Antimicrobials

 

• Background

  Efficacy by Gram stain

  • Gram positive: penicillins, macrolides, glycopeptides.
  • Gram negative: aminoglycosides, quinolones.

  Broad-spectrum antibiotics

  • Broad: tetracyclines, chloramphenicol, cephalosporins (especially 3rd/4th generation).
  • Very broad (G+, G-, anaerobes): piperacillin, ticarcillin, carbapenems.

  Common side effects

  GI symptoms (nausea, abdo pain, diarrhoea) and rashes are a common side effect of many antimicrobials, including common agents like penicillins.

  Renal and hepatic considerations

  Renal impairment:

  • Gentamicin and vancomycin require a lower dose with any level of impairment.
  • Others depend on severity.

  Monitor LFTs with:

  • β-lactams: co-amoxiclav, flucloxacillin, ceftriaxone.
  • Others: moxifloxacin, fusidic acid.
  • Fluconazole and itraconazole.
  • Anti-TB drugs.
  • Antiretrovirals

  Interactions with alcohol

  The vast majority of antimicrobials are safe with alcohol, except a few that cause disulfiram-like symptoms i.e. flushing, nausea and vomiting, sweating:

  • Metronidazole
  • Co-trimoxazole
  • Tinidazole

  Protein synthesis inhibitors

  Mechanism mnemonic: buy AT 30, CeLL at 50:

  • Aminoglycocides and Tetracyclines work at the 30S ribosome site.
  • Clarithromycin (and other macrolides), Chloramphenicol, Clindamycin, and Linezolid work at the 50S ribosome site.

  Bacteriostatics:

  • All the protein synthesis inhibitors are bacteriostatic, not bacteriocidal, meaning that they prevent reproduction but rely on the host immune system to clear existing bacteria.
  • Other bacterioSTatics are Sulphonamides and Trimethoprim.

• Penicillins

  Mechanism

  • β-lactam: inhibits synthesis of peptidoglycan layer of bacterial cell wall.
  • Some bacteria produce β-lactamase and require the use of β-lactamase resistant (βLR) penicillins.

  Side effects

  • Rash
  • Diarrhoea (esp. co-amoxiclav).
  • Hypersensitivity: anaphylaxis, serum sickness.
  • Encephalopathy
  • Renal: AIN, crystalluria (amoxicillin).
  • Liver: cholestasis (flucloxacillin).

  Contrainidications

  • Hypersensitivity
  • ↓Dose in renal impairment.

  Drugs and indications

  Note that, with the exception of benzylpenicillin for N. meningitidis and the very broad spectrum penicillins, they are mainly used against Gram +ve bacteria.

  • Amoxicillin: pneumonia, acute otitis media, UTI, H. pylori.
  • Co-amoxiclav (βLR): pneumonia, acute pyelonephritis, facial cellulitis, anaerobes.
  • Benzylpenicillin (aka penicillin G): syphilis, meningococcal disease, cellulitis, streptococcal infective endocarditis. Comes in benzathine or procaine form. Side effects: ↑Na+ ± seizures in kidney failure (especially benzathine).
  • Phenoxymethylpenicillin (aka penicillin V): Group A Strep URTI or soft tissue infection.
  • Flucloxacillin (βLR): Staph. aureus infections including skin and soft tissue (impetigo and cellulitis) and infective endocarditis.

  Very broad spectrum:

  • 2 options, which are both combined with β-lactamase inhibitors: piperacillin/tazobactam (Tazocin), ticarcillin/clavulanic acid (Timentin).
  • Use sparingly: hospital acquired pneumonia, sepsis, anaerobes, and Pseudomonas.

• Cephalosporins

  Mechanism

  • β-lactam: inhibits synthesis of peptidoglycan layer of bacterial cell wall.
  • Early generations were Gram +ve only, but successive generations have greater Gram -ve effects.

  Side effects and contraindications

  • Hypersensitivity. In addition, up to 10% of penicillin-allergic individuals may have cross-reactivity to 1st and 2nd generation cephalosporins.
  • Potentiates warfarin.
  • Don't cover anaerobes.
  • ↓Dose in renal impairment.
  • Autoimmune haemolytic anaemia.

  Drugs and their indications

  By generation:

  • 1st: cefalexin. 2nd line in pneumonia, UTI, and otitis media.
  • 2nd: cefuroxime. Use for surgical prophylaxis with metronidazole. 2nd line in pneumonia, UTI, and otitis media.
  • 3rd: ceftriaxone (gonorrhea, PID), cefotaxime (meningococcal disease), ceftazidime. Used in sepsis.
  • 4th: cefepime.

• Carbapenems

  Mechanism

  β-lactam – inhibits synthesis of peptidoglycan layer of bacterial cell wall – with β-lactamase resistance.

  Side effects

  • Neuro: headache, dizziness, seizures.
  • GI: diarrhoea and vomiting.
  • Haematological: ↓Hb, ↑eosinophils, ↓WBC, Coombs +ve haemolytic anaemia.

  Contraindications

  Pregnancy and breastfeeding.

  Drugs and their indications

  Imipenem and meropenem: both very broad spectrum and used in severe infections.

• Aminoglycosides

  Mechanism

  Inhibits protein synthesis at the bacterial 30S ribosome site.

  Contraindications and interactions

  • Pregnancy
  • Furosemide
  • Myasthenia gravis: exacerbates weakness.

  Side effects

  • Ototoxicity
  • Nephrotoxicity

  Drugs and their indications

  • Effective against Gram -ve bacteria.
  • Gentamicin: used with piperacillin/tazobactam in sepsis and hospital acquired pneumonia, used with benzylpenicillin in strep infective endocarditis.
  • Streptomycin: TB.

