Carbapenems: the pinnacle of the ß-lactam antibiotics or room for improvement?

Jeffrey R. Edwards* and Michael J. Betts

Cancer and Infection Research Department, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK

This article provides a perspective on carbapenems, two examples of which, imipenem/cilastatin and meropenem, are currently available for clinical use. Another analogue, panipenem, which is co-administered with betamipron to act as a nephro-protectant, is registered for use in Japan.1 This compound has activity and pharmacokinetics similar to imipenem/cilastatin. Several other examples have failed to reach the market whilst at least one is currently in clinical trials. The structure of these is presented in the FigureGo, which displays an explanation of substituent positioning. However, the focus of this review will be to contrast the two widely available agents, to define differences and then to comment on what advances might be introduced into new analogues.



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Figure. (a) Numbering system used here for carbapenems. (b) The structures of some of the carbapenems.

 
ß-Lactam antibiotics, embracing penicillins with or without ß-lactamase inhibitors, cephalosporins, cephamycins, oxacephamycins, monobactams, carbacephems, penems and carbapenems, represent the most commonly prescribed antibacterial agents. It has been opportune that new ß-lactam agents have been introduced continuously since the 1940s during which time many bacteria have developed resistance to the older examples. Resistance has occurred because of impaired entry into bacteria, instability to bacterial serine- or metallo-ß-lactamases or inability to saturate penicillin-binding proteins (PBPs). Recently, efflux has also been implicated. In some instances more than one of these mechanisms is responsible and in others mosaic PBPs explain the resistance. The most common type of resistance in Gram-negative bacilli is now due to hydrolysis by ß-lactamases, which are either chromosomal enzymes that can be overexpressed (derepressed) or encoded by plasmids; these enzymes can hydrolyse important penicillins and cephalosporins. The ability to circumvent the effect of ß-lactamase inhibitors, now common with chromosomal enzymes, is also seen with some of the newer plasmid enzymes. The whole area of resistance to ß-lactam antibiotics has been reviewed comprehensively by Livermore and Williams.2

Merck in their US laboratories conducted the pioneering carbapenem work and in isolating thienamycin, the first carbapenem (FigureGo), identified the potential of the class as exceptionally broad-spectrum agents. Subsequently, this was explained by their efficient penetration into bacteria, stability to hydrolysis by almost all clinically important serine-ß-lactamases and high affinity for essential PBPs of Gram-negative bacteria including PBPs 1a and 1b which have cell-lytic consequences. The promise therefore, was of a single agent with the potential to treat infections caused by single or multiple Gram-positive or -negative aerobes or anaerobes. Thienamycin proved to be chemically unstable as a result of cleavage of the ß-lactam ring of one molecule by the primary amine in the 2' side chain of another. Subsequently the analogue imipenem was synthesized bearing the more basic amidine function, which is protonated at physiological pH, and thus unable to take part in such nucleophilic attack. Poor urinary recovery from animals, however, revealed an additional instability to a mammalian ß-lactamase, renal dehydropeptidase-I (DHP-I), which required the development of an additional compound, cilastatin, for co-administration with imipenem to prevent hydrolysis by DHP-I. A further advantage of the addition of cilastatin was a reduction in the nephrotoxicity seen in animals dosed with imipenem alone.3 However, whilst having overcome these hurdles, at the time of launch imipenem/cilastatin was known to be inactive against some important pathogenic bacteria. The most striking gaps were lack of activity against methicillin-resistant staphylococci and some species of enterococci, and suboptimal potency against Pseudomonas aeruginosa. Perceived to be of lesser importance was modest potency against other less common pseudomonads and instability to the metallo-ß-lactamases expressed by Stenotrophomonas maltophilia and other bacteria. Clinical experience in an extensive range of indications4 showed that imipenem/cilastatin largely fulfilled the laboratory prediction of utility, although, as may have been expected, emergence of resistance in P. aeruginosa was sometimes seen during therapy.5,6 These trials led to the recommendation of a 6 h dosing interval, typically with a 0.5 g unit dose for fully susceptible pathogens and up to 1 g, every 8 h for severe or life-threatening infections with less susceptible organisms. Drug-related CNS side effects seen in the initial clinical trial programme were usually, but not always, associated with higher doses, especially in patients with renal impairment and/or pre-existing CNS problems.7 Hence, imipenem/cilastatin is an excellent broad-spectrum agent with a role in empirical antibacterial therapy, the potential of which may be limited somewhat by toxicity.

