)
Unlike other antibiotics that inhibit later stages of bacterial protein synthesis (e.g., elongation), linezolid inhibits protein synthesis at the very first step of translation.
Nonselective monoamine oxidase inhibition (MAOI)
Bactericidal against streptococci
CNS penetration → good
Route of elimination → both biliary and renal elimination after hepatic metabolism
Clinical Use:
Gram ⊕ species including MRSA and VRE.
Adverse Effects:
Bone marrow suppression (especially thrombocytopenia), peripheral neuropathy, serotonin syndrome (increase risk with SSRIs, MAOIs, SNRIs, bupropion), optic neuropathy (decrease visual acuity, decrease color perception, scotomas), GI upset.
Contraindications:
Concurrent use with MAOIs and selective serotonin reuptake inhibitors (SSRIs)
Mechanism of resistance:
Point mutation of 23S rRNA
Erythromycin
Macrolide Oral or IV form CNS penetration → poor Route of elimination → biliary All macrolides (except azithromycin) have a short half-life.
Mechanism:
Bind to 23S ribosomal RNA molecule of the 50S subunit → blockage of translocation → inhibition of bacterial protein synthesis (bacteriostatic effect)
Clinical Use:
Atypical pneumonia caused by Mycoplasma pneumonia, Legionella pneumophila, Chlamydophila pneumoniae
Bordetella pertussis
STIs caused by Chlamydia
Gram-positive cocci (especially for the treatment of streptococcal infection in patients who are allergic to penicillin)
Neisseria spp.
Second-line prophylaxis for N. meningitidis
Ureaplasma urealyticum
Erythromycin is used off-label for the treatment of gastroparesis because it increases GI motility.
Adverse Effects: Increased intestinal motility → GI upset QT-interval prolongation, arrhythmia Acute cholestatic hepatitis Eosinophilia Rash
Drug Interactions:
Erythromycin enhances the effect of oral anticoagulants (e.g., warfarin).
Erythromycin and clarithromycin increase theophylline serum concentrations due to CYP3A4 inhibition (cytochrome P450 inhibitors)
Contraindications:
Erythromycin estolate and clarithromycin are contraindicated in pregnant women (potentially hazardous to the fetus).
Mechanisms of Resistance:
Methylation of the binding site of 23S rRNA prevents the macrolide from binding to rRNA.
Clarithromycin
Macrolide Oral or IV form CNS penetration → poor Route of elimination → biliary All macrolides (except azithromycin) have a short half-life.
Mechanism:
Bind to 23S ribosomal RNA molecule of the 50S subunit → blockage of translocation → inhibition of bacterial protein synthesis (bacteriostatic effect)
Clinical Use:
Atypical pneumonia caused by Mycoplasma pneumonia, Legionella pneumophila, Chlamydophila pneumoniae
Bordetella pertussis
STIs caused by Chlamydia
Gram-positive cocci especially for the treatment of streptococcal infection in patients who are allergic to penicillin)
Neisseria spp.
Second-line prophylaxis for N. meningitidis
Mycobacterium avium (prophylaxis: azithromycin; treatment: azithromycin, clarithromycin)
H. pylori (clarithromycin is the part of triple therapy)
Ureaplasma urealyticum
Adverse Effects: Increased intestinal motility → GI upset QT-interval prolongation, arrhythmia Acute cholestatic hepatitis Eosinophilia Rash
Drug Interactions:
Erythromycin and clarithromycin increase theophylline serum concentrations due to CYP3A4 inhibition (cytochrome P450 inhibitors)
Contraindications:
Erythromycin estolate and clarithromycin are contraindicated in pregnant women (potentially hazardous to the fetus) .
Azithromycin and clarithromycin are contraindicated in patients with hepatic failure (erythromycin should be used cautiously).
Cautious use of clarithromycin in patients with renal failure
Mechanisms of Resistance:
Methylation of the binding site of 23S rRNA prevents the macrolide from binding to rRNA.
Polymyxin B
IV or IM form
Mechanism: Cationic detergent (polypeptides) molecule that binds to phospholipids of the cytoplasmic membrane of gram-negative bacteria → increased membrane permeability → leakage of cell contents → cell death (bactericidal effect) Binds to and inactivates endotoxins CNS penetration → poor Route of elimination → mostly renal
Clinical Use:
Severe infections caused by multidrug-resistant gram-negative bacteria
Effective only against gram-negative bacteria including P. aeruginosa, K. pneumoniae, E. coli, Acinetobacter baumannii, and Enterobacteriaceae spp.
Proteus, Neisseria, and Serratia spp. are resistant to polymyxins.
Not effective against gram-positive bacteria (because gram-positive bacteria do not have an outer membrane)
Polymyxin B is a component of a triple antibiotic ointment (bacitracin, neomycin, and polymyxin B) used for superficial skin infections
Oral polymyxin B may be used to disinfect the bowel to prevent ICU infections (polymyxins have a poor oral absorption)
Adverse Effects:
Nephrotoxicity, neurotoxicity (e.g., paresthesias, weakness, speech disorders, neuromuscular blockage), respiratory failure.
Urticaria, eosinophilia, and/or anaphylactoid reactions
Contraindications:
Hypersensitivity to polymyxins
Cautious use in patients with renal dysfunction
Polymyxin E (Colistin)
IV or IM form
Mechanism: Cationic detergent (polypeptides) molecule that binds to phospholipids of the cytoplasmic membrane of gram-negative bacteria → increased membrane permeability → leakage of cell contents → cell death (bactericidal effect) Binds to and inactivates endotoxins CNS penetration → poor Route of elimination → mostly renal
Clinical Use:
Severe infections caused by multidrug-resistant gram-negative bacteria
Effective only against gram-negative bacteria including P. aeruginosa, K. pneumoniae, E. coli, Acinetobacter baumannii, and Enterobacteriaceae spp.
Proteus, Neisseria, and Serratia spp. are resistant to polymyxins.
Not effective against gram-positive bacteria (because gram-positive bacteria do not have an outer membrane)
Adverse Effects:
Nephrotoxicity, neurotoxicity (e.g., paresthesias, weakness, speech disorders, neuromuscular blockage), respiratory failure.
Urticaria, eosinophilia, and/or anaphylactoid reactions
Contraindications:
Hypersensitivity to polymyxins
Cautious use in patients with renal dysfunction
Nitrofurantoin
Mechanism:
Reduced by bacterial nitroreductases to reactive metabolites → bind to bacterial ribosomes → impaired metabolism, impaired synthesis of protein, DNA, and RNA → cell death (bactericidal effect)
Route of elimination → primarily renal (rapidly excreted after absorption), small amounts in feces
Clinical Use:
Urinary tract pathogens
Gram-positive → Enterococci, Staphylococcus saprophyticus, group B streptococcus, Staphylococcus aureus, Staphylococcus epidermidis
Gram-negative → E. coli, Enterobacter spp., Shigella spp., Salmonella spp., Citrobacter spp, Neisseria spp, Bacteroides spp., Klebsiella spp.
Not effective against Pseudomonas and/or Proteus
Treatment and prophylaxis of acute uncomplicated UTIs (e.g., urethritis, cystitis)
Asymptomatic bacteriuria or symptomatic UTI in pregnant women
Should not be used in (suspected) pyelonephritis because nitrofurantoin does not achieve adequate concentration in renal tissue
Adverse Effects: Pulmonary fibrosis Hemolytic anemia in patients with G6PD deficiency GI upset Reversible peripheral neuropathy
Contraindications:
Children < 1 month of age
Breastfeeding women
Women at 38–42 weeks’ gestation or during delivery (because of the risk of hemolytic anemia in an infant due to the lack of erythrocyte glutathione peroxidase)
Hepatic dysfunction
Renal dysfunction with a creatinine clearance < 60 mL/min (in renal failure, urinary drug levels do not reach concentrations required to treat UTIs, and the retention of nitrofurantoin in systemic circulation increases the risk of adverse effects.)
Sulfa Drugs
Antibiotics (sulfamethoxazole (SMX), sulfadiazine, sulfisoxazole)
Diuretics (thiazides, furosemide, acetazolamide)
Anti-inflammatory drugs (sulfasalazine, celecoxib)
Sulfonylureas
Probenecid
Trimethoprim (TMP)
Oral or IV cotrimoxazole (TMP/SMX)
Mechanism:
Inhibition of bacterial folic acid synthesis
Inhibit dihydrofolate reductase (DHFR) (DHFR uses NADPH to reduce dihydrofolic acid to tetrahydrofolic acid (THF); THF can 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))
Bacteriostatic but become bactericidal when combined with sulfonamides
The combination of TMP and SMX also prevents antibiotic resistance.
CNS penetration → good
Route of elimination → primarily renal (via tubular secretion) (only a small amount is excreted with bile)
Clinical Use: Common indications include UTIs and acute otitis media. -TMP/SMX Shigella Salmonella Empiric treatment for simple UTI Prophylaxis and treatment of P. jirovecii Prophylaxis of toxoplasmosis
Adverse Effects:
Megaloblastic anemia
Leukopenia, granulocytopenia (can be prevented with concomitant folinic acid administration)
In high doses → hyperkalemia, particularly in HIV-positive patients
Artificially increased creatinine (despite unchanged GFR) (similar to the actions of amiloride TMP blocks the epithelial Na+ channel in the DCT and collecting duct, this reduces transepithelial voltage and impairs Na/K exchange, leading to reduced potassium excretion and hyperkalemia. This effect is often magnified elderly population, renal failure and those given other K sparing diuretics, ACE inhibitors and ARBs).
Contraindications: Children < 2 years of age Pregnant women Breastfeeding women Cautious use in people with hepatic failure, renal failure
Pyrimethamine
Oral sulfadiazine in combination with pyrimethamine
Mechanism:
Inhibition of bacterial folic acid synthesis
Inhibit dihydrofolate reductase (DHFR) (DHFR uses NADPH to reduce dihydrofolic acid to tetrahydrofolic acid (THF); THF can 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))
Bacteriostatic but become bactericidal when combined with sulfonamides
The combination of TMP and SMX also prevents antibiotic resistance.