  Monitoring

  Monitor serum levels if on parenteral aminoglycosides:

  • Check after 3 doses or dose changes. More frequent in kidney impairment.
  • Check just before next dose for 'trough' level: if high, increase interval between doses.
  • Also take 1 hr after dose for 'peak' level: if high, reduce dose.

• Tetracyclines

  Mechanism

  Inhibits protein synthesis at the bacterial 30S ribosome site.

  Side effects and contraindications

  • Photosensitivity
  • Diarrhoea and vomiting.
  • Contraindicated in pregnancy, breastfeeding, and children <12 years old, as they cause teeth discolouration.
  • Tetracycline is contraindicated in kidney failure.

  Drugs and their indications

  • Doxycycline: infective exacerbation of COPD, PID, some MRSA. 2nd-line for pneumonia, chlamydia. Also malaria, Lyme, rickettsia.
  • Tetracycline: Lyme, brucellosis, rickettsia, acne.
  • Tigecycline: MRSA.

• Macrolides

  Mechanism

  Inhibits protein synthesis at the bacterial 50S ribosome site.

  Side effects

  • GI (common): nausea, vomiting, and diarrhoea. Worse with erythromycin.
  • Hepatotoxicity
  • Rash

  Contraindications and cautions

  Macrolides are P450 enzyme inhibitors, so they can potentiate warfarin, statins, theophylline, ergotamine, and carbamazepine.

  Drugs and their indications

  • Effective against Gram +ve bacteria.
  • Azithromycin: whooping cough, chlamydia.
  • Erythromycin: childhood pneumonia, acne, alternative in pneumonia for penicillin-allergic patients.
  • Clarithromycin: severe community-acquired pneumonia, H. pylori, severe gastroenteritis.

• Quinolones

  Mechanism

  • Inhibit bacterial DNA synthesis via topoisomerase II or DNA gyrase inhibition.
  • Most are fluoroquinolones.

  Contraindications

  Pregnancy

  Side effects

  • GI: diarrhoea and vomiting, C. diff.
  • Neuro: headache, dizziness, seizure risk in those with epilepsy, peripheral neuropathy.
  • MSK: tendon rupture, arthralgia.
  • CV: ↑QT, aortic dissection and rupture.
  • Rash
  • ↑LFTs

  Drugs and their indications

  • Ciprofloxacin: particularly effective for Gram -ve infections, but also covers Gram +ve. Commonly used in gastroenteritis, genitourinary infections including acute pyelonephritis, prostatitis, and epididymo-orchitis.
  • Levofloxacin and moxifloxacin are typically used for pneumonia.

• Glycopeptides

  Mechanism

  Inhibits synthesis of peptidoglycan layer of bacterial cell wall

  Drugs and their indications

  • Effective against Gram +ve bacteria.
  • Vancomycin: MRSA, severe C. diff. Can be oto- and nephro-toxic, so monitor serum trough level every 24 hrs.
  • Teicoplanin: MRSA.

• Azole antifungals

  Mechanism

  • Inhibit cell walls via ergosterol inhibition.
  • Most are triazoles, except clotrimazole, which is an imidazole.

  Drugs

  • Clotrimazole: Candida, dermatophytes (ringworm).
  • Fluconazole: Candida.
  • Ketoconazole: Candida, dermatophytes (ringworm), Histoplasma, seborrheic dermatitis.
  • Voriconazole: Aspergillus.

• Other antibiotics

  Chloramphenicol

  • Mechanism: inhibits protein synthesis at the bacterial 50S ribosome site.
  • Indications: conjunctivitis.
  • Side effects: bone marrow suppression, neuritis, GI upset.
  • Contraindications: warfarin.

  Clindamycin

  • Mechanism: inhibits protein synthesis at the bacterial 50S ribosome site.
  • Indications: cellulitis (with flucloxacillin), toxic shock syndrome, acne.
  • Side effects: C. diff and pseudomembranous colitis.

  Linezolid

  • Mechanism: an oxazolidine antibiotic that inhibits protein synthesis at the bacterial 50S ribosome site.
  • Indications: MRSA.
  • Side effects: peripheral neuropathy, bone marrow suppression especially ↓platelets.
  • Contraindications: ↑BP, thyrotoxicosis.

  Trimethoprim

  • Mechanism: prevents reduction of dihydrofolic acid to tetrahydrofolic acid, thus inhibiting bacterial DNA synthesis.
  • Indications: UTI, used with sulfamethoxazole as co-trimoxazole (Septrin) for PCP.
  • Side effects: bone marrow suppression, diarrhoea and vomiting. Co-trimoxazole: jaundice, hypersensitivity.
  • Contraindications: methotrexate.

  Nitrofurantoin

  • Mechanism: inhibit bacterial ribosome proteins, thus inhibiting protein, DNA, and cell wall synthesis.
  • Indications: UTI.
  • Side effects: GI (take after meal), dark urine.
  • Avoid if eGFR <45.

  Fusidic acid

  • Mechanism: inhibits bacterial protein synthesis by preventing elongation factor G (EF-G) translocation.
  • Indications: used topically for S. aureus skin and eye infections, or combined with flucloxacillin for S. aureus osteomyelitis or endocarditis.
  • Side effects: GI upset, altered LFTs.

  Metronidazole

  • Mechanism: a nitroimidazole that is reduced by anaerobic bacteria to its active form, thus inhibiting DNA synthesis.
  • Indications: anaerobic bacteria including C. difficile, protozoa including Giardia and Trichomonas, and various other uses including H. pylori eradication, BV, PID, and surgery prophylaxis with cefuroxime.
  • Cautions and interactions: pregnancy (avoid high doses), alcohol (disulfiram like reaction), warfarin, phenytoin, cimetidine.
  • Side effects: neuropathy.