Overview of antibiotic therapy

Antibiotics are a class of drugs employed mainly against bacterial infections. Some antibiotics are also used against parasitic infections. Antibiotics can have bacteriostatic (i.e., stopping bacterial reproduction), bactericidal (i.e., killing bacteria), or both mechanisms of action. Antibiotics are effective against either a small group of bacteria (narrow-spectrum) or a wide range of pathogens (broad-spectrum). Most antibiotics work by inhibiting cell wall synthesis, protein synthesis, or certain enzymes (e.g., THF, RNA-polymerase) in bacteria. Common side effects of antibiotic treatment include hypersensitivity reactions, as well as nephrotoxic and hepatotoxic effects. Many antibiotics are contraindicated in certain patient groups (e.g., children, pregnant and/or breastfeeding women). In the case of severe infection, one or more antibiotics may be initiated without waiting for a microbiological confirmation (empiric antibiotic therapy) to target the most likely pathogens. Antibiotics are widely used because they are instrumental in the management of infectious diseases; however, use of antibiotics without valid indications and with inappropriate dosages and timing has led to the emergence of antibiotic-resistant pathogens (e.g., MRSA, Pseudomonas).

Definitions

• Antibiotics: antimicrobial drugs effective against bacteria
• Bactericidal drug: a substance that kills bacteria (e.g., β-lactams, glycopeptides, epoxides)
  • Some antibiotics are only effective if used:
    • In combination (e.g., sulfonamides combined with diaminopyrimidine; streptogramin A combined with streptogramin B
    • Against certain pathogens (e.g., oxazolidinones are only bactericidal against Streptococci)
    • In higher concentrations (e.g., amphenicols)
• Bacteriostatic drug: a substance that slows bacterial growth or stops bacterial reproduction (e.g., tetracyclines, glycylcyclines, macrolides)
  • Some antibiotics are bacteriostatic only against certain pathogens (e.g., glycopeptides against C. difficile).
  • Some antibiotics can be both bactericidal and bacteriostatic (e.g., dapsone ).
  • Antibiotics that are interfering with bacterial protein synthesis target the subunits (30S and 50S) of bacterial ribosomes (70S) and do not affect human ribosomes (80S).

As a general rule, agents that inhibit cell wall synthesis are bactericidal (except ethambutol), while those that inhibit protein synthesis are bacteriostatic (except rifamycins, and aminoglycosides).

Overview ^[1][2]

AcTions at 30, CELebrationS at 50: Aminoglycosides and Tetracyclines are 30S inhibitors; Chloramphenicol/Clindamycin, macrolides (e.g., Erythromycin), Linezolid, and Streptogramin are 50S inhibitors.

All protein synthesis inhibitors are bacteriostatic, except aminoglycosides (bactericidal) and linezolid (can be either bactericidal or bacteriostatic depending on concentration).

Beta-lactams

• Definition: : a group of antibiotics that contains beta-lactam ring in their molecular structure; and includes penicillins, carbapenems, monobactams, and cephalosporins
• Mechanism of action
  • Inhibit cell wall synthesis by blocking peptidoglycan crosslinking
    • β-lactam mimics the D-ala-D-ala structure of bacterial peptidoglycan residue.
    • β-lactam irreversibly binds to penicillin-binding proteins (PBPs) which act as transpeptidases → stalled cross-linking of peptidoglycan in cell wall; (β-lactam cannot be cleaved) → inability to synthesize new cell wall during replication → bacterial death (bactericidal effect)
  • Activate autolytic enzymes ^[9]
• CNS penetration
  • Only when meninges are inflamed
  • Exceptions: ceftriaxone and aztreonam always have good CNS penetration.
• Route of elimination
  • Primarily renal (via tubular secretion)
  • Exceptions
    • Primarily biliary: nafcillin
    • Both renal and biliary: other anti-staphylococcal penicillins (e.g., oxacillin, dicloxacillin), ceftriaxone
• General adverse effects
  • Jarisch-Herxheimer reaction (e.g., in treatment of syphilis)
  • Hypersensitivity reactions

Beta-lactamase inhibitors

• β-lactamases
  • Are usually produced by gram-negative and anaerobic organisms
  • Can split the β-lactam ring and render certain β-lactam antibiotics ineffective
• β-lactamase inhibitors
  • 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
• Examples
  • Clavulanate (combined with amoxicillin)
  • Avibactam (combined with ceftazidime)
  • Sulbactam (combined with ampicillin)
  • Tazobactam (combined with piperacillin)

CATS: Clavulanate, Avibactam, Tazobactam, Sulbactam are β-lactamase inhibitors.