CNS penetration → good
Route of elimination → primarily renal (via tubular secretion) (only a small amount is excreted with bile)
Clinical Use: Common indications include UTIs and acute otitis media. -TMP/SMX Shigella Salmonella Empiric treatment for simple UTI Prophylaxis and treatment of P. jirovecii Prophylaxis of toxoplasmosis
Adverse Effects:
Megaloblastic anemia
Leukopenia, granulocytopenia (can be prevented with concomitant folinic acid administration)
In high doses → hyperkalemia, particularly in HIV-positive patients
Artificially increased creatinine (despite unchanged GFR)
Contraindications: Children < 2 years of age Pregnant women Breastfeeding women Cautious use in people with hepatic failure, renal failure
Sulfamethoxazole (SMX)
Sulfonamide
Oral or IV cotrimoxazole (TMP/SMX)
Mechanism:
Inhibition of bacterial folic acid synthesis
Inhibit dihydropteroate synthase.
Bacteriostatic but become bactericidal when combined with TMP
The combination of TMP and SMX also prevents antibiotic resistance.
CNS penetration → good
Route of elimination → primarily renal (via tubular secretion) (only a small amount is excreted with bile)
Metabolized in the liver via acetylation
Clinical Use: Common indications include UTIs and acute otitis media. -TMP/SMX Shigella Salmonella Empiric treatment for simple UTI Prophylaxis and treatment of P. jirovecii Prophylaxis of toxoplasmosis
Adverse Effects:
Fever
Photosensitivity
Sulfonamides hypersensitivity reactions (especially urticaria or hives) (sulfonamides are the second most common antibacterial to cause hypersensitivity reactions, after β-lactams)
Stevens-Johnson syndrome
Triggers hemolytic anemia in G6PD-deficient patients
Aplastic anemia, thrombocytopenia, and pancytopenia
Agranulocytosis
Hyperkalemia
GI upset
Nephrotoxicity (especially acute tubulointerstitial nephritis)
Kernicterus in infancy
Displacement of other drugs (e.g., warfarin) from albumin (SMX has a higher binding affinity to albumin, so it can displace drugs like warfarin from albumin, resulting in increased free plasma concentrations of the displaced drug)
Drug interactions due to CYP450 inhibition
Contraindications: Children < 2 years of age Pregnant women Breastfeeding women Cautious use in people with hepatic failure, renal failure
Mechanisms of Resistance:
Mutation in bacterial dihydropteroate synthase
Decreased uptake of sulfonamide
Increased para-aminobenzoate (PABA) synthesis (PABA is a substrate of dihydropteroate synthase and a precursor of folic acid)
Sulfadiazine
Sulfonamide
Oral sulfadiazine in combination with pyrimethamine
Mechanism:
Inhibition of bacterial folic acid synthesis
Inhibit dihydropteroate synthase.
CNS penetration → good
Route of elimination → primarily renal (via tubular secretion) (only a small amount is excreted with bile)
Bacteriostatic but become bactericidal when combined with pyrimethamine (sequential block of folate synthesis)
Clinical use:
Common indications include UTIs and acute otitis media.
Shigella
Salmonella
Empiric treatment for simple UTI
Prophylaxis and treatment of P. jirovecii
Prophylaxis of toxoplasmosis
Adverse Effects:
Fever
Photosensitivity
Sulfonamides hypersensitivity reactions (especially urticaria or hives) (sulfonamides are the second most common antibacterial to cause hypersensitivity reactions, after β-lactams)
Stevens-Johnson syndrome
Triggers hemolytic anemia in G6PD-deficient patients
Aplastic anemia, thrombocytopenia, and pancytopenia
Agranulocytosis
Hyperkalemia
GI upset
Nephrotoxicity (especially acute tubulointerstitial nephritis)
Kernicterus in infancy
Displacement of other drugs (e.g., warfarin) from albumin (SMX has a higher binding affinity to albumin, so it can displace drugs like warfarin from albumin, resulting in increased free plasma concentrations of the displaced drug)
Drug interactions due to CYP450 inhibition
Contraindications: Children < 2 years of age Pregnant women Breastfeeding women Cautious use in people with hepatic failure, renal failure
Mechanisms of Resistance:
Mutation in bacterial dihydropteroate synthase
Decreased uptake of sulfonamide
Increased para-aminobenzoate (PABA) synthesis (PABA is a substrate of dihydropteroate synthase and a precursor of folic acid)
Sulfisoxazole
Sulfonamide
Oral sulfisoxazole
Mechanism of action
Inhibition of bacterial folic acid synthesis
Inhibit dihydropteroate synthase.
CNS penetration → good
Route of elimination → primarily renal (via tubular secretion) (only a small amount is excreted with bile)
Clinical Use: Common indications include UTIs and acute otitis media. Gram-positive bacteria and gram-negative bacteria N. meningitidis Chlamydia trachomatis Nocardia asteroides Toxoplasma gondii Plasmodia spp.
Adverse Effects:
Fever
Photosensitivity
Sulfonamides hypersensitivity reactions (especially urticaria or hives) (sulfonamides are the second most common antibacterial to cause hypersensitivity reactions, after β-lactams)
Stevens-Johnson syndrome
Triggers hemolytic anemia in G6PD-deficient patients
Aplastic anemia, thrombocytopenia, and pancytopenia
Agranulocytosis
Hyperkalemia
GI upset
Nephrotoxicity (especially acute tubulointerstitial nephritis)
Kernicterus in infancy
Displacement of other drugs (e.g., warfarin) from albumin (SMX has a higher binding affinity to albumin, so it can displace drugs like warfarin from albumin, resulting in increased free plasma concentrations of the displaced drug)
Drug interactions due to CYP450 inhibition
Contraindications: Children < 2 years of age Pregnant women Breastfeeding women Cautious use in people with hepatic failure, renal failure
Mechanisms of Resistance:
Mutation in bacterial dihydropteroate synthase
Decreased uptake of sulfonamide
Increased para-aminobenzoate (PABA) synthesis (PABA is a substrate of dihydropteroate synthase and a precursor of folic acid)
Daptomycin
Mechanism:
Incorporate K+ channels into the cell membrane of gram-positive bacteria → rapid membrane depolarization → loss of membrane potential → inhibition of synthesis of DNA, RNA, and proteins → cell death (bactericidal effect)
Route of elimination → renal
Clinical Use:
Gram-positive bacteria
S. aureus, especially MRSA
Mainly used in skin and skin structure infections, bacteremia, and endocarditis
Vancomycin-resistant Enterococci (VRE)
Not used in pneumonia (daptomycin is bound and inactivated by surfactant)
Adverse Effects:
Reversible myopathy
Muscle pain after 1 week starting therapy
Rhabdomyolysis (monitor creantinine phosphate (CPK))
Allergic pneumonitis
Contraindications:
Hypersensitivity
Mechanisms of Resistance:
Repulsion of daptomycin molecules due to the change in the bacterial surface charge
Dapsone
Mechanism:
Competitive antagonist of para-aminobenzoic acid (PABA) for dihydropteroate synthetase → inhibition of dihydrofolic acid synthesis
Bacteriostatic and weakly bactericidal effect
Structurally different from sulfonamides but a similar mechanism of action
Route of elimination → mostly renal
Clinical Use:
M. leprae (lepromatous and tuberculoid leprosy)
P. jiroveci pneumonia (prophylaxis; treatment → used in combination with TMP as an alternative to TMP/SMX)
Dermatitis herpetiformis
Alternative to the combination of sulfadiazine and pyrimethamine for toxoplasmosis
In combination with pyrimethamine as an alternative for chloroquine-resistant malaria
Adverse Effects: Methemoglobinemia Triggers hemolytic anemia in patients with G6PD deficiency Agranulocytosis GI upset Peripheral neuropathy
Contraindications:
G6PD deficiency
Cautious use in patients with renal and/or hepatic dysfunction
Mechanism of Resistance:
Mutations of folP1 gene coding for dihydropteroate synthase
Mention 1st generation Fluoroquinolone
Nalidixic acid (oral)
Fluoroquinolones
1st generation → nalidixic acid (oral)
2nd generation → norfloxacin, ciprofloxacin, ofloxacin (oral), enoxacin (oral or IV)
3rd generation → levofloxacin (oral or IV)
4th generation → moxifloxacin, gemifloxacin, gatifloxacin (oral)
Levofloxacin, moxifloxacin, and gemifloxacin are respiratory fluoroquinolones.
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV → DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
CNS penetration → good
Route of elimination → primarily renal (via glomerular filtration and tubular secretion)
Moxifloxacin undergoes biliary excretion.
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Clinical Use:
-Norfloxacin, ciprofloxacin, and ofloxacin
Gram-negative rods causing urinary and gastrointestinal infections
Some gram-positive pathogens
Genitourinary infections caused by Neisseria gonorrhoeae, Chlamydia trachomatis, and/or Ureaplasma urealyticum
Ciprofloxacin → Pseudomonas aeruginosa (e.g., malignant otitis externa)
-Levofloxacin, moxifloxacin, and gemifloxacin:
Atypical bacteria (e.g., Legionella spp., Mycoplasma spp., Chlamydophila pneumoniae)
Also effective against anaerobes
Gemifloxacin is highly potent against penicillin-resistant pneumococci.
Moxifloxacin → 2nd-line treatment of tuberculosis in patients who cannot tolerate antitubercular drugs and in multidrug resistant tuberculosis
Moxifloxacin poor antipseudomonal activity
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation (altered amino acid composition) in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Mention 3rd generation Fluoroquinolone
Levofloxacin (oral or IV)
Mention 4th generation Fluoroquinolone
Moxifloxacin
Gemifloxacin
Gatifloxacin
Mention Respiratory Fluoroquinolones
Levofloxacin
Moxifloxacin
Gemifloxacin
Nalidixic acid
1st generation fluoroquinolone
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
CNS penetration → good
Route of elimination → primarily renal (via glomerular filtration and tubular secretion)
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Clinical Use:
-Norfloxacin, ciprofloxacin, and ofloxacin
Gram-negative rods causing urinary and gastrointestinal infections
Some gram-positive pathogens
Genitourinary infections caused by Neisseria gonorrhoeae, Chlamydia trachomatis, and/or Ureaplasma urealyticum
Ciprofloxacin → Pseudomonas aeruginosa (e.g., malignant otitis externa)
-Levofloxacin, moxifloxacin, and gemifloxacin:
Atypical bacteria (e.g., Legionella spp., Mycoplasma spp., Chlamydophila pneumoniae)
Also effective against anaerobes
Gemifloxacin is highly potent against penicillin-resistant pneumococci.
