Parenteral Carbapenems P

REVIEW Parenteral carbapenems P. M. Shah J. W. Goethe Universitaet, Arzt fuer Innere Medizin, Mikrobiologie und Infektion sepidemiologie, Biapenem Frankfurt, Germany ABSTRACT Among the many different structurally distinct classes of b-lactams, the carbapenem class is regarded as that which is most potent and which has the widest spectrum of antimicrobial activity. Rapidly bactericidal, and demonstrating time-dependent killing, carbapenemes have a spectrum of antimicrobial activity that includes Gram-positive and Gram-negative aerobic and anaerobic pathogens. Their in-vitro activity includes extended-spectrum b-lactamase (ESBL)-producing pathogens and carbapenems are currently considered to be the treatment of choice for serious infections due to ESBL-producing organisms. However, isolates acquiring resistance under treatment have been reported. Imipenem, meropenem and ertapenem are licensed in the European Community and panipenem and biapenem are also available in Japan and South Korea. Other carbapenemes are under development. Keywords ertapenem, extented-spectrum beta-lactamases, imipenem, meropenem, panipenem Clin Microbiol Infect 2008; 14 (Suppl. 1): 175–180 sive account of carbapenems has been written by INTRODUCTION Bryskier [3]. Thienamycin was found to be highly active Imipenem was licensed in 1984 in Germany. It against a variety of isolates [1]. The ‘carbapenem was more than 10 years before a second carbape- story’ started with the detection of thienamycin in nem, meropenem, was licensed in 1995, while the laboratories of Merck, Sharp & Dohme (NJ, ertapenem was licensed by the European Com- USA), from a culture of Streptomyces cattleya, munity in 2002. In Japan and South Korea, which was isolated by Compan˜ia Espanõla de la panipenem and biapenem are also available. Penicillinia y Antibioticos [2] but was extremely Other carbapenems, e.g., doripenem and CS-023 unstable and efforts were made to develop a more (R-115685), are still under development, and at stable compound. The result of this was the first the time of the conference were not licensed in carbapenem to be licensed for clinical use, namely any country. This article reviews the key attri- imipenem. butes of licensed carbapenems and modifies the Among the many different structurally distinct proposed classification scheme for the carbape- classes of b-lactams, the carbapenem class is nem class to include future compounds [4]. considered to be the most potent and to have the widest spectrum of antimicrobial activity. MICROBIOLOGY Carbapenems are rapidly bactericidal, and dem- onstrate time-dependent killing. Their spectrum Carbapenems are active against many clinically of antimicrobial activity includes Gram-positive important pathogens and are particularly stable to and Gram-negative aerobic and anaerobic patho- a wide variety of b-lactamases (including the gens. Their in-vitro activity includes the ex- ESBLs and AmpC-type enzymes). As a conse- tended-spectrum b-lactamase (ESBL)-producing quence, they retain activity against a wide variety pathogens, which are increasingly being reported of multiply resistant pathogens, especially ceph- from different parts of the world. A comprehen- alosporin-resistant Gram-negative bacteria. This is of importance, as the incidence of strains expressing ESBLs (and often more than one ESBL Corresponding author and reprint requests: P. M. Shah, per organism) is increasing [5–8]. For example, Gutzkowstr. 69, D-60594 Frankfurt am Main, Germany E-mail: [email protected] the Paul-Ehrlich-Society’s multicentre survey on Ó 2008 The Author Journal Compilation Ó 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 1), 175–180 176 Clinical Microbiology and Infection, Volume 14, Supplement 1, January 2008 Table 1. MICs for extended-spectrum b-lactamase-pro- found to be slightly less stable in the presence of ducing Klebsiella b-lactamase than imipenem. Kiffer et al. [14] Number of isolates inhibited compared the pharmacodynamic potencies of imipenem, meropenem and ertapenem—mea- MIC (mg ⁄ L) Ertapenem Imipenem sured as percentage of dosing interval during which free drug was above the MIC and modelled 0.007 8 via a 5000-subject Monte-Carlo simula- 0.015 49 0.03 71 tion—against 133 ESBL-producing isolates. They 0.06 39 14 also predicted that ertapenem was slightly less 0.12 9 125 effective than imipenem or meropenem. Colodner 0.25 22 et al. [29] from Israel reported that imipenem was 0.5 2 15 114the most active carbapenem against ESBL pro- 211ducers, followed by meropenem, with ertapenem 4 being the least active. 