Natural penicillins (prototype beta-lactam antibiotics)

• Examples
  • Penicillin G (benzylpenicillin)
    • IV: crystalline penicillin G
    • IM: procaine penicillin G, benzathine penicillin G
  • Oral: penicillin V (phenoxymethylpenicillin)
• Clinical use
  • Gram-positive aerobes (esp. Streptococcus pyogenes, Streptococcus pneumoniae)
  • Gram-negative cocci (esp. Neisseria meningitidis)
  • Spirochetes (esp. Treponema pallidum)
  • Branching gram-positive anaerobes (especially Actinomyces)
• Adverse effects
  • Hypersensitivity reactions
  • Hemolytic anemia positive direct Coombs test
  • Drug-induced interstitial nephritis
  • Seizures ^[10]
• Mechanisms of resistance
  • Cleavage of the β-lactam ring by β-lactamases (penicillinases)
  • PBP mutations

Penicillinase-resistant penicillins

• Examples (oral or IV)
  • Nafcillin
  • Dicloxacillin
  • Oxacillin
  • Floxacillin
  • Methicillin
• Special characteristics: intrinsically β-lactamase resistant through the addition of bulky side chains (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.
• Adverse effects
  • 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)

Use NAF (nafcillin) for STAPH (S. aureus).

Aminopenicillins (penicillinase-sensitive penicillins)

• Examples
  • Oral or IV: amoxicillin (combined with clavulanate; )
  • IV or IM: ampicillin (with or without sulbactam)
• Special characteristics
  • 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
• Clinical use: broader spectrum of activity than penicillin (extended-spectrum penicillin)
  • Gram-positive aerobes
  • Gram-negative rods (not effective against Enterobacter spp.)
  • Most effective against:
    • H. pylori
    • H. influenzae
    • E. coli
    • Listeria monocytogenes
    • Proteus mirabilis
    • Salmonella
    • Shigella
    • Enterococci
    • Spirochetes
• Adverse effects
  • Diarrhea
  • Pseudomembranous colitis
  • Hypersensitivity reactions
  • Drug-induced rash
  • Possibly acute interstitial nephritis
• Mechanisms of resistance: cleavage of the β-lactam ring by penicillinases

AmOxicillin is administered Orally, while amPicillin is administered by a Prick!

Aminopenicillin therapy HHEELPSSS against H. influenzae, H. pylori, E. coli, Enterococci, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, Spirochetes.

Antipseudomonal penicillins

• Examples
  • IV ureidopenicillins: piperacillin (combined with tazobactam) , mezlocillin
  • IV carboxypenicillins (e.g., ticarcillin)
  • PO carbenicillin
• Clinical use: extended spectrum but penicillinase-sensitive
  • Gram-negative rods, especially Pseudomonas
  • Also effective against anaerobes (e.g., Bacteroides fragilis)
  • Gram-positive aerobes: not effective against S. viridans
• Adverse effects: hypersensitivity reactions

The PIPER in his CAR full of TICks ran over Pseudomonas: PIPERacillin, CARbenicillin, and TICarcillin are antipseudomonals.

• Examples
  • IV imipenem (combined with cilastatin)
  • IV meropenem
  • IV ertapenem
  • IV doripenem
• Special characteristics
  • 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.
• Clinical use
  • 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 and Enterococcus faecium, which are intrinsically resistant)
    • Gram-negative rods, including Pseudomonas aeruginosa (except ertapenem which has limited activity against Pseudomonas)
    • Anaerobes
• Adverse effects
  • Secondary fungal infections ^[11]
  • CNS toxicity: can lower seizure threshold at high serum concentrations
    • Highest risk: imipenem
    • Lowest risk: meropenem
  • Gastrointestinal upset
  • Rash
  • Thrombophlebitis ^[12]
• Mechanism of resistance: inactivation by carbapenemase
  • A type of β-lactamase
  • Produced by carbapenemase-producing Enterobacteriaceae (e.g., E. coli, K. pneumoniae, K. aerogenes)

Get a kill that is lastin' with imipenem plus cilastatin.

don't DIe on ME: Doripenem, lmipenem, Meropenem, and Ertapenem are carbapenems and used in life-threatening infections.