Moxifloxacin → 2nd-line treatment of tuberculosis in patients who cannot tolerate antitubercular drugs and in multidrug resistant tuberculosis
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Norfloxacin
2nd generation fluoroquinolone
Oral form
CNS penetration → good
Route of elimination → primarily renal (via glomerular filtration and tubular secretion)
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
Clinical Use:
Gram-negative rods causing urinary and gastrointestinal infections
Some gram-positive pathogens
Genitourinary infections caused by Neisseria gonorrhoeae, Chlamydia trachomatis, and/or Ureaplasma urealyticum
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Ciprofloxacin
2nd generation fluoroquinolone
Oral form
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
CNS penetration → good
Route of elimination → primarily renal (via glomerular filtration and tubular secretion)
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Clinical Use:
Gram-negative rods causing urinary and gastrointestinal infections
Some gram-positive pathogens
Genitourinary infections caused by Neisseria gonorrhoeae, Chlamydia trachomatis, and/or Ureaplasma urealyticum
Pseudomonas aeruginosa (e.g., malignant otitis externa)
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Ofloxacin
2nd generation fluoroquinolone
Oral form
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
CNS penetration → good
Route of elimination → primarily renal (via glomerular filtration and tubular secretion)
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Clinical Use:
Gram-negative rods causing urinary and gastrointestinal infections
Some gram-positive pathogens
Genitourinary infections caused by Neisseria gonorrhoeae, Chlamydia trachomatis, and/or Ureaplasma urealyticum
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Levofloxacin
3rd generation respiratory fluoroquinolone
Oral or IV form
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
CNS penetration → good
Route of elimination → primarily renal (via glomerular filtration and tubular secretion)
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Clinical Use:
Atypical bacteria (e.g., Legionella spp., Mycoplasma spp., Chlamydophila pneumoniae)
Also effective against anaerobes
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Moxifloxacin
4th generation respiratory fluoroquinolone
Oral or IV form
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
CNS penetration → good
Undergoes biliary excretion.
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Clinical Use:
Atypical bacteria (e.g., Legionella spp., Mycoplasma spp., Chlamydophila pneumoniae)
Also effective against anaerobes
2nd-line treatment of tuberculosis in patients who cannot tolerate antitubercular drugs and in multidrug resistant tuberculosis
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Gemifloxacin
4th generation respiratory fluoroquinolone
Oral form
Mechanism:
Inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)
CNS penetration → good
Route of elimination → primarily renal (via glomerular filtration and tubular secretion)
Absorption is reduced when coadministered with polyvalent cations (e.g., magnesium, calcium, iron).
Clinical Use:
Atypical bacteria (e.g., Legionella spp., Mycoplasma spp., Chlamydophila pneumoniae)
Also effective against anaerobes
Highly potent against penicillin-resistant pneumococci.
Adverse Effects:
GI upset
Neurological symptoms (mild headache, dizziness, mood changes, peripheral neuropathy, can lower seizure threshold (increased risk in patients taking NSAIDs [NSAIDs increase the displacement of GABA from its receptor caused by quinolones] and those with a previous history of epilepsy))
Hyperglycemia/hypoglycemia (especially with gatifloxacin, which has been removed from the US market for this reason)
QT prolongation
Photosensitivity
Skin rash
Superinfection (most commonly with gram-positive pathogens)
Potentially life-threatening exacerbations in patients with myasthenia gravis
In children → potential damage to growing cartilage → reversible arthropathy
Muscle ache, leg cramps, tendinitis, tendon rupture, especially of the Achilles tendon (the risk of tendon rupture is higher for individuals over 60 years of age and for individuals on steroid therapy)
Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
Contraindications:
Children and teenagers < 18 years of age (the only exception is ciprofloxacin which can be used in this cohort for complicated UTI including pyelonephritis and anthrax)
Patients > 60 years of age and those taking cortisol
Pregnant women
Breastfeeding women
Epilepsy, stroke, CNS lesions/inflammation
QT prolongation
Myasthenia gravis (potentially life-threatening exacerbations)
Cautious use in patients with renal failure, hepatic failure
Antacid use (aluminum- and magnesium-containing antacids decrease the absorption of fluoroquinolones)
Known aortic aneurysm or increased risk of aneurysms (e.g., Marfan syndrome, Ehlers-Danlos syndrome, advanced age, peripheral atherosclerotic disease, hypertension)
Mechanism of Resistance:
Chromosome-encoded mutation in DNA gyrase and topoisomerase IV enzymes
Altered cell wall permeability
Plasmid-encoded mutations in efflux pump proteins
Metronidazole
Oral or IV form
Mechanism:
Creates free radicals within the bacterial cell → DNA-strand breaks → cell death (bactericidal and antiprotozoal effect)
CNS penetration → good
Route of elimination → renal
Clinical Use:
Certain protozoa (e.g., Entamoeba histolytica, Giardia, Trichomonas)
Anaerobes (e.g., C. difficile, Bacteroides spp.)
Facultative anaerobes
Gardnerella vaginalis
Rosacea
Helicobacter pylori in place of amoxicillin (e.g., in case of penicillin allergy) as part of a triple therapy regimen
Not effective against aerobes (In anaerobes, metronidazole is reduced to its active metabolite. In aerobes, the presence of oxygen, which increases electron acceptance, prevents the reduction of metronidazole and its consequent formation into an active metabolite)
Adverse Effects:
Headache
Disulfiram-like reaction (nitroimidazoles inhibit acetaldehyde dehydrogenase → accumulation of acetaldehyde → immediate hangover-like symptoms after ethanol intake). Symptoms include flushing, tachycardia, and hypotension.
Metallic taste
Peripheral neuropathy (particularly with prolonged use)
Tinidazole
Oral or IV form
Mechanism:
Creates free radicals within the bacterial cell → DNA-strand breaks → cell death (bactericidal and antiprotozoal effect)
CNS penetration → good
Route of elimination → renal
Clinical Use:
Certain protozoa (e.g., Entamoeba histolytica, Giardia, Trichomonas)
Anaerobes (e.g., C. difficile, Bacteroides spp.)
Facultative anaerobes
Gardnerella vaginalis
Rosacea
Helicobacter pylori in place of amoxicillin (e.g., in case of penicillin allergy) as part of a triple therapy regimen
Not effective against aerobes (In anaerobes, metronidazole is reduced to its active metabolite. In aerobes, the presence of oxygen, which increases electron acceptance, prevents the reduction of metronidazole and its consequent formation into an active metabolite)
Adverse Effects:
Headache
Disulfiram-like reaction (nitroimidazoles inhibit acetaldehyde dehydrogenase → accumulation of acetaldehyde → immediate hangover-like symptoms after ethanol intake). Symptoms include flushing, tachycardia, and hypotension.
Metallic taste
Peripheral neuropathy (particularly with prolonged use)
Pentamidine
Mechanism:
Antimicrobial agent with a poorly understood mechanism
Clinical Use: African trypanosomiasis Babesiosis Leishmaniasis To prevent or treat Pneumocystis pneumonia (especially in patients unable to take TMP-SMX).
Adverse Effects:
Fatigue, dizziness, decreased appetite, and respiratory symptoms (e.g., cough, dyspnea, wheezing).
Rifamycins
Oral or IV rifampin (rifampicin)
Oral rifabutin
Oral rifaximin
Oral rifapentine
Mechanism:
Inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Route of elimination → biliary
Clinical Use:
Mycobacteria
Tuberculosis (together with isoniazid, pyrazinamide, and ethambutol)
Rifaximin is not absorbed systemically and is therefore used as a gut antibiotic.
Leprosy
-Long-term treatment of tuberculoid form → dapsone and rifampin (rifampin delays resistance to dapsone)
-Long-term treatment of lepromatous form → combination of dapsone, clofazimine, and rifampin
M. avium-intracellulare prophylaxis and treatment (rifabutin) (treatment of the most dangerous form, disseminated, consists of clarithromycin combined with ethambutol with a possible addition of rifabutin)
Meningococcal prophylaxis
Brucella
Chemoprophylaxis for people who had contact with children infected with H. influenzae type b
Rifaximin → second-line therapy in hepatic encephalopathy (can be added to nonabsorbable disaccharides (e.g., lactulose, lactitol) to decrease ammonia production by reducing the amount of urease-producing colonic bacteria)
Adverse Effects:
Harmless red-orange discoloration of body fluids (e.g., urine, tears)
Flu-like symptoms (fever, arthralgia; in severe cases hemolytic anemia, thrombocytopenia, and renal failure)
Minor hepatotoxicity (zone III)
Cytochrome P450 induction (CYP3A4, CYP2C9) (rifabutin is preferred for the treatment of mycobacterial infections in patients with HIV because it has a lower potential for CYP induction than rifampin; protease inhibitors and NNRTIs (e.g., efavirenz) are also cytochrome P450 substrates).
Intermittent therapy is associated with an increased risk of renal failure, so rifamycins should be administered daily (acute interstitial nephritis)
Contraindications:
Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
RNA polymerase mutations decrease the affinity of rifamycins to RNA polymerase (mutations in the β subunit of the bacterial RNA polymerase confer near-complete resistance to the drug)
Resistance develops rapidly if used as monotherapy
Rifampin (rifampicin)
Oral or IV form
Mechanism:
Inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Route of elimination → biliary
Clinical Use:
Mycobacteria
Tuberculosis (together with isoniazid, pyrazinamide, and ethambutol)
Leprosy
-Long-term treatment of tuberculoid form → dapsone and rifampin (rifampin delays resistance to dapsone)
-Long-term treatment of lepromatous form → combination of dapsone, clofazimine, and rifampin
Meningococcal prophylaxis
Chemoprophylaxis for people who had contact with children infected with H. influenzae type b
Adverse Effects:
Harmless red-orange discoloration of body fluids (e.g., urine, tears)
Flu-like symptoms (fever, arthralgia; in severe cases hemolytic anemia, thrombocytopenia, and renal failure)
Minor hepatotoxicity
Cytochrome P450 induction (CYP3A4, CYP2C9) (rifabutin is preferred for the treatment of mycobacterial infections in patients with HIV because it has a lower potential for CYP induction than rifampin; protease inhibitors and NNRTIs (e.g., efavirenz) are also cytochrome P450 substrates).