81 Resistance to carbapenems has been reported in Data from [12,13]. many species of Gram-negative bacilli [15–29] In 1999, Martinez-Martinez et al. [15] reported that, resistance, which has been conducted on a regular in two clinical isolates of ESBL-producing basis since 1975, reported, for the years 2001 and K. pneumoniae, resistance to carbapenems was 2004, ESBL phenotypes in 1.8% and 5.1% of due to porin loss and the presence of these b- Escherichia coli, in 12.7% and 7.3% of Klebsiella lactamases. Lee et al. claim to be the first to report pneumoniae, and in 5.3% and 12.4% of Klebsiella reduced carbapenem susceptibility in K. pneumo- oxytoca isolates, respectively [9]. niae strains due to combined DHA b-lactamases Imipenem, meropenem and ertapenem are (discovered at Dhahran) production and porin generally considered to be equally active against loss [30]. Woodford et al. from the UK confirmed most Gram-negative and Gram-positive patho- ertapenem resistance in 95 Klebsiella spp. and 76 gens [10–12]. However, there are subtle differ- Enterobacter spp. sent to their reference centre [31]. ences, depending partly on the b-lactamase These had combinations of ESBLs or AmpC and produced by the organisms. impermeability. Only 8% of the Klebsiella spp.and In 2001, Livermore et al. reported differences in 32% of the Enterobacter spp. were resistant to activity between ertapenem and imipenem imipenem, and 26% of both species were resistant against Klebsiella isolates in relation to b-lactamase to meropenem. According to Woodford et al., the profiles. The MIC50 and MIC90 of ertapenem for differential susceptibility to carbapenems war- ESBL producers were 0.03 and 0.06 mg ⁄ L, respec- rants further investigation and ‘may reflect rela- tively, whereas those of imipenem were 0.12 and tive penetration rates through minor porins, 0.5 mg ⁄ L, respectively. Table 1 gives the distri- differential susceptibility to efflux or relative bution of strains inhibited at various concentra- susceptibility to slow hydrolysis by AmpC en- tions [13]. Livermore et al. also investigated zymes or ESBLs’ [31]. A report from Spain, where inoculum effects on MIC. They reported that the Hernandez et al. found 8% imipenem resistance maximum inoculum effect with ertapenem for an in Salmonella enterica from chicken, is alarming ESBL producer was eight-fold and that most [32]. All previously licensed carbapenems are effects were four-fold or less; effects with imipe- clinically inactive against methicillin-resistant nem were unrelated to ESBL production and were staphylococci, but a newer analogue (CS-023; slightly greater than those with ertapenem. Sankyo, Tokyo, Japan) is active in vitro against A K. pneumoniae strain that produced a carbape- such isolates [33]. nemase (IMP-1 enzyme), but lacked an outer- Of clinical interest is the selection of carbape- membrane porin, was highly resistant to both nem non-susceptible mutants under treatment. ertapenem and imipenem (MIC >32 mg ⁄ L). The first report I am aware of was published from A variant of the same strain that retained the France by Mainardi et al. in 1997 [34]. They carbapenemase but regained porin expression cultured an imipenem-resistant strain of Citrob- was more susceptible to imipenem (MIC 2 mg ⁄ L) acter freundii that did not produce carbapenemase, and ertapenem (MIC 6 mg ⁄ L). Ertapenem was and the authors concluded that the resistance was Ó 2008 The Author Journal Compilation Ó 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 1), 175–180 Shah Parenteral carbapenems 177 associated with reduced porin-mediated perme- has a half-life of 4 h, permitting once-daily dos- ability with high-level cephalosporinase producing. All carbapenems are widely distributed in the tion. Since then, similar anecdotal case reports of body and penetrate a broad range of body tissues carbapenem resistance selected under carbape- and fluids. The usual daily dose for imipenem, nem treatment have been published by several meropenem and panipenem ranges from 1.5 to authors, concerning imipenem and meropenem 3.0 g, depending on the pathogen and the site of [35], imipenem [36], meropenem [37], ertapenem infection. Biapenem was dosed at 300 mg twice- and meropenem [38], imipenem and meropenem daily in the Japanese clinical trials; however, in [39], and ertapenem [40]. the Swedish trials the dose selected was 500 mg three times daily [46]. PHARMACOKINETIC PROPERTIES CLASSIFICATION OF CARBAPENEMS Imipenem and panipenem are subject to degra- dation by dehydropeptidase-I, a renal tubular Based on antimicrobial activity, as well as expe- enzyme, and are thus co-administered with a rience from clinical use and clinical trials, a dehydropeptidase-I inhibitor, cilastatin or bet- classification of carbapenems is proposed amipron. Meropenem, biapenem and ertapenem (Table 3) [4]. In comparison to imipenem, me- are more stable and do not require protection ropenem,

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