• Examples: : IV aztreonam
• Special characteristics:
  • Specifically binds to PBP3: inhibits peptidoglycan cross-linking ^[13]
  • Less susceptible to β-lactamases
• Clinical use
  • Effective against gram-negative bacteria only , including nosocomial Pseudomonas, H. influenzae, and N. meningitidis
  • Not effective against gram-positive rods or anaerobes
  • Alternative for penicillin-allergic patients (no cross-sensitivity with penicillins)
  • Can be used as an alternative to aminoglycosides for patients with renal insufficiency because it is synergistic with aminoglycosides
  • Broad-spectrum coverage in combination with vancomycin or clindamycin
• Adverse effects: rare
  • GI upset
  • Injection reactions
  • Rash

• Special characteristics: less susceptible to penicillinases
• Adverse effects
  • Potential cross-reactivity in patients with penicillin allergies (the rate is low even in patients with allergy to penicillin)
  • Autoimmune hemolytic anemia (AIHA) ^[14]
  • Vitamin K deficiency, which increases the risk of bleeding ^[15][16]
  • Disulfiram-like reaction, especially when consumed with alcohol (flushing, tachycardia, hypotension)
  • Increases nephrotoxic effect of aminoglycosides when administered together with cephalosporins
  • Neurotoxicity (can lower seizure threshold) ^[17]
  • In neonates: hyperbilirubinemia (ceftriaxone)
• Mechanisms of resistance
  • Inactivation by cephalosporinase (a type of β-lactamase)
  • Change in transpeptidase (PBP) structure

1 PEcK: 1^st generation cephalosporins cover Proteus mirabilis, E. coli, Klebsiella pneumoniae.
2 HENS PEcK: 2^nd generation cephalosporins cover H. influenzae, Enterobacter aerogenes (now Klebsiella aerogenes), Neisseria, Serratia marcescens, Proteus mirabilis, E. coli, Klebsiella pneumoniae.

2^nd graders wear fake fox fur to tea parties: 2^nd generation cephalosporins include cefaclor, cefoxitin, cefuroxime, and cefotetan.

Cephalosporins are LAME: 1^st–4^th generation cephalosporins do not act against Listeria, Atypical organisms (e.g., Chlamydia, Mycoplasma), MRSA, and Enterococci (with the exception of ceftaroline, which does act against MRSA).

• Examples
  • Oral or IV vancomycin, teicoplanin
  • Topical bacitracin
• Mechanism of action
  • 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
  • Is 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
• Adverse effects
  • Intravenous administration
    • Nephrotoxicity
    • Ototoxicity/vestibular toxicity
    • Thrombophlebitis
    • Vancomycin flushing reaction: an anaphylactoid reaction caused by rapid infusion of vancomycin
      • Nonspecific mast cell degranulation → rapid release of histamine
      • Symptoms
        • Diffuse flushing of the skin, pruritus mainly of the upper body
        • Muscle spasms and pain in the back and chest
        • Possible hypotension and dyspnea ^[18]
      • Can be prevented by slowing the rate of infusion and pretreating with antihistamines
    • DRESS syndrome ^[19]
    • Neutropenia ^[20]
    • Dysgeusia and gastrointestinal side effects (e.g., nausea, vomiting, abdominal pain)
  • Oral administration: predominantly dysgeusia and gastrointestinal side effects
• Contraindications: Consider use in pregnant women only if the benefits outweigh the risks. ^[21]
• 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

The vancomycin van carries a TON of flashy DRESSes: the side effects of vancomycin are Thrombophlebitis, Ototoxicity, Nephrotoxicity, vancomycin flushing reaction, and DRESS syndrome.

The fine for VANdalism is one DALlAr in LACjac: VANcomycin resistance is caused by amino acid modification (D-Ala-D-Ala to D-Ala-D-Lac).

• Examples: : oral and IV fosfomycin
• Mechanism of action: : 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) ^[22]
• Route of elimination: renal
• Clinical use: : women with uncomplicated urinary tract infections (e.g., cystitis due to E. coli or E. faecalis) ^[3][23]
• Adverse effects
  • Mild electrolyte imbalances (e.g., hypernatremia, hypokalemia)
  • Diarrhea ^[3]
• Contraindications: hypersensitivity
• Mechanisms of resistance: MurA mutations ^[24]

• Examples: daptomycin
• Mechanism of action: 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) ^[25]
• 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) ^[25]
• Adverse effects
  • Reversible myopathy
  • Rhabdomyolysis
  • Allergic pneumonitis ^[26]
• Contraindications: hypersensitivity
• Mechanisms of resistance: repulsion of daptomycin molecules due to the change in the bacterial surface charge ^[27]

Dap-to-my-cin is good to my skin: daptomycin is used to treat skin infections.