Intermittent therapy is associated with an increased risk of renal failure, so rifamycins should be administered daily
Contraindications:
Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
RNA polymerase mutations decrease the affinity of rifamycins to RNA polymerase.
Resistance develops rapidly if used as monotherapy (mutations in the β subunit of the bacterial RNA polymerase confer near-complete resistance to the drug)
Rifabutin
Oral form
Mechanism:
Inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Route of elimination → biliary
Clinical Use:
Mycobacteria
Tuberculosis (together with isoniazid, pyrazinamide, and ethambutol)
M. avium-intracellulare prophylaxis and treatment (rifabutin) (treatment of the most dangerous form, disseminated, consists of clarithromycin combined with ethambutol with a possible addition of rifabutin)
Meningococcal prophylaxis
Chemoprophylaxis for people who had contact with children infected with H. influenzae type b
Adverse Effects:
Harmless red-orange discoloration of body fluids (e.g., urine, tears)
Flu-like symptoms (fever, arthralgia; in severe cases hemolytic anemia, thrombocytopenia, and renal failure)
Minor hepatotoxicity
Cytochrome P450 induction (CYP3A4, CYP2C9) (rifabutin is preferred for the treatment of mycobacterial infections in patients with HIV because it has a lower potential for CYP induction than rifampin; protease inhibitors and NNRTIs (e.g., efavirenz) are also cytochrome P450 substrates).
Intermittent therapy is associated with an increased risk of renal failure, so rifamycins should be administered daily
Contraindications:
Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
RNA polymerase mutations decrease the affinity of rifamycins to RNA polymerase (mutations in the β subunit of the bacterial RNA polymerase confer near-complete resistance to the drug)
Resistance develops rapidly if used as monotherapy
Rifaximin
Oral form
Mechanism:
Inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Route of elimination → biliary
Clinical Use:
Not absorbed systemically and is therefore used as a gut antibiotic.
Second-line therapy in hepatic encephalopathy (can be added to nonabsorbable disaccharides (e.g., lactulose, lactitol) to decrease ammonia production by reducing the amount of urease-producing colonic bacteria)
Adverse Effects:
Harmless red-orange discoloration of body fluids (e.g., urine, tears)
Flu-like symptoms (fever, arthralgia; in severe cases hemolytic anemia, thrombocytopenia, and renal failure)
Minor hepatotoxicity
Cytochrome P450 induction (CYP3A4, CYP2C9) (rifabutin is preferred for the treatment of mycobacterial infections in patients with HIV because it has a lower potential for CYP induction than rifampin; protease inhibitors and NNRTIs (e.g., efavirenz) are also cytochrome P450 substrates).
Intermittent therapy is associated with an increased risk of renal failure, so rifamycins should be administered daily
Contraindications:
Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
RNA polymerase mutations decrease the affinity of rifamycins to RNA polymerase.
Resistance develops rapidly if used as monotherapy (mutations in the β subunit of the bacterial RNA polymerase confer near-complete resistance to the drug)
Rifapentine
Oral form
Mechanism:
Inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Route of elimination → biliary
Clinical Use:
Mycobacteria
Meningococcal prophylaxis
Chemoprophylaxis for people who had contact with children infected with H. influenzae type b
Adverse Effects:
Harmless red-orange discoloration of body fluids (e.g., urine, tears)
Flu-like symptoms (fever, arthralgia; in severe cases hemolytic anemia, thrombocytopenia, and renal failure)
Minor hepatotoxicity
Cytochrome P450 induction (CYP3A4, CYP2C9) (rifabutin is preferred for the treatment of mycobacterial infections in patients with HIV because it has a lower potential for CYP induction than rifampin; protease inhibitors and NNRTIs (e.g., efavirenz) are also cytochrome P450 substrates).
Intermittent therapy is associated with an increased risk of renal failure, so rifamycins should be administered daily
Contraindications:
Cautious use in patients with hepatic dysfunction
Mechanisms of Resistance:
RNA polymerase mutations decrease the affinity of rifamycins to RNA polymerase.
Resistance develops rapidly if used as monotherapy (mutations in the β subunit of the bacterial RNA polymerase confer near-complete resistance to the drug)
Isoniazid
Mechanism:
Prodrug and needs to be converted into its active metabolite by bacterial catalase-peroxidase (encoded by KatG).
Prevents cell wall synthesis by inhibiting the synthesis of mycolic acid
CNS penetration → variable
Metabolization → primarily hepatic
INH is converted into various metabolites (e.g., via acetylation), some of which are hepatotoxic (e.g., hydrazine, acetylhydrazine).
Main metabolic enzyme → N-acetyltransferase (NAT) → involved in metabolite formation and subsequent neutralization
The rate of NAT acetylation is genetically determined.
-Individuals with slow acetylation → higher half-life due to lack of hepatic NAT → increased risk of drug-induced toxicity
-Individuals with fast acetylation → lower half-life of active drug → administration of a higher dose is required for reaching the same blood concentration compared to individuals with slow acetylation
Inhibits cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C19, and CYP3A4)
Route of elimination → renal elimination after hepatic metabolism (dose adjustment is not required in the case of renal failure)
Clinical Use:
Treatment of TB (together with rifampin, pyrazinamide, and ethambutol)
The only drug that can be used as monoprophylaxis against TB
First-line monotherapy for latent TB
Adverse Effects:
Hepatotoxicity
Anion gap metabolic acidosis
Drug-induced lupus erythematosus
High doses of INH can precipitate benzodiazepine-refractory seizures
Vitamin B6 deficiency (INH should be administered with pyridoxine to avoid vitamin B6 deficiency)
Peripheral neuropathy due to S-adenosylmethionine accumulation
Sideroblastic anemia (inhibits pyridoxine phosphokinase and decrease pyridoxine conversion to PLP, an ALA synthase cofactor), aplastic anemia, thrombocytopenia
Optic neuropathy (less common compared to treatment with ethambutol)
Pellagra
Contraindications:
Cautious use in patients with renal and/or hepatic dysfunction
Mechanisms of Resistance:
Mutations causing decreased KatG (coding for bacterial catalase-peroxidase) → decreased expression of catalase-peroxidase → less/no biologically active INH
Pyrazinamide
Mechanism:
Not completely understood
Prodrug → converted into active form pyrazinoic acid
Most effective at acidic pH (e.g., in acidic phagolysosomes)
Bactericidal effect
CNS penetration → only when meninges are inflamed
Route of elimination → renal elimination after hepatic metabolism
Clinical Use:
M. tuberculosis
Adverse Effects:
Hyperuricemia (decrease uric acid clearance; can precipitate gout)
Hepatotoxicity
Contraindications:
Consider use in pregnant and breastfeeding women only if benefits outweigh the risks
Hepatic failure
Acute gout
Mechanisms of Resistance:
Mutations in RpsA gene coding for ribosomal protein S1 (the mechanism through which the mutation leads to the resistance to pyrazinamide is unknown)
Ethambutol
Mechanism:
Inhibits arabinosyltransferase → ↓ carbohydrate polymerization → prevention of mycobacterial cell wall synthesis (bacteriostatic effect) (arabinosyltransferase catalyzes the production of arabinogalactan, a constituent of the cell wall of Mycobacteria)
CNS penetration → only when meninges are inflamed
Route of elimination → primarily renal
Clinical Use:
M. tuberculosis therapy (together with isoniazid, rifampin, and pyrazinamide)
M. avium-intracellulare treatment (together with azithromycin or clarithromycin; ciprofloxacin or rifabutin can be added)
Adverse Effects:
Optic neuropathy with decreased visual acuity and red-green color blindness which may result in irreversible blindness
Resistance develops rapidly if used as monotherapy
Contraindications:
Contraindicated in patients who are unable to report visual changes
Contraindicated in patients with optic neuritis
Mechanisms of Resistance:
Mutations of EmbCAB gene coding for arabinosyltransferase
Antibiotics Contraindicated in Children
Aminoglycosides
Tetracyclines (< 8 years old (except doxycycline))
Tigecycline (< 8 years old)
Chloramphenicol
Fluoroquinolones
Sulfonamides, trimethoprim (TMP) and pyrimethamine (< 2 years old)
Nitrofurantoin (< 1 month old)
Ethambutol (young children who are unable to report visual changes)
Antibiotics Contraindicated in Pregnant Women
Aminoglycosides
Tetracyclines
Tigecycline
Chloramphenicol
Fluoroquinolones
Sulfonamides with trimethoprim (TMP) or pyrimethamine
Macrolides (clarithromycin and erythromycin estolate) (the rate of hepatotoxicity is higher in pregnant women if using erythromycin estolate)
Antibiotics Contraindicated in Individuals with Renal Failure
Fosfomycin Aminoglycosides Tetracyclines Sulfonamides with trimethoprim (TMP) or pyrimethamine Nitrofurantoin
Antibiotics Contraindicated in Individuals with Hepatic Failure
Tetracyclines
Macrolides (azithromycin and clarithromycin)
Sulfonamides with trimethoprim (TMP) or pyrimethamine
Nitrofurantoin
Pyrazinamide
Antibiotics Safe to Use in Individuals with Hepatic Failure
β-lactams Vancomycin Fosfomycin Daptomycin Polymyxin Aminoglycosides Clindamycin Streptogramin (quinupristin, dalfopristin) Linezolid Ethambutol
Antibiotics Safe to Use in Individuals with Renal Failure
β-lactams
Vancomycin
Daptomycin
Clindamycin
Streptogramin (quinupristin, dalfopristin)
Linezolid
Metronidazole
Rifamycins (should be administered daily because intermittent therapy is associated with an increased risk of renal failure)
Pyrazinamide
Ethambutol
Macrolides (erythromycin and azithromycin)
Antibiotics Safe to Use in Pregnant Women
β-lactams
Fosfomycin
Daptomycin
Macrolides (azithromycin and erythromycin) (except erythromycin estolate)
Amphotericin B
Routes of administration → intravenous, intrathecal, bladder irrigation
Mechanism: Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes. Binds cholesterol to a degree, which explains a larger number of its adverse effects
Clinical Use:
Severe systemic mycoses, such as:
-Cryptococcal disease (in combination with flucytosine for cryptococcal meningitis)
-Sporotrichosis
-Aspergillosis
-Blastomycosis
-Candidiasis
-Coccidioides (administered intrathecally for coccidioidal meningitis)
-Histoplasmosis
-Mucormycosis
-Fungal cystitis (administered via bladder irrigation)