It was known that stability to human renal DHP-I could be achieved by the introduction of a 1-ß-methyl substituent into the structure. The combination of this feature with a precise stereochemistry in the pendent pyrrolidine ring at the 2' position to ensure sustained antibacterial potency, led to the synthesis of meropenem.8 This new analogue was chemically less prone to hydrolysis by DHP-I, and proved to have sufficient stability to human renal DHP-I to permit it to be developed as a single product.8 An additional pharmacological advance achieved was the potential for the use of meropenem in CNS infections,9,10 which clinical experience had shown was contraindicated with imipenem/ cilastatin.7,11 Microbiologically, meropenem is intrinsically a little less potent than imipenem against Gram-positive aerobes but more active against Gram-negative aerobes, including P. aeruginosa, and similar in activity against Gram-negative anaerobes.12 As with imipenem/cilastatin, clinical trials of meropenem fulfilled the laboratory prediction of utility and, up to the stage of regulatory filing, emergence of resistance in P. aeruginosa was seen in only a handful of patients. The majority of trials evaluated meropenem as empirical monotherapy in serious infections at a dose of 1 g given at 8 h intervals, but others showed the success of 0.5 g and of 2 g every 8 h in the treatment of meningitis and lower respiratory tract infections in cystic fibrosis patients.13 Meropenem, even at high doses, is well tolerated14 and enhanced solubility permits bolus dosing without infusion rate-related nausea or vomiting.15 Thus, perhaps the most significant advance in meropenem is the combination of good tolerability and flexible dosing, whilst eradication of pathogens is little different from imipenem/ cilastatin.

Against the background of clinical efficacy in the vast majority of bacterial infections, including those caused by antibiotic-resistant strains of pneumococci, Enterobacteriaceae harbouring cephalosporin-hydrolysing chromosomal or plasmid enzymes, and multi-resistant P. aeruginosa, microbiological failures do occur. Clinical resistance in P. aeruginosa, due primarily to loss of an outer membrane porin (oprD2), is seen and very infrequent examples of resistance in Enterobacteriaceae are recorded.16,17 Carbapenems are probably the drugs of choice in the treatment of infections caused by Acinetobacter spp., but diminished susceptibility is now being seen, albeit rarely; the precise mechanism of this resistance in Acinetobacter spp. remains to be defined but ß-lactamases may be important.18

If the most important feature of a carbapenem is an antibacterial spectrum that permits empirical use in seriously ill patients, given these occurrences and intrinsic inactivity against methicillin-resistant staphylococci, Enterococcus faecium and some non-fermenters, what enhancements in spectrum beyond meropenem/imipenem might be anticipated? In a broad sense, activity against Grampositive organisms is favoured by more lipophilic molecules, with L-786392 as an extreme example. In contrast, Gram-negative activity is favoured by hydrophilicity in a molecule, since this property confers the ability to penetrate via the aqueous channels of porins. Antipseudomonal activity is particularly favoured by zwitterionic molecules. The 2' side chain is either permanently charged (biapenem) or potentially so at physiological pH (imipenem, meropenem), while the carboxylic acid exists as the anion. In consequence, to achieve breadth of spectrum requires balancing these opposing physical properties and so far neither an overall enhancement nor an additional specific organism has been added. L-786392 is reported to be active in vitro against Gram-positive aerobes including methicillin-resistant staphylococci19 and enterococci.20 It also has sustained anti-anaerobe activity but, relative to available carbapenems, has significantly reduced activity against Enterobacteriaceae and is without anti-pseudomonal activity. This compound will not progress to the clinic [H. Rosen (Merck), personal communication]. Compounds with stability to hydrolysis by metallo-ß-lactamases are not yet available, though the addition of specific inhibitors of these enzymes, as has been achieved with clavulanic acid for serine ß-lactamases,2 may become possible.