• Examples
  • IV or IM polymyxin B
  • IV or IM polymyxin E (colistin) ^[28]
• Mechanism of action
  • A 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.
  • Not effective against gram-positive bacteria
  • Topical antibiotics: triple antibiotic ointment; (bacitracin, neomycin, and polymyxin B) for superficial skin infections
  • Oral polymyxin B may be used to disinfect the bowel to prevent ICU infections
• Adverse effects
  • Nephrotoxicity
  • Neurotoxicity; (e.g., paresthesias, weakness, speech disorders, neuromuscular blockage)
  • Urticaria, eosinophilia, and/or anaphylactoid reactions ^[29]
  • Respiratory failure
• Contraindications:
  • Hypersensitivity to polymyxins
  • Cautious use in patients with renal dysfunction

• Examples
  • IV or IM gentamicin
  • IV or IM amikacin
  • IV or IM tobramycin
  • IV or IM streptomycin
  • Oral neomycin
  • Capreomycin
  • Kanamycin
• Mechanism of action
  • 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
• CNS penetration: poor
• Route of elimination: renal (via glomerular filtration)
• Clinical use ^[30]
  • 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
• Adverse effects
  • Nephrotoxicity
  • Ototoxicity and vestibulotoxicity (risk of ototoxicity is higher when used concurrently with loop diuretics) resulting in:
    • Tinnitus
    • Ataxia
    • Vertigo
  • Neuromuscular blockade
  • 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

Me and my NEw AMIgA are taking GENeral STEPs to AMeliorate our TOBacco intake but are still unsuccessful: NEomycin, AMIkAcin, GENtamicin, STrEPtomycin AMinoglycosides, and TOBramycin are unsuccessful in killing anaerobes.

Ah, MI(y) NEPHew's OTter keeps TERrorizing our block: the side effects of AMInoglycosides include NEPHrotoxicity, OTotoxicity, TERatogenicity, and neuromuscular blockade.

• Examples
  • Oral or IV minocycline
  • Oral or IV tetracycline
  • Oral doxycycline
  • Oral demeclocycline
• Mechanism of action: bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome acceptor site → inhibition of bacterial protein synthesis (bacteriostatic effect)
• 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)
• 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
  • Other: Ehrlichia, Vibrio cholerae, Francisella tularensis
  • Cutibacterium acnes (oral doxycycline is used to treat acne) ^[31]
  • Community-acquired MRSA (doxycycline)
• Special considerations
  • 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.
  • CNS penetration is limited
• 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) ^[32]
  • Degraded tetracyclines are associated with Fanconi syndrome. ^[33]
  • Rarely: pseudotumor cerebri ^[34]
• Contraindications
  • Children < 8 years of age (except doxycycline) ^[35]
  • Pregnant women
  • Breastfeeding women
  • 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.

Teethracyclines: teeth discoloration is a side effect of tetracyclines.

• Examples: tigecycline
• Mechanism of action ^[36]
  • Tetracycline derivate ^[4]
  • Bind to 30S subunit ; → blockage of entry of amino-acyl tRNA into ribosomal A site → inhibition of protein synthesis (bacteriostatic effect) ^[4]
• CNS penetration: poor
• Route of elimination: mostly biliary
• Clinical use
  • Gram-positive aerobes (not effective against S. viridans or Enterococci; limited efficacy against MSSA)
  • MRSA
  • VRE
  • Anaerobes (broad spectrum)
  • Partially effective against gram-negative aerobes (no effect against Proteus species)
  • Gram-intermediate bacteria: Borrelia, Mycoplasma, Rickettsia, Chlamydia ^[37][38]
• Special considerations
  • Good soft tissue penetration: effective for treating deep tissue infections
  • Glycylcyclines should not be taken with milk, antacids, or iron supplements because divalent cations inhibit the absorption of glycylcyclines in the intestines.
• Adverse effects ^[4]
  • GI upset (nausea, vomiting)
  • Hepatotoxicity
  • Deposition in bones and teeth
  • Photosensitivity
• Contraindications ^[39]
  • Children < 8 years of age
  • Pregnant women
  • Breastfeeding women
  • Cautious use in patients with hepatic dysfunction

