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Carbapenems

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Pharmacokinetic-pharmacodynamic relationship

  • time dependent killing but have significant post-antibiotic effect
  • optimal time above MIC (T>MIC) unknown but does not need to be entire dosing interval
  • T>MIC to obtain bacteriostasis in vivo seems to be lower for carbapenems than for other ▀ lactams

Imipenem and cilastin

Imipenem: carbapenem beta-lactam antibiotic

Cilastin: inhibitor of renal dehydropeptidase I - enzyme responsible for hydrolysis of imipenem to nephrotoxic metabolites with no antibacterial activity. Does not increase plasma levels of imipenem but does prevent nephrotoxicity and maintains urinary levels of the intact drug.

Spectrum of activity

  • active against most clinically important bacteria including anaerobes. Intrinsically resistant organisms include Enterococcus faecium, MRSA, coagulase negative staph, Chlamydia trachomatis and Stenotrophomonas maltophilia
  • not destroyed by most beta-lactamases including those that mediate resistance to cefuroxime, cefotaxime and ceftazidime
  • potent inducer of beta-lactamase production - may be important if therapy subsequently changed from imipenem to an antibiotic destroyed by this enzyme
  • Ps. aeruginosa can become resistant during therapy due to a mutation which reduces bacterial permeability to the drug. Cross-resistance to other beta-lactams is unusual.

Pharmacokinetics

  • IV admin only
  • half life of both drugs approx 1 hour
  • when given together 2/3 of dose of imipenem is excreted unchanged in urine; remaining 1/3 in hyrolysed form
  • < 1% excreted in bile - too little to disturb colonic flora
  • plasma protein binding of imipenem only 20%
  • cilastin excreted almost entirely by kidney
  • imipenem but not cilastin can be cleared by extra-renal mechanisms. In anuric patients the plasma half life of imipenem is 4 hours and of cilastin 16 hours. Recommended dosage reduction in renal failure achieves normal maintenance plasma levels of imipenem but cilastin and some metabolites of imipenem accumulate. Levels of cilastin much lower than those found to be toxic in animals but little is known about the toxicity of imipenem in patients. Some metabolites of imipenem are neurotoxic with effects such as tremor, seizure and confusional state. Both drugs are cleared by haemodialysis and haemofiltration. Data sheet recommends that patient with a creatinine clearance of 5ml or less should not be given imipenem-cilastin unless haemodialysis is started within 48 hours. Reduce dose in patients on haemofiltration.

Adverse effects

Relatively infrequent.

  • phlebitis or pain at site of infusion
  • nausea
  • vomiting
  • fits (usually in patients with pre-existing CNS disease or patients with renal failure and excessively high levels of imipenem metabolites)

Ertapenem

Spectrum of activity

Aerobes

  • Gram negatives
    • Enterobacteriaceae including strains which produce extended spectrum beta lactamases and AmpC beta lactamases
    • common Gram negative respiratory tract pathogens (including Moraxella catarrhalis and Haemophilus influenzae)
    • negligible activity against Pseudomonas aeruginosa and Acinetobacter baumanni
  • Gram positives
    • active against most Gram positives including penicillin susceptible and resistant pneumococcus and MSSA
    • not active against Enterococcus spp. or MRSA

Anaerobes

  • active against a wide range of Gram positive and negative anaerobes
  • limited activity against Lactobacillus spp.

Pharmacokinetics

  • admin: IV or IM
  • 80-95% plasma protein bound
  • predominantly renally excreted
  • mean plasma t1/2 ~4h

Dose

  • Usual adult dose: 1g daily. Reduce to 500mg daily if creatinine clearance <30 ml/kg/1.73m2

Meropenem

Spectrum of activity

  • broad spectrum of Gram positives and gram negatives including extended spectrum beta lactamase producers, Pseudomonas aeruginosa and Acinetobacter baumanni
  • slightly greater Gram negative and slightly less Gram positive activity compared to imipenem, particularly against Enterococcus faecalis
  • more active in vitro against intermediate and high-level penicillin-resistant pneumococci
  • inhibitory action against Listeria and demonstrates in vitro activity against M. tuberculosis, M.avium intracellulare complex and M. fortuitum
  • Stenotrophomonas maltophilia usually resistant

Pharmacokinetics

  • admin: IV
  • ~10% protein bound. Extensively distributed in extracellular fluid - concentrations are in same range as in plasma
    • ~20% penetration into CSF with wide inter-individual variation, possibly due to varying degrees of inflammation of meninges
  • predominant renal excretion by glomerular filtration. One major (inactive) metabolite
    • eliminated well by haemofiltration: reported sieving coefficient usually in the range of 1.02-1.17
  • elimination t 1/2 ~1 h (normal renal function)

Adverse effects

  • seizures. No more likely to cause seizures than other beta lactams
  • diarrhoea
  • nausea and vomiting
  • rash
  • pruritus
  • transient elevation of liver transaminases
    • no good evidence that meropenem causes liver disease
  • thrombocytosis
  • eosinophilia

Further reading

Hellinger WC, Brewer NS. Carbapenems and monobactams: Imipenem, meropenem and aztreonam. Mayo Clinic Proceedings 1999; 74(4):420-34

Mouton JW et al. Comparative pharmacokinetics of the carbapenems. Clin Pharmacokinet 2000; 39(3):185-201

Potential conflict of interest

The Dept of Anaesthesia & Intensive Care, The Chinese University of Hong Kong received sponsorship for Intensive Care educational activities from Merck Sharp & Dohme and Astra Zeneca in 2001-4


 

ęCharles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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