Two carbapenems, biapenem21 and lenapenem,22 both with typical carbapenem pharmacokinetics and broad spectrum, with some minor improvements claimed against resistant strains of P. aeruginosa, were tested in patients but seem not to have progressed towards registration.

The introduction of oral activity has also been possible, for example with the ester prodrugs CS 834 and sanfetrinem cilexetil. The latter exemplifies the new class of trinems, in which an extra carbocyclic ring has been attached. Along with these esters we may consider the penems, which combine elements of the penicillin and carbapenem systems. Thus faropenem has recently been introduced in Japan as an oral agent, and an ester with improved bioavailability is in development. The use of esters and prodrugs highlights the problems of identifying parent molecules with good bioavailability following oral administration. In the absence of a specific uptake system, molecules must rely on passive diffusion for transport through the intestinal wall, and this in general requires an uncharged, lipophilic molecule. In consequence the ionized carboxylic acid is best masked by the use of prodrugs, though modest absorption of the parent may be possible (faropenem). The presence of basic groups that will protonate (imipenem) or of intrinsically charged functions (biapenem) is not compatible with good diffusion. This type of functionality is thus missing from the oral compounds, which in consequence have poorer Gram-negative activity and lack a useful level of activity against P. aeruginosa.

A review of the currently available literature information shows that a carbapenem with a spectrum expansion beyond meropenem/imipenem remains elusive. This leads us to the conclusion that, given the current position of bacterial resistance to antibiotics, it is important that carbapenems are prescribed at optimal doses to appropriate patients to maximize efficacy and minimize the risk of development of resistance.

Notes

* Tel: +44-1625-590913; Fax: +44-1625-512748; E-mail: Jeff.Edwards{at}astrazeneca.com Back

References

1 . Naganuma, H., Tokiwa, H., Hirouchi, Y., Kawahara, Y., Fukushiga, J. I. & Fujami, M. (1991). Nephroprotective effect and its mechanism of betamipron (1): relationship of renal transport. Chemotherapy (Tokyo) 39, Suppl. 3, 166–77.

2 . Livermore, D. M. & Williams, J. D. (1996). ß-Lactams: mode of action and mechanisms of bacterial resistance. In Antibiotics in Laboratory Medicine, 4th edn, (Lorian, V., Ed.), pp. 502–78. Williams & Wilkins, Baltimore, MD.

3 . Birnbaum, J., Kahan, F. M., Kropp, H. & MacDonald, J. S. (1985). Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin. American Journal of Medicine 78, 3–21.[ISI][Medline]

4 . Clissold, S. P., Todd, P. A. & Campoli-Richards, D. M. (1987). Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 33, 183–241.[ISI][Medline]

5 . Mouton, Y., Deboscker, Y., Bazin, C., Fourrier, F., Moulront, S., Philippon, A. et al. (1990). Etude prospective randomisee controlee imipeneme–cilastatine versus cefotaxime-amikacine dans le traitement des infections respiratoires inferieures et des septicemies de reanimation. Presse Medicale 19, 607–12.[ISI][Medline]

6 . Norrby, S. R., Finch, R. G. & Glauser, M. (1993). Monotherapy in serious hospital-acquired infections: a clinical trial of ceftazidime versus imipenem/cilastatin. European Study Group. Journal of Antimicrobial Chemotherapy 31, 927–37.[Abstract]

7 . Calandra, G., Lydick, E., Carrigan, J., Weiss, L. & Guess, H. (1988). Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin. American Journal of Medicine 84, 911–8.[ISI][Medline]