• Examples
  • Oral or IV: erythromycin, azithromycin, clarithromycin
  • Oral: Roxithromycin
• Mechanism of action: bind to 23S ribosomal RNA molecule of the 50S subunit → blockage of translocation → inhibition of bacterial protein synthesis; (bacteriostatic effect)
• CNS penetration: poor
• Route of elimination: biliary
• Clinical use
  • Atypical pneumonia caused by:
    • Mycoplasma pneumonia
    • Legionella pneumophila
    • Chlamydia 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)
• Adverse effects
  • Increased intestinal motility → GI upset
  • QT-interval prolongation; , arrhythmia
  • Acute cholestatic hepatitis
  • Rash
  • Increased risk of hypertrophic pyloric stenosis (erythromycin and azithromycin) in infants up to 6 weeks of age ^[40]
• Drug interactions
  • Erythromycin enhances the effect of oral anticoagulants (e.g., warfarin).
  • Erythromycin and clarithromycin
    • Increased theophylline serum concentrations ^[41]
    • CYP3A4 inhibition (cytochrome P450 inhibitors)
• Special considerations
  • All macrolides (except azithromycin) have a short half-life.
  • Erythromycin is used off-label for the treatment of gastroparesis because it increases GI motility.
• Contraindications ^[42][43][44]
  • Erythromycin estolate and clarithromycin are contraindicated in pregnant women (potentially hazardous to the fetus)
    • Erythromycin estolate use in pregnant women during the first trimester is associated with an increased risk of hepatic failure in the women.
    • All the other forms of erythromycin (e.g., ethyl succinate, stearate, etc.) can be safely used.
  • Azithromycin and clarithromycin are contraindicated in patients with hepatic failure (erythromycin should be used cautiously).
  • Consider use of erythromycin in children < 12 years of age only if benefits outweigh the risks, as safety in this population has not been established.
  • Consider use of clarithromycin and azithromycin in children < 6 months of age only if benefits outweigh the risks, as safety in this population has not been established.
  • Cautious use in breastfeeding women
  • 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.

Macroslides: macrolides inhibit translocation during protein synthesis, in which ribosomes slide along mRNA.

The adverse effects of MACROlides include gastrointestinal Motility issues, Arrhythmia (due to prolonged QT interval), acute Cholestatic hepatitis, Rash, and eOsinophilia.

• Examples: clindamycin
• Mechanism of action: 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
• Clinical use
  • Anaerobes, such as Clostridium perfringens, Bacteroides spp. (clindamycin is less effective against Bacteroides than other anaerobic species)
    • Aspiration pneumonia
    • Lung abscesses
    • Oral infections
  • Group A streptococcus: especially invasive infections
  • Partially effective against gram-positive aerobes
    • Can be used in MRSA infections
    • Not effective against Enterococci
  • Babesia (together with quinine) ^[45]
• Special considerations: cross-resistance with macrolides
• Adverse effects
  • GI upset (e.g., diarrhea)
  • Pseudomembranous colitis
  • Fever
  • Teratogenicity ^[46]
• Contraindications: cautious use in pregnant patients during the 1^st trimester and in breastfeeding patients ^[47]

• Examples: IV quinupristin-dalfopristin
• Mechanism of action ^[48]
  • Synergistic effect
    • Dalfopristin
      • Inhibits the early phase of protein synthesis
      • Binds to 23S portion of 50S subunit → change of conformation → enhanced binding of quinupristin
      • Inhibits peptidyl transferase
    • Quinupristin
      • Inhibits the late phase of protein synthesis
      • Binds to 50S subunit → elongation of polypeptide is prevented → release of incomplete chains ^[5]
  • Bacteriostatic when used separately, but bactericidal when used in combination ^[49]
• Route of elimination: biliary and renal ^[50]
• Clinical use
  • Skin and skin structure infection with:
    • S. aureus (methicillin-susceptible and resistant)
    • S. pyogenes
    • Vancomycin-resistant E. faecium
  • Not effective against E. faecalis ^[5][51][52]
• Special considerations: inhibits CYP3A4 ^[52]
• Adverse effects
  • Nausea, vomiting
  • Diarrhea
  • Headache
  • Arthralgia, myalgia
  • Thrombophlebitis
  • Rash, pruritus
  • Pseudomembranous colitis
• Contraindications: consider use in the following populations only if benefits outweigh the risks, as safety in these has not been established ^[52]
  • Pregnant and/or breastfeeding women
  • Children < 16 years of age
• Mechanisms of resistance
  • Modification of bacterial ribosome binding site
  • Enzyme-mediated methylation
  • Efflux pumps ^[50]

• Examples: linezolid
• Mechanism of action
  • Binds to 50S subunit (23S RNA) of bacterial ribosome; → inhibition of initiation complex formation → inhibition of bacterial protein synthesis (bacteriostatic effect)
  • Nonselective monoamine oxidase inhibition (MAOI) ^[53]
  • Bactericidal against streptococci
• CNS penetration: good
• Route of elimination: both biliary and renal elimination after hepatic metabolism
• Clinical use: multidrug-resistant gram-positive bacteria (VRE, MRSA)
• Adverse effects
  • GI upset
  • Pancytopenia (especially thrombocytopenia) due to bone marrow suppression
  • Peripheral neuropathy
  • Serotonin syndrome: Linezolid partially inhibits monoamine oxidase, which is responsible for the break down of neurotransmitters like serotonin.
• Contraindications
  • Concurrent use with MAOIs and selective serotonin reuptake inhibitors (SSRIs)
  • Consider use in pregnant women only if benefits outweigh the risks, as safety in this population has not been established.
• Mechanism of resistance: point mutation of 23S rRNA ^[54]