-Fungal meningitis (intrathecal administration)
Adverse Effects:
Nephrotoxicity (lipid-based formulations of the drug and IV hydration reduce nephrotoxicity)
IV phlebitis (administration via a central line will reduce the risk of IV phlebitis)
Impaired renal tubule permeability → hypokalemia and hypomagnesemia (restoring K+ and Mg2+ while administering the drug can counter this effect)
Distal renal tubular acidosis (type 1)
Fever, chills (amphotericin B is sometimes referred to as “shake and bake”)
Anemia (suppression of renal EPO synthesis)
Arrhythmias
Hypotension
Headache
Contraindications:
Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia)
Renal dysfunction
Pregnancy
Nystatin
Mechanism: Same as amphotericin B. Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes. Topical use only as too toxic for intravenous use
Clinical Use: Topical -Vaginal candidiasis -Diaper rash -NOT effective against dermatophytes Oral (swish and swallow) -Oropharyngeal candidiasis
Adverse effects
Gastrointestinal symptoms (e.g., diarrhea, nausea, pain)
Contact dermatitis
Stevens-Johnson syndrome
Contraindications:
Pregnancy
Flucytosine
Route of administration → oral
Mechanism:
Converted to 5-fluorouracil by fungal cytosine deaminase, thereby inhibiting DNA and RNA synthesis
Clinical Use:
Combination with amphotericin B → systemic fungal infections (especially cryptococcal meningitis)
Monotherapy → non-life-threatening infections, such as genitourinary candida infections, that do not respond to other drugs
Adverse Effects:
Bone marrow suppression with pancytopenia
Hepatic injury (elevated liver enzymes, especially in patients with flucytosine blood levels > 100 mg/L)
Renal failure
Gastrointestinal upset
Contraindications:
Renal impairment
Pregnancy and breastfeeding
Azoles
Group of antifungal agents with a broad spectrum of activity that can be divided into triazoles and imidazoles
Routes of administration:
Imidazoles → topical, oral
Triazoles → oral, IV
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Ketoconazole → inhibition of 17α-hydroxylase/17,20-lyase
Inhibition of cytochrome P450 can influence serum concentrations of other medications
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline))
(serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Ketoconazole → adrenal cortex insufficiency (caused by inhibited cortisol synthesis (the effect can be used therapeutically to treat Cushing syndrome))
Voriconazole → dose-dependent, reversible visual disorders (e.g., photosensitivity)
Contraindications:
Cardiac arrhythmias
Severe cardiac insufficiency
Clotrimazole
Imidazole derivative (topical, oral)
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use: Primarily topical fungal infections Vaginal candidiasis Tinea infections Oropharyngeal candidiasis
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline))
(serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Miconazole
Imidazole derivative
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use: Primarily topical fungal infections Vaginal candidiasis Tinea infections Oropharyngeal candidiasis
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline))
(serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Ketoconazole
Imidazoles derivative (topical, oral) Triazoles → oral, IV
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Ketoconazole → inhibition of 17α-hydroxylase/17,20-lyase
Inhibition of cytochrome P450 can influence serum concentrations of other medications
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use:
Tinea versicolor
Prostate cancer
Psoriasis (applied topically to prevent fungal skin infections)
Hypercortisolism (e.g., Cushing syndrome) (because it inhibits cortisol synthesis)
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline)) (serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Ketoconazole → adrenal cortex insufficiency (caused by inhibited cortisol synthesis (the effect can be used therapeutically to treat Cushing syndrome))
Fluconazole
Triazoles derivative (oral, IV)
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use: Drug of choice maintenance therapy of cryptococcal meningitis in patients with AIDS (initially, cryptococcal meningitis is treated with amphotericin B PLUS either flucytosine or fluconazole) Candidiasis (all forms) Coccidioidomycosis Histoplasmosis Blastomycosis
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline))
(serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Voriconazole
Triazoles derivative (oral, IV)
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use:
Drug of choice for invasive aspergillosis
Some forms of Candida
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline))
(serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Voriconazole → dose-dependent, reversible visual disorders (e.g., photosensitivity)
Itraconazole
Triazoles derivative (oral, IV)
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use: Histoplasmosis Blastomycosis Coccidioidomycosis Sporotrichosis Allergic bronchopulmonary aspergillosis, aspergilloma Particularly effective in dermatophytosis (e.g., onychomycosis) Oropharyngeal/esophageal candidiasis
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline))
(serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Posaconazole
Triazoles derivative (oral, IV)
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use:
Oropharyngeal candidiasis
Prophylactic treatment of invasive aspergillosis and Candida infections in immunocompromised patients
Adverse Effects:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline)) (serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Isavuconazole
Triazoles derivative (oral, IV)
Mechanism:
Inhibition of 14-alpha demethylase, a fungal cytochrome P450 → ↓ fungal synthesis of ergosterol from lanosterol → ↓ levels of ergosterol → membrane instability → cellular death.
Cautious use in patients with renal and/or hepatic dysfunction
PPIs must be discontinued (azoles require a low pH to be absorbed)
Clinical Use:
Invasive aspergillosis
Invasive mucormycosis
Adverse Effects:
-Topical Use:
Local burning sensation
Pruritus
-Systemic Use:
Hepatotoxicity (inhibits cytochrome P450 → ↑ concentration of many drugs metabolized by CYP450 (e.g., warfarin, simvastatin, cyclosporine, theophylline)) (serum transaminases and alkaline phosphatase elevation (especially severe with ketoconazole))
Gynecomastia due to inhibition of testosterone synthesis (especially seen with ketoconazole)
Gastrointestinal upset
QT prolongation → torsade de pointes
Hypokalemia (especially ketoconazole and itraconazole)
Terbinafine
Route of administration → oral
Mechanism:
Inhibition fungal squalene epoxidase → ↓ synthesis of ergosterol → accumulation of squalene → ↑ membrane permeability → cell death
Clinical Use:
Dermatophytosis (most commonly onychomycosis)
Tinea infections (e.g., tinea pedis)
Adverse Effects: Hepatotoxicity Dysgeusia Gastrointestinal upset Headache Exacerbation of autoimmune diseases (e.g., systemic lupus erythematosus)
Contraindications:
Impaired liver function
Systemic lupus erythematosus
Breastfeeding
Echinocandins
Caspofungin
Anidulafungin
Micafungin
Route of administration → IV
Mechanism:
Inhibition of β-glucan synthesis → disruption of fungal cell wall synthesis → ↓ resistance against osmotic forces → cell death
Clinical Use: Invasive aspergillosis (less toxic than amphotericin B) Invasive candidiasis (particularly biofilm-embedded Candida)
Adverse Effects: Flushing (due to release of histamine) Hepatotoxicity (serum transaminases and alkaline phosphatase elevation) Gastrointestinal upset Hypotension Phlebitis/pain at the injection site Fever, shivering
Ciclopirox
Route of administration → topical
Mechanism:
Not fully understood
Likely disruption of DNA, RNA, and protein synthesis
Clinical Use:
Tinea versicolor
Dermatophytosis (e.g., onychomycosis)
Seborrheic dermatitis of the scalp
Adverse Effects: Facial edema Ventricular tachycardia Skin irritations (should not be applied to the eye or mucous membranes) Pruritus
Griseofulvin
Route of administration → oral
Mechanism:
Binds to keratin precursor cells → accumulation in keratin-rich tissues (e.g., nails, hair) → entry into the fungal cell → interference with microtubule function → disruption of fungal mitosis
Clinical Use:
Dermatophyte infections (e.g., tinea pedis)
Not effective against tinea versicolor
Adverse Effects: Hepatotoxicity Carcinogenicity Teratogenicity Enzyme induction → ↓ concentration of many drugs metabolized by cytochrome P450 (e.g., warfarin) Confusion, headaches Disulfiram-like reaction Urticaria and severe skin reactions (e.g., Stevens-Johnson syndrome)
Contraindications:
Porphyria
Hepatic failure
Eflornithine
Mechanism:
Inhibits ornithine carboxylase, which is required for cell differentiation and proliferation
CNS penetration
Clinical Use: Trypanosoma brucei (not efficient in the treatment of East African sleeping sickness because T. b. rhodesiense has a much higher turnover rate of ornithine carboxylase than T.b. gambiense)
Adverse Effects: Bone marrow toxicity Seizures Hearing loss Alopecia, rash Diarrhea
Nifurtimox
Mechanism:
Not clearly understood
Most likely induces reactions that create oxidative stress
CNS penetration
Clinical Use:
Trypanosoma brucei
Second-line drug in the treatment of Chagas disease (American trypanosomiasis).
Adverse Effects:
Seizures
Cognitive impairment
Melarsoprol
Mechanism:
A prodrug that contains arsenic
Taken up by amino-purine transporters (e.g., P2) of T. brucei → metabolized into an active melarsen oxide → lysis of T. brucei through an unknown mechanism
Only a small amount of melarsoprol (< 1%) enters the CSF.
Clinical Use:
Trypanosoma brucei
Adverse Effects: Post-treatment reactive encephalopathy (PTRE) (clinical manifestations include headache, high fever, tremors, impaired speech, and seizures. In order to prevent PTRE, patients should receive glucocorticoids shortly before initiating therapy and until the end of treatment) Jarisch-Herxheimer reaction Nephrotoxicity Peripheral neuropathy Thrombophlebitis
Suramin
Mechanism:
Not clearly understood
Most likely inhibits enzymes involved in DNA replication and protein synthesis
No CNS penetration
Clinical Use:
Onchocerciasis
Trypanosoma brucei
Adverse Effects: Hypersensitivity (skin test with 100–200 mg of IV eflornithine must be performed before administering suramin) Nephrotoxicity Peripheral neuropathy Hypogonadism among male patients
Sodium stibogluconate
Mechanism:
Inhibits the production of purine triphosphate molecules (e.g. ATP), ultimately stalling the metabolism of Leishmania species.