8 . Edwards, J. R. & Turner, P. J. (1995). Laboratory data which differentiate meropenem and imipenem. Scandinavian Journal of Infectious Diseases Supplementum 96, 5–10.[Medline]

9 . Klugman, K. P. & Dagan, R. (1995). Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Meropenem Meningitis Study Group. Antimicrobial Agents and Chemotherapy 39, 1140–6.[Abstract]

10 . Rodriguez, W. J., Bradley, J. S. & Odio, C. (1997). Meropenem vs. cefotaxime in the treatment of pediatric meningitis. In Program and Abstracts of the Thirty-Seventh Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997. Abstract LM-2, p. 364. American Society for Microbiology, Washington, DC.

11 . Wong, V. K., Wright, H. T., Ross, L. A., Mason, W. H., Inderlied, C. B. & Kim, K. S. (1991). Imipenem/cilastatin treatment of bacterial meningitis in children. Pediatric Infectious Disease Journal 10, 122–5.[ISI][Medline]

12 . Edwards, J. R. (1995). Meropenem: a microbiological overview. Journal of Antimicrobial Chemotherapy 36, Suppl. A, 1–17.[ISI][Medline]

13 . Blumer, J. L. (1997). Meropenem: evaluation of a new generation carbapenem. International Journal of Antimicrobial Agents 8, 73–92.[ISI]

14 . Norrby, S. R., Newell, P. A., Faulkner, K. L. & Lesky, W. (1995). Safety profile of meropenem: international clinical experience based on the first 3125 patients treated with meropenem. Journal of Antimicrobial Chemotherapy 36, Suppl. A, 207–23.[ISI][Medline]

15 . Jones, H. K., Kelly, H. C., Hutchison, M., Yates, R. A., Ross, F., Lomax, C. et al. (1997). A comparison of the pharmacokinetics of meropenem after intravenous administration by injection over 2, 3 and 5 minutes. European Journal of Drug Metabolism and Pharmacokinetics 22, 193–9.[ISI][Medline]

16 . Rasmussen, B. A., Bush, K., Keeney, D., Yang, Y., Hare, R., O'Gara, C. et al. (1996). Characterisation of IMI-1 ß-lactamase, a class A carbapenem-hydrolysing enzyme from Enterobacter cloacae. Antimicrobial Agents and Chemotherapy 40, 2080–6.[Abstract]

17 . Mainardi, J. L., Mugnier, P., Coutrot, A., Buu-Hoi, A., Collatz, E. & Gutmann, L. (1997). Carbapenem resistance in a clinical isolate of Citrobacter freundii. Antimicrobial Agents and Chemotherapy 41, 2352–4.[Abstract]

18 . Afzal-Shah, M. & Livermore, D. M. (1998). Worldwide emergence of carbapenem-resistant Acinetobacter spp. Journal of Antimicrobial Chemotherapy 41, 576–7.[Free Full Text]

19 . Huber, J., Dorso, K. L., Kohler, J., Kropp, H., Rosen, H. & Silver, L. L. (1998). Anti-staphylococcal activity of the MRS-active carbapenem L-786392. In Program and Abstracts of the Thirty-Eighth Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract 48-F, F-30, p. 240. American Society for Microbiology, Washington, DC.

20 . Dorso, K. L., Kohler, J., Kropp, H., Rosen, H. & Silver, L. L. (1998). In vitro anti-enterococcal activity of L-786392 alone and in combination with other antibacterial agents. In Program and Abstracts of the Thirty-Eighth Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract 48-F, F-28, p. 240. American Society for Microbiology, Washington, DC.

21 . Catchpole, C. R., Wise, R., Thornber, D. & Andrews, J. M. (1992). In vitro activity of L-627, a new carbapenem. Antimicrobial Agents and Chemotherapy 36, 1928–34.[Abstract]

22 . Kato, Y., Otsuki, M. & Nishino, T. (1997). Antibacterial properties of BO-2727, a new carbapenem antibiotic. Journal of Antimicrobial Chemotherapy 40, 195–203.[Abstract]