• Examples: chloramphenicol
• Mechanism of action: bind 50S subunit → blockage of peptidyltransferase → inhibition of bacterial protein synthesis (bacteriostatic effect) ^[55]
• CNS penetration: good
• Route of elimination: renal elimination after hepatic metabolism
• Clinical use
  • Meningitis caused by H. influenzae, N. meningitidis, and/or S. pneumoniae
  • Rickettsia infections (e.g., Rocky Mountain spotted fever caused by Rickettsia rickettsii)
• Special considerations
  • Potent inhibitory effect on cytochrome P450 isoforms CYP2C19 and CYP3A4 ^[55]
  • Rare in the US due to adverse effects
  • Most commonly used in resource-limited countries due to low drug costs
• Adverse effects
  • Dose-dependent bone marrow suppression: aplastic anemia, leukopenia, and/or thrombocytopenia
  • Gray baby syndrome
    • Occurs mainly in premature infants because of developmental lack of UDP-glucuronyltransferase
    • Symptoms: cyanosis, vomiting, flaccidity, hypothermia, shock
• Contraindications
  • Infancy
  • Pregnancy
  • Cautious use in patients with renal and/or hepatic dysfunction
• Mechanisms of resistance: drug inactivation via plasmid-encoded acetyltransferase

• Examples
  • 1^st generation: nalidixic acid (oral)
  • 2^nd generation: norfloxacin, ciprofloxacin, ofloxacin; (oral), enoxacin (oral or IV)
  • 3^rd generation: levofloxacin (oral or IV)
  • 4^th generation: moxifloxacin, gemifloxacin, gatifloxacin (oral)
  • Levofloxacin, moxifloxacin, and gemifloxacin are respiratory fluoroquinolones.
• Mechanism of action: 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) ^[56]
• CNS penetration: good ^[57]
• 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., Chlamydia 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 and those with a previous history of epilepsy)
  • Hyperglycemia/hypoglycemia
  • QT prolongation
  • Photosensitivity
  • Skin rash
  • Superinfection (most commonly with gram-positive pathogens) ^[58][59]
  • Potentially life-threatening exacerbations in patients with myasthenia gravis ^[60]
  • 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)
    • Clinical features: tendon pain that develops within days after initiation of therapy
    • Management
      • Stop fluoroquinolone therapy and change regimen to a non-fluoroquinolone antibiotic
      • Avoid exercise
• Special considerations
  • Increased risk for drug interactions as ciprofloxacin inhibits cytochrome P450
  • Concomitant administration of substances that contain divalent cations (e.g., dairy, antacids) and oral fluoroquinolones → decreased absorption of fluoroquinolone → lower serum concentrations
• Contraindications
  • Children and teenagers < 18 years of age
  • Patients > 60 years of age and those taking cortisol
  • Pregnant women
  • Breastfeeding women
  • Epilepsy, stroke, CNS lesions/inflammation
  • QT prolongation
  • Myasthenia gravis
  • Cautious use in patients with:
    • Renal failure
    • Hepatic failure
    • Antacid use ^[61]
    • 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

Fluoroquinolones hurt the attachments to your bones.

• Examples
  • Oral or IV metronidazole
  • Oral or IV tinidazole
• Mechanism of action: 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.) ^[62]
  • Facultative anaerobes
    • Gardnerella vaginalis
    • Helicobacter pylori in place of amoxicillin (e.g., in case of penicillin allergy) as part of a triple therapy regimen
  • Not effective against aerobes
• Adverse effects
  • Headache ^[63]
  • Disulfiram-like reaction: Nitroimidazoles are no longer believed to cause disulfiram-like reactions. ^[47]
    • Despite case reports suggesting that concomitant metronidazole and alcohol intake can trigger a disulfiram-like reaction, evidence of an association is lacking. ^[47]
    • Metronidazole does not inhibit acetaldehyde dehydrogenase and therefore does not increase blood acetaldehyde concentrations. ^[64]
    • Possible explanations behind the reaction involve metronidazole-induced changes in the gut flora and histamine reactions. ^[64]
  • Metallic taste and gastrointestinal side effects (e.g., nausea, vomiting, abdominal pain)
  • Peripheral neuropathy (particularly with prolonged use), CNS toxicity ^[65]
• Contraindications
  • Consider use in the following populations, if benefits outweigh the risks, as safety in this populations has not been established.
    • Breastfeeding women ^[66]
    • Pregnant women
    • Children
  • Cautious use in patients with hepatic dysfunction

Take the Metro To lonG BEaCH: Metronidazole treats Trichomonas, Giardia/Gardnerella, Bacteroides, Entamoeba, Clostridium, and H. pylori.