Clinical Use:
All forms of Leishmaniasis.
Permethrin
5% lotion
Mechanism: Topical application (additionally, ivermectin can be given orally) Blocks the deactivation of Na+ channels → uncontrollable depolarization of neuronal membranes → seizures and ultimately paralysis and death of arthropod Should be applied to every part of the body and left on the skin for 8–12 hours before rinsing off; application may be repeated 1 week later.
Clinical Use:
Scabies (Sarcoptes scabiei)
Lice (Pediculosis capitis, pediculosis pubis)
Adverse Effects:
Pruritus
Erythema
Dimeticone
Mechanism:
Local application in head lice infestation. Dosage is dependent on the hair length.
Penetrates into the respiratory orifice of lice and blocks breathing
Clinical Use:
Lice (Pediculosis capitis)
Adverse Effects:
Pruritus
Erythema
Malathion
Mechanism:
Commonly used as an insecticide in agriculture and public recreation areas
Topical application (additionally, ivermectin can be given orally)
Irreversible acetylcholinesterase inhibitor
Clinical Use:
Scabies (Sarcoptes scabiei)
Lice (Pediculosis capitis, pediculosis pubis)
Adverse Effects:
Carcinogenic
Bendazoles (e.g., albendazole, mebendazole)
Mechanism:
Inhibit microtubule polymerization resulting in:
-Decreased glucose uptake and glycogen synthesis
-Degeneration of mitochondria and endoplasmic reticulum
-Lysosomal release
Clinical Use: Ascariasis Enterobiasis Trichuriasis Strongyloidiasis Hookworm infection Cysticercosis Trichinellosis Toxocariasis
Adverse Effects: Headache GI upset (especially in short term use) Increased liver enzymes Rash, urticaria Hair loss Agranulocytosis
Pyrantel pamoate
Mechanism:
Neuromuscular blocking agents that inhibit the release of acetylcholine and acetylcholinesterase
Clinical Use:
Ascariasis (in pregnant women)
Enterobiasis
Hookworm infection
Adverse Effects: Headache Fever Dizziness Nausea, vomiting Diarrhea Abdominal pain Increased liver enzymes
Praziquantel
Mechanism:
Causes vacuolization of the schistosome integument and increases cell membrane permeability to calcium resulting in paralysis, dislodgement, and death of parasite
A single dose is sufficient for most worms.
Clinical Use: Taeniasis Dyphllobothriasis Schistosomiasis Neurocysticercosis Clonorchiasis Paragonomiasis
Adverse Effects: Nausea, vomiting Abdominal pain Increased liver enzymes Rash, pruritis Joint/muscle pain Headache Seizure
Ivermectin
Mechanism:
Paralyzes parasite by:
-Enhancing γ-aminobutyric acid (GABA) mediated neurotransmission
-Binding to muscle glutamate-gated chloride ion channels → cell hyperpolarization
Clinical Use:
Onchocerciasis
Strongyloidiasis
Hookworm infection
Adverse Effects: Fever Dizziness Tachycardia Hypotension Nausea, vomiting Abdominal pain Rash, pruritis Lymphangitis Joint/muscle pain
Diethylcarbamazine
Mechanism:
Immobilizes microfilariae
Sensitizes the microfilariae to phagocytosis through immobilization
Alteration of surface structure and displacement from the attachment site
Clinical Use:
Loaiasis
Lymphatic filariasis
Adverse Effects: Headache Malaise, weakness Anorexia, vomiting Rash, facial swelling Muscle and joint pain Vision loss Eosinophilia Leukocytosis
Chloroquine/hydroxychloroquine
Mechanism:
The precise mechanisms of action are unknown, but the following are the most widely accepted hypotheses:
-Antimalarial action → drug accumulation in the parasite’s food vacuole → inhibition of heme polymerization (and thus, detoxification) into hemozoin and formation of highly toxic heme-chloroquine complexes → lysis of membranes and death of the parasites
-Antirheumatoid action → interference with antigen processing in macrophages and other APCs → ↓ formation of peptide-MHC protein complexes → ↓ immune response against autoantigenic peptides
Clinical Use:
Treatment and prophylaxis of malaria due to Plasmodium malariae, P. ovale, or P. vivax (strains of P. falciparum are usually resistant)
Rheumatoid arthritis (basic therapy)
Systemic lupus erythematosus and discoid lupus erythematosus (without organ involvement) (hydroxychloroquine is used for therapy as well as prevention of further attacks in these autoimmune conditions)
Porphyria cutanea tarda (in low doses) (chloroquine binds to porphyrins which are then excreted by the kidneys)
Adverse Effects: Gastrointestinal Nausea with cramps (most common) Anorexia Vomiting Visual disturbances: -Irreversible bilateral retinopathy (key fundoscopic feature is bull's eye maculopathy and paracentral scotomata) (incidence of retinopathy from chloroquine and hydroxychloroquine (the less toxic metabolite of chloroquine) increases with both the dose and the duration of treatment) -Blurred vision -Photophobia Pruritus (most commonly seen in dark-skinned individuals) (dark-skinned individuals have a higher amount of melanin. A number of studies have shown that chloroquine preferentially binds to melanocytes. This could be a reason why pruritus especially affects dark-skinned individuals) Photosensitivity Alopecia Whitening of hair Neurologic Myasthenia-like muscle weakness Sensorineural deafness Tinnitus Cranial nerve palsies Torsades de pointes (due to possible QT prolongation), can cause sudden death Thrombocytopenia, leukopenia Worsening of preexisting conditions → epilepsy, psoriasis, porphyria and preexisting retinal damage
Mechanism of Resistance:
Attributed to the development of membrane efflux pumps, which decrease the intracellular concentration of the drug (occurs especially in P. falciparum)
Amantadine
Mechanism:
M2 ion channel blocker (protons flow into the interior of the virus via the M2 ion channel, which leads to viral uncoating. Amantadine blocks these channels, inhibiting the release of the viral genome)
Weak NMDA receptor antagonist (increases dopamine release and blocks dopamine reuptake, reducing bradykinesia in patients with Parkinson disease.)
Clinical Use:
Influenza A (not recommended as first-line treatment, but may be given to patients with oseltamivir-resistant influenza A)
Parkinson disease
Adverse Effects: Ataxia Anxiety Nausea Vomiting Livedo reticularis Peripheral edema
Amantadine only
- Orthostatic dysregulation
- QT interval prolongation
Rimantadine
Mechanism:
M2 ion channel blocker
Clinical Use: Influenza A (not recommended as first-line treatment, but may be given to patients with oseltamivir-resistant influenza A)
Adverse Effects: Ataxia Anxiety Nausea Vomiting Livedo reticularis Peripheral edema
Oseltamivir/Zanamivir
Mechanism:
Neuraminidase inhibitor: blockage of viral budding and prevention of viral dissemination into the bloodstream by inhibiting neuraminidase enzyme
Administration within 2 days of symptom onset is vital to reduce the duration of illness and alleviate symptoms.
Clinical Use:
Treatment of influenza A and B (reduces symptom duration if taken within 1–2 days of symptom onset)
Prophylaxis of influenza in adults and pediatric patients ≥ 5 years of age
Adverse Effects: Upper respiratory tract infections Nausea Vomiting Headache
Peramivir
Mechanism:
Neuraminidase inhibitor: blockage of viral budding and prevention of viral dissemination into the bloodstream by inhibiting neuraminidase enzyme
Administration within 2 days of symptom onset is vital to reduce the duration of illness and alleviate symptoms.
Clinical Use:
Treatment of influenza A and B (reduces symptom duration if taken within 1–2 days of symptom onset)
Prophylaxis of influenza in adults and pediatric patients ≥ 5 years of age
Adverse Effects: Upper respiratory tract infections Nausea Vomiting Headache
Valacyclovir
Valacyclovir (prodrug of acyclovir with greater oral bioavailability)
Mechanism:
Guanosine analogs.
Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells –> few adverse effects.
Triphosphate formed by cellular enzymes.
Preferentially inhibit viral DNA polymerase by chain termination.
Clinical Use:
HSV and VZV. Weak activity against EBV.
No activity against CMV.
Used for HSV- induced mucocutaneous and genital lesions as well as for encephalitis.
Prophylaxis in immunocompromised patients.
Only affects actively replicating viruses and has no effect on latent infections of HSV and VZV.
For herpes zoster, use famciclovir.
Adverse Effects: Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated Thrombotic thrombocytopenic purpura Gastrointestinal symptoms (e.g., nausea) ↑ Transaminases
Mechanism of Resistance:
Mutated viral thymidine kinase.
Penciclovir
Mechanism:
Guanosine analogs.
Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells –> few adverse effects.
Triphosphate formed by cellular enzymes.
Preferentially inhibit viral DNA polymerase by chain termination.
Clinical Use:
HSV and VZV. Weak activity against EBV.
No activity against CMV.
Used for HSV- induced mucocutaneous and genital lesions as well as for encephalitis.
Prophylaxis in immunocompromised patients.
Only affects actively replicating viruses and has no effect on latent infections of HSV and VZV.
For herpes zoster, use famciclovir.
Adverse Effects:
Thrombotic thrombocytopenic purpura
Gastrointestinal symptoms (e.g., nausea)
↑ Transaminases
Mechanism of Resistance:
Mutated viral thymidine kinase.
Famciclovir
Prodrug of penciclovir with greater oral bioavailability
Mechanism:
Guanosine analogs.
Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells –> few adverse effects.
Triphosphate formed by cellular enzymes.
Preferentially inhibit viral DNA polymerase by chain termination.
Clinical Use:
HSV and VZV. Weak activity against EBV.
No activity against CMV.
Used for HSV- induced mucocutaneous and genital lesions as well as for encephalitis.
Prophylaxis in immunocompromised patients.
Only affects actively replicating viruses and has no effect on latent infections of HSV and VZV.
For herpes zoster, use famciclovir.
Adverse Effects:
Thrombotic thrombocytopenic purpura
Gastrointestinal symptoms (e.g., nausea)
↑ Transaminases
Mechanism of Resistance:
Mutated viral thymidine kinase.
