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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 ß lactams
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)
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
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
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