• Drug classes
  • Diaminopyrimidine derivatives: trimethoprim (TMP), pyrimethamine
  • Sulfonamides
    • Antibiotics: sulfamethoxazole (SMX), sulfadiazine, sulfisoxazole
    • Nonantibiotic sulfonamides
      • Diuretics: thiazides, furosemide, acetazolamide
      • Anti-inflammatory drugs: sulfasalazine, celecoxib
      • Sulfonylureas
      • Probenecid
• Examples
  • Oral or IV cotrimoxazole (TMP/SMX)
  • Oral sulfadiazine in combination with pyrimethamine
  • Oral sulfisoxazole
• Mechanism of action
  • Inhibition of bacterial folic acid synthesis
    • Sulfonamides inhibit dihydropteroate synthase.
    • Diaminopyrimidine derivatives 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).
  • Both are bacteriostatic but become bactericidal when combined (sequential block of folate synthesis)
• CNS penetration: good
• Route of elimination: primarily renal (via tubular secretion)
• Clinical use: Common indications include UTIs and acute otitis media.
  • Sulfisoxazole
    • Gram-positive bacteria and gram-negative bacteria
    • N. meningitidis
    • Chlamydia trachomatis
    • Nocardia asteroides
    • Toxoplasma gondii
    • Plasmodia spp. ^[67]
  • TMP/SMX
    • Shigella
    • Salmonella
    • Empiric treatment for simple UTI
    • Prophylaxis and treatment of P. jirovecii
    • Prophylaxis of toxoplasmosis
• Adverse effects of sulfonamides
  • Drug interactions due to CYP450 inhibition
  • Displacement of other drugs (e.g., warfarin) from albumin
  • Kernicterus in infancy
  • Nephrotoxicity (especially acute tubulointerstitial nephritis) ^[68]
  • GI upset
  • Hyperkalemia ^[69]
  • Agranulocytosis
  • Aplastic anemia, thrombocytopenia, and pancytopenia ^[70]
  • Triggers hemolytic anemia in G6PD-deficient patients
  • Stevens-Johnson syndrome
  • Hypersensitivity reactions (especially urticaria and hives) ^[71]
  • Photosensitivity
  • Fever
• Adverse effects of diaminopyrimidine derivatives
  • Megaloblastic anemia
  • Leukopenia, granulocytopenia (can be prevented with concomitant administration of folinic acid)
  • Hyperkalemia
    • Caused by competitive inhibition of ENaC channels in the distal convoluted tubule → ↓ Na⁺ reabsorption → ↓ K⁺ secretion ^[72]
    • Patients with HIV are commonly affected because they often take higher doses of trimethoprim. ^[69]
  • Increased creatinine ^[72]
    • Caused by decreased tubular secretion
    • GFR is unchanged.
• Contraindications
  • Pregnant women
  • Children < 2 months of age
  • Breastfeeding women
  • Cautious use in people with
    • Hepatic failure
    • Renal failure
• Mechanisms of resistance
  • Sulfonamides
    • Mutation in bacterial dihydropteroate synthase
    • Decreased uptake of sulfonamide
    • Increased para-aminobenzoate (PABA) synthesis

TMP Treats Marrow Poorly.

ROCk, PAper, SCiSSors: the most important sulfa drugs are fuROsemide, (hydro)Chlorthalidone, Probenecid, Acetazolamide, Sulfamethoxazole/Sulfadiazine, Celecoxib, Sulfasalazine, and Sulfonylureas).

• Examples: nitrofurantoin
• Mechanism of action: : reduced by bacterial nitroreductases to reactive metabolites → bind to bacterial ribosomes → impaired metabolism, impaired synthesis of protein, DNA, and RNA → cell death (bactericidal effect)^[7][8]
• Route of elimination: : primarily renal , 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
  • Clinical indications include:
    • 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
  • Nitrofurantoin-induced lung disease (NILD) ^[73]
    • Types
      • Acute NILD: a hypersensitivity reaction that usually occurs approximately nine days after the first exposure
      • Chronic NILD: a cell-mediated or toxic reaction that usually occurs ∼ 6 months after initiation of the drug
    • Clinical features
      • Acute NILD: fever, dyspnea, cough, and rash
      • Chronic NILD: manifests gradually with cough and dyspnea and can lead to permanent pulmonary fibrosis
    • Diagnostics
      • Presence of characteristic clinical and diagnostic features with nitrofurantoin exposure
      • Chest x-ray: reticular shadowing, bilateral alveolar or interstitial infiltrates, pleural effusion
      • PFT: restrictive pattern, ↓ DLCO
      • Eosinophilia may be present in serum or bronchoalveolar lavage sample.
    • Differential diagnoses: heart failure, infection, and ARDS
    • Treatment: cessation of nitrofurantoin
  • Pulmonary fibrosis (see “Chronic NILD”)
  • 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
  • Hepatic dysfunction ^[74]
  • Renal dysfunction with a creatinine clearance < 60 mL/min

See “Treatment” in “Tuberculosis.”