Ganciclovir Mechanism
- Guanosine analog (nucleoside analog)
- Phosphorylation to 5’ monophosphate by the CMV-coded UL97 kinase (serine/threonine kinase) → further phosphorylation to triphosphate by cellular kinases
Incorportaion of the phosphorylated drug into the replicating viral DNA strand → inhibition of viral DNA polymerase → termination of viral DNA synthesis - Lower selectivity than acyclovir and penciclovir → inhibition of host cells’ DNA replication → higher toxicity
Valganciclovir
Prodrug of ganciclovir with greater oral availability
Mechanism: Guanosine analog (nucleoside analog) Phosphorylation to 5' monophosphate by the CMV-coded UL97 kinase (serine/threonine kinase) → further phosphorylation to triphosphate by cellular kinases Incorportaion of the phosphorylated drug into the replicating viral DNA strand → inhibition of viral DNA polymerase → termination of viral DNA synthesis Lower selectivity than acyclovir and penciclovir → inhibition of host cells' DNA replication → higher toxicity
Clinical Use:
Systemic treatment of choice for CMV retinitis in immunocompromised patients (e.g., patients with AIDS)
CMV prophylaxis in transplant recipients
Adverse Effects: Myelotoxicity (pancytopenia (additive effect when administered with NRTIs)) Nephrotoxicity Gastrointestinal symptoms (e.g., nausea) CNS Headache Confusion Paresthesias
Mechanism of Resistance:
Mutation of viral UL97 kinase
Foscarnet (pyrophosphate analog)
Mechanism:
Inhibition of DNA/RNA polymerase and HIV reverse transcriptase → direct inhibition of viral DNA polymerases via attachment to the pyrophosphate-binding site of the enzyme
Does not require activation by viral kinase
Clinical Use:
CMV retinitis in immunocompromised patients when ganciclovir fails
Acyclovir-resistant HSV.
Adverse Effects: Nephrotoxicity Gastrointestinal symptoms (e.g., nausea) Headache Confusion Seizures due to electrolyte abnormalities (e.g., hypocalcemia, hypokalemia) Paresthesias Leukopenia Neutropenia
Mechanism of Resistance:
Mutation of viral DNA polymerase
Cidofovir
Mechanism:
Viral DNA polymerase inhibitor with a long half-life
Direct inhibition of viral DNA polymerases
Does not require activation by viral kinase
Clinical Use:
CMV retinitis in immunocompromised individuals (e.g., patients with AIDS)
Acyclovir-resistant HSV
Adverse Effects:
Nephrotoxicity (reduced with administration of probenecid and IV fluids)
Mechanism of Resistance:
Mutation of viral DNA polymerase
Fomivirsen
Mechanism:
Antisense antiviral that blocks translation of viral mRNA (possesses a base sequence that is complementary to CMV mRNA and therefore blocks protein synthesis)
Clinical Use:
Local treatment of CMV retinitis in patients with AIDS (intraocular injection)
Adverse Effects:
Eye infections
Increase in intraocular pressure
Macular edema
Pegylated interferon-α and interferon-α
Mechanism: Antiviral and immunomodulatory effect via intercellular and intracellular mechanisms (interferons bind to cellular receptors via protein kinase R (PKR)) Inhibition of viral protein synthesis Promotion of breakdown of viral RNA Increased expression of MHC class I molecules
Clinical Use:
Monotherapy in acute hepatitis C and chronic active hepatitis B
As a combination treatment in chronic hepatitis C (triple therapy with sofosbuvir, ribavirin, and interferon-α)
Adverse Effects: Flu-like symptoms Bone marrow suppression CNS Depressive mood Seizures Induction of autoantibodies Myopathy
Contraindications: Decompensated cirrhosis Psychiatric conditions Pregnancy Autoimmune conditions Leukopenia or thrombocytopenia
Tenofovir
Mechanism: Nucleotide analog (adenosine analog): phosphorylated to triphosphate in hepatic cells (activation) → binds to viral DNA polymerase → causes premature termination of DNA transcription
Clinical Use:
Chronic active hepatitis B
HIV
Adverse Effects:
Nephrotoxicity (e.g., Fanconi syndrome)
Headache and abdominal pain
Disease exacerbation is possible.
Adefovir
Mechanism: Nucleotide analog (adenosine analog): phosphorylated to triphosphate in hepatic cells (activation) → binds to viral DNA polymerase → causes premature termination of DNA transcription
Entecavir
Mechanism:
Nucleoside analog: inhibition of reverse transcriptase
Clinical Use:
Frst-line drug in hepatitis B infection because of its potent antiviral activity and its low drug resistance rate
HIV
Adverse Effects: Occasional -Gastrointestinal symptoms -Fever -Headache Rare -Vasculitides -Neuropathies -Neutropenia -Lactic acidosis
Lamivudine
Mechanism:
Nucleoside analog: inhibition of reverse transcriptase
Clinical Use:
Chronic active hepatitis B (third-line treatment due to high rate of resistance).
HIV
Adverse Effects: Adverse Effects: Occasional -Gastrointestinal symptoms -Fever -Headache Rare -Vasculitides -Neuropathies -Neutropenia -Lactic acidosis
Telbivudine
Mechanism:
Nucleoside analog: inhibition of reverse transcriptase
Clinical Use:
Chronic active hepatitis B
HIV
Adverse Effects: Occasional -Gastrointestinal symptoms -Fever -Headache Rare -Vasculitides -Neuropathies -Neutropenia -Lactic acidosis
Glecaprevir
Mechanism:
NS3/4A protease inhibitors
Inhibition of NS3/4A (an HCV serine protease required for viral replication) → ↓ viral replication
Available and used in combination with NS5A inhibitor pibrentasvir.
Clinical Use:
Chronic hepatitis C infection (all genotypes)
Adverse Effects:
Headache
Fatigue
Nausea
Grazoprevir
Mechanism:
NS3/4A protease inhibitors
Inhibition of NS3/4A (an HCV serine protease required for viral replication) → ↓ viral replication
Available and used in combination with NS5A inhibitor elbasvir.
Clinical Use:
Chronic hepatitis C infection (genotypes 1a, 1b, and 4)
Adverse Effects:
Headache
Fatigue
Nausea
Paritaprevir
Mechanism:
NS3/4A protease inhibitors
Inhibition of NS3/4A (an HCV serine protease required for viral replication) → ↓ viral replication
Only available in combination with ombitasvir, ritonavir, and dasabuvir.
Clinical Use:
Chronic hepatitis C infection (genotype 1 or 4)
Adverse Effects: Headache Fatigue Nausea Insomnia Asthenia Pruritus Allergic skin reactions
Simeprevir
Mechanism:
NS3/4A protease inhibitors
Inhibition of NS3/4A (an HCV serine protease required for viral replication) → ↓ viral replication
Clinical Use:
Chronic hepatitis C infection (as part of triple antiviral combination, in addition to peginterferon-α and ribavirin)
Adverse Effects: Photosensitivity Rash Fatigue Headache Abdominal pain Diarrhea
Voxilaprevir
Mechanism:
NS3/4A protease inhibitors
Inhibition of NS3/4A (an HCV serine protease required for viral replication) → ↓ viral replication
Available and used in combination with sofosbuvir and velpatasvir in patients with initial treatment failure.
Clinical Use:
Chronic hepatitis C infection (all genotypes)
Adverse Effects: Headache Fatigue Diarrhea Nausea
Daclatasvir
Mechanism:
Non-nucleoside NS5A polymerase inhibitors
Exact mechanism of action is unknown
Inhibition of the viral NS5A phosphoprotein, which is essential for replication → prevention of HCV RNA replication
Clinical Use:
Chronic hepatitis C infection
Adverse Effects: Headache Fatigue Diarrhea Nausea
Elbasvir
Mechanism:
Non-nucleoside NS5A polymerase inhibitors
Exact mechanism of action is unknown
Inhibition of the viral NS5A phosphoprotein, which is essential for replication → prevention of HCV RNA replication
Clinical Use:
Chronic hepatitis C infection
Adverse Effects: Headache Fatigue Diarrhea Nausea
Ledipasvir
Mechanism:
Non-nucleoside NS5A polymerase inhibitors
Exact mechanism of action is unknown
Inhibition of the viral NS5A phosphoprotein, which is essential for replication → prevention of HCV RNA replication
Clinical Use:
Chronic hepatitis C infection
Adverse Effects: Headache Fatigue Diarrhea Nausea
Ombitasvir
Mechanism:
Non-nucleoside NS5A polymerase inhibitors
Exact mechanism of action is unknown
Inhibition of the viral NS5A phosphoprotein, which is essential for replication → prevention of HCV RNA replication
Clinical Use:
Chronic hepatitis C infection
Adverse Effects: Headache Diarrhea Fatigue Nausea Insomnia Asthenia Pruritus Skin reactions
Pibrentasvir
Mechanism:
Non-nucleoside NS5A polymerase inhibitors
Exact mechanism of action is unknown
Inhibition of the viral NS5A phosphoprotein, which is essential for replication → prevention of HCV RNA replication
Clinical Use:
Chronic hepatitis C infection
Adverse Effects: Headache Fatigue Nausea Diarrhea
Velpatasvir
Mechanism:
Non-nucleoside NS5A polymerase inhibitors
Exact mechanism of action is unknown
Inhibition of the viral NS5A phosphoprotein, which is essential for replication → prevention of HCV RNA replication
Clinical Use:
Chronic hepatitis C infection
Adverse Effects:
Headache
Diarrhea
Fatigue
Dasabuvir
Mechanism:
NS5B inhibitors
Inhibition of NS5B (a RNA-dependent RNA polymerase) → chain termination and disruption of RNA synthesis → prevention of HCV replication
Clinical Use:
Chronic hepatitis C infection
Adverse Effects: Fatigue Headache Insomnia Pruritus Asthenia Nausea
Baloxavir
Mechanism:
Inhibits the “cap snatching” endonuclease activity of the influenza virus RNA polymerase viral replication.
Clinical Use:
Treatment within 48 hours of symptom onset shortens duration of illness.
Remdesivir
Mechanism:
Prodrug of an ATP analog.