• Examples
  • Oral or IV rifampin (rifampicin)
  • Oral rifabutin
  • Oral rifaximin
  • Oral rifapentine
• Mechanism of action: 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 ^[36]
  • 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
    • M. avium-intracellulare prophylaxis and treatment (rifabutin)
  • Meningococcal prophylaxis
  • Chemoprophylaxis for people who had contact with children infected with H. influenzae type b
  • Rifaximin: second-line therapy in hepatic encephalopathy. ^[75]
• 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)
    • Causes minor drug interactions
    • Rifabutin is preferred for the treatment of mycobacterial infections in patients with HIV because it has a lower potential for CYP induction than rifampin.
  • Intermittent therapy is associated with an increased risk of renal failure, so rifamycins should be administered daily ^[76]
  • False positive urine opiate screening ^[77]
• Contraindications
  • Breastfeeding women
  • Should be used during pregnancy only if clearly needed
  • Cautious use in patients with hepatic dysfunction
• Mechanisms of resistance
  • RNA polymerase mutations decrease the affinity of rifamycins to RNA polymerase. ^[78]
  • Resistance develops rapidly if used as monotherapy.

The 6Rs of Rifampin: Red or orange urine, RNA polymerase Repression, Ramping up of cytochrome P450 activity, and Rapid Resistance development if used alone.

Rifampin really amplifies (induces) cytochrome P450, but rifabutin does not.

• Mechanism of action
  • Isoniazid is a 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 ^[79][80]
  • Inhibits cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C19, and CYP3A4) ^[80]
• Route of elimination: renal elimination after hepatic metabolism
• Clinical use: ^[81]
  • Treatment of TB (together with rifampin, pyrazinamide, and ethambutol)
  • The only drug that can be used as monoprophylaxis against TB
• Adverse effects
  • Hepatotoxicity (drug-induced hepatitis)
  • 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, aplastic anemia, thrombocytopenia
    • Pellagra
• Contraindications
  • Should be used during pregnancy only if clearly needed
  • Cautious use in patients with renal and/or hepatic dysfunction
• Mechanisms of resistance: mutations causing decreased KatG; → decreased expression of catalase-peroxidase → less/no biologically active INH

INH Is Not Healthy In Neurons and Hepatocytes.

Neurotoxicity may be prevented by supplementing with pyridoxine (vitamin B6).

• Mechanism of action
  • 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
  • Hepatotoxicity
• Contraindications
  • Consider use in pregnant and breastfeeding women only if benefits outweigh the risks ^[82]
  • Hepatic failure ^[83]
  • Acute gout
• Mechanisms of resistance: mutations in RpsA gene coding for ribosomal protein S1 ^[84]

• Mechanism of action: inhibits arabinosyltransferase → ↓ carbohydrate polymerization → prevention of mycobacterial cell wall synthesis (bacteriostatic effect)
• 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
  • Hyperuricemia ^[85]
• Contraindications
  • Contraindicated in patients who are unable to report visual changes
  • Contraindicated in patients with optic neuritis
  • Consider use in the following populations only if benefits outweigh the risks, as safety in these has not been established
    • Children < 13 years of age
    • Pregnant women
    • Breastfeeding women ^[86]
• Mechanisms of resistance: mutations of EmbCAB gene coding for arabinosyltransferase ^[87]

EYEthambutol: Ethambutol causes optic neuropathy.

• Mechanism of action
  • Competitive antagonist of para-aminobenzoic acid (PABA) for dihydropteroate synthetase → inhibition of dihydrofolic acid synthesis
  • Bacteriostatic and weakly bactericidal effect ^[88]
  • Structurally different from sulfonamides but a similar mechanism of action
• Route of elimination: mostly renal
• Clinical use
  • M. leprae: lepromatous and tuberculoid leprosy ^[88]
  • P. jiroveci pneumonia
    • Prophylaxis
    • Treatment: used in combination with TMP as an alternative to TMP/SMX
  • Dermatitis herpetiformis ^[89]
  • 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
  • Consider use in pregnant and breastfeeding women only if benefits outweigh the risks
  • Cautious use in patients with renal and/or hepatic dysfunction
• Mechanism of resistance: mutations of folP1 gene coding for dihydropteroate synthase ^[90]