The active metabolite inhibits viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN) –> decrease viral RNA production.
Clinical Use:
Recently approved for treatment of COVID-19 requiring hospitalization.
Zidovudine (ZDV, formerly AZT)
Mechanism:
NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3’ to 5’ phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Clinical Use:
HIV
Adverse Effects: Bone marrow suppression → anemia (especially zidovudine), neutropenia Mitochondrial toxicity (myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis) HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat (loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities; metabolic changes → impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL); probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump))
Resistance:
Caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Lamivudine (3TC)
Mechanism:
NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3’ to 5’ phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Clinical Use:
HIV
Adverse Effects: Bone marrow suppression → anemia (especially zidovudine), neutropenia Mitochondrial toxicity (myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis) HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat (loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities; metabolic changes → impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL); probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump))
Resistance:
Caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Emtricitabine (FTC)
Mechanism:
NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3’ to 5’ phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Clinical Use:
HIV
Adverse Effects: Bone marrow suppression → anemia (especially zidovudine), neutropenia Mitochondrial toxicity (myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis) HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat (loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities; metabolic changes → impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL); probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump))
Resistance:
Caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Abacavir (ABC)
Mechanism:
NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3’ to 5’ phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Clinical Use:
HIV
Adverse Effects: Bone marrow suppression → anemia (especially zidovudine), neutropenia Mitochondrial toxicity (myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis) Abacavir-related hypersensitivity syndrome (potentially life-threatening systemic reaction with fever and maculopapular rash). Abacavir should be avoided in HLA-B*57:01-positive patients HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat (loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities; metabolic changes → impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL); probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump))
Resistance:
Caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Stavudine (d4T)
Mechanism:
NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3’ to 5’ phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Clinical Use:
HIV
Adverse Effects:
Bone marrow suppression → anemia (especially zidovudine), neutropenia
Mitochondrial toxicity (myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis)
Pancreatitis (didanosine/stavudine)
HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat (loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities; metabolic changes → impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL); probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump))
Resistance:
Caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Didanosine (ddI)
Mechanism:
NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3’ to 5’ phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
Activation requires intracellular phosphorylation, thus their efficacy is reliant on kinase availability and activity, which varies depending on cell functionality and activation state.
Clinical Use:
HIV
Adverse Effects:
Bone marrow suppression → anemia (especially zidovudine), neutropenia
Mitochondrial toxicity (myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis)
Pancreatitis (didanosine/stavudine)
HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat (loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities; metabolic changes → impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL); probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump))
Resistance:
Caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Tenofovir
Nucleotide analog, also called nucleotide reverse-transcriptase inhibitor (NtRTI)
Mechanism:
NRTIs act as nucleoside analogs → competitive blockage of nucleoside binding to reverse transcriptase → inhibition of formation of 3’ to 5’ phosphodiester linkages → termination of DNA chain → inhibition of RNA to DNA reverse transcription
Clinical Use:
HIV
Adverse Effects: Bone marrow suppression → anemia (especially zidovudine), neutropenia Mitochondrial toxicity (myopathy, peripheral neuropathy, hepatic steatosis, lactic acidosis) HIV-associated lipodystrophy (Cushing-like syndrome): abnormal distribution of fat (loss of subcutaneous fatty tissue (lipoatrophy) in face and extremities; metabolic changes → impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL); probable accumulation of fat in liver, muscles, abdomen, breasts, and neck (buffalo hump)) Tenofovir → nephrotoxicity (proximal tubular dysfunction, acute tubular necrosis, and subsequent acute kidney injury. Affected individuals show elevated creatinine, subnephrotic proteinuria, and glycosuria. Discontinuation lead to significant recovery and suggests reversibility of the toxic tenofovir effects.)
Resistance:
Caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Nevirapine
Mechanism:
Noncompetitive inhibitors of viral reverse transcriptase (NNRTIs) that bind to the reverse transcriptase at a different location than NRTIs
NNRTIs do not require intracellular phosphorylation for activation but are instead direct inhibitors.
Clinical Use:
HIV-1 (NOT HIV-2)
Adverse Effects:
Hepatotoxicity (nevirapine)
Hypersensitivity reactions: rash, Stevens-Johnson syndrome
Efavirenz
Mechanism:
Noncompetitive inhibitors of viral reverse transcriptase (NNRTIs) that bind to the reverse transcriptase at a different location than NRTIs
NNRTIs do not require intracellular phosphorylation for activation but are instead direct inhibitors.
Clinical Use:
HIV-1 (NOT HIV-2)
Adverse Effects:
CNS toxicity and vivid or disturbing dreams (efavirenz)
Hypersensitivity reactions: rash, Stevens-Johnson syndrome
Delavirdine
Mechanism:
Noncompetitive inhibitors of viral reverse transcriptase (NNRTIs) that bind to the reverse transcriptase at a different location than NRTIs
NNRTIs do not require intracellular phosphorylation for activation but are instead direct inhibitors.
Clinical Use:
HIV-1 (NOT HIV-2)
Adverse Effects:
Hypersensitivity reactions: rash, Stevens-Johnson syndrome
HIV Protease Inhibitors
Indinavir, Ritonavir, Nelfinavir, Lopinavir, Atazanavir, Darunavir, Fosamprenavir, Saquinavir
Mechanism:
Inhibition of viral HIV-1 protease (encoded by pol gene) → inability to cleave viral mRNA into functional units → generation of impaired viral proteins → production of immature (noninfectious) virions
Clinical Use:
HIV
Adverse Effects:
GI upset (nausea, diarrhea)
Lipodystrophy and fat accumulation (are far more likely to cause fat accumulation than other ARTs)
Nephrolithiasis, crystal-induced nephropathy, and hematuria
Thrombocytopenia (indinavir)
Hyperglycemia (inhibition of insulin-dependent glucose transporters (GLUT 4) → peripheral insulin resistance → impaired glucose tolerance)
Ritonavir can be used to increase concentrations of other drugs since it inhibits cytochrome P450.
Integrase Inhibitors
Raltegravir, Dolutegravir, Bictegravir, Elvitegravir
Mechanism:
Inhibition of the viral integrase → blockade of viral DNA integration into the host’s DNA → inhibition of viral replication
Clinical Use:
HIV
Adverse Effects:
↑ creatine kinase
Enfuvirtide
Mechanism:
Inhibit binding or fusion of HIV virions with human cells.
Fusion inhibitor
Competitively binds to the viral protein gp41 and thereby prevents fusion with the cell
Clinical Use:
HIV-1 (NOT HIV-2)
Adverse Effects:
Skin irritation at the site of drug injection
Maraviroc
Mechanism:
Blocks the CCR5 coreceptor on T cells and monocytes that is essential to cell infection for some HIV genotypes (R5 HIV-1) → inhibits gp120 interaction → prevents virus docking
Clinical Use:
HIV
Adverse Effects:
Hepatotoxicity, allergic reactions
Cobicistat
Mechanism:
CYP3A4 inhibitor
Clinical Use:
Pharmacokinetic enhancement of antiretroviral therapy for HIV infection.
Decreases the breakdown of certain antiretroviral, including darunavir and atazanavir.
Ganciclovir Clinical Use
- Systemic treatment of choice for CMV retinitis in immunocompromised patients (e.g., patients with AIDS)
CMV prophylaxis in transplant recipients
Ganciclovir Adverse Effects
- Myelotoxicity (pancytopenia (additive effect when administered with NRTIs))
- Nephrotoxicity
- Gastrointestinal symptoms (e.g., nausea)
- Headache
- Confusion
- Paresthesias
Ganciclovir Mechanism of Resistance
Mutation of viral UL97 kinase
Azithromycin Clinical Use
Macrolide IV or oral form Poor CNS penetration poor Route of elimination → biliary All macrolides (except azithromycin) have a short half-li fe.
- Atypical pneumonia caused by Mycoplasma pneumonia, Legionella pneumophila, Chlamydophila pneumoniae
- Bordetella pertussis
- STIs caused by Chlamydia
- Gram-positive cocci especially for the treatment of streptococcal infection in patients who are allergic to penicillin
- Neisseria spp.
- Second-line prophylaxis for N. meningitidis
- Dual therapy with ceftriaxone for N. gonorrhoeae (azithromycin)
- Mycobacterium avium (prophylaxis: azithromycin; treatment → azithromycin, clarithromycin)
- Ureaplasma urealyticum
- Babesia spp. (azithromycin in combination with atovaquone)
Azithromycin Adverse Effects
Macrolide IV or oral form Poor CNS penetration poor Route of elimination: biliary All macrolides (except azithromycin) have a short half-life.
- Increased intestinal motility → GI upset
- QT-interval prolongation, arrhythmia
- Acute cholestatic hepatitis
- Eosinophilia
- Rash
Contraindications:
Azithromycin and clarithromycin are contraindicated in patients with hepatic failure (erythromycin should be used cautiously).
Azithromycin Mechanism of Resistance
Macrolide IV or oral form Poor CNS penetration poor Route of elimination: biliary All macrolides (except azithromycin) have a short half-life.
Methylation of the binding site of 23S rRNA prevents the macrolide from binding to rRNA.
Carbapenems Adverse Effects
IV imipenem (combined with cilastatin)
IV meropenem
IV ertapenem
IV doripenem
Imipenem is always given with cilastatin, which inhibits human dehydropeptidase I (a renal tubular enzyme that breaks down imipenem).
Meropenem is stable to dehydropeptidase I.
- Secondary fungal infections
- CNS toxicity (can lower seizure threshold at high serum concentrations) (highest risk → imipenem; lowest risk → meropenem)
- Gastrointestinal upset
- Rash
- Thrombophlebitis
Carbapenems Mechanism of Resistance
IV imipenem (combined with cilastatin)
IV meropenem
IV ertapenem
IV doripenem
Imipenem is always given with cilastatin, which inhibits human dehydropeptidase I (a renal tubular enzyme that breaks down imipenem).
Meropenem is stable to dehydropeptidase I.
- Inactivation by carbapenemase (type of β-lactamase produced by carbapenemase-producing Enterobacteriaceae (e.g., E. coli, K. pneumoniae, K. aerogenes))
