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

INTRODUCTION Thienamycin was found to be highly active against a variety of isolates [1]. The ‘carbapenem story’ started with the detection of thienamycin in the laboratories of Merck, Sharp & Dohme (NJ, USA), from a culture of Streptomyces cattleya, which was isolated by Compan˜ia Espan˜ola de la Penicillinia y Antibioticos [2] but was extremely unstable and efforts were made to develop a more stable compound. The result of this was the first carbapenem to be licensed for clinical use, namely imipenem. Among the many different structurally distinct classes of b-lactams, the carbapenem class is considered to be the most potent and to have the widest spectrum of antimicrobial activity. Carbapenems are rapidly bactericidal, and demonstrate time-dependent killing. Their spectrum of antimicrobial activity includes Gram-positive and Gram-negative aerobic and anaerobic pathogens. Their in-vitro activity includes the extended-spectrum b-lactamase (ESBL)-producing pathogens, which are increasingly being reported from different parts of the world. A comprehen-

Corresponding author and reprint requests: P. M. Shah, Gutzkowstr. 69, D-60594 Frankfurt am Main, Germany E-mail: [email protected]

sive account of carbapenems has been written by Bryskier [3]. Imipenem was licensed in 1984 in Germany. It was more than 10 years before a second carbapenem, meropenem, was licensed in 1995, while ertapenem was licensed by the European Community in 2002. In Japan and South Korea, panipenem and biapenem are also available. Other carbapenems, e.g., doripenem and CS-023 (R-115685), are still under development, and at the time of the conference were not licensed in any country. This article reviews the key attributes of licensed carbapenems and modifies the proposed classification scheme for the carbapenem class to include future compounds [4]. MICROBIOLOGY Carbapenems are active against many clinically important pathogens and are particularly stable to a wide variety of b-lactamases (including the ESBLs and AmpC-type enzymes). As a consequence, they retain activity against a wide variety of multiply resistant pathogens, especially cephalosporin-resistant Gram-negative bacteria. This is of importance, as the incidence of strains expressing ESBLs (and often more than one ESBL per organism) is increasing [5–8]. For example, the Paul-Ehrlich-Society’s multicentre survey on

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176 Clinical Microbiology and Infection, Volume 14, Supplement 1, January 2008

Table 1. MICs for extended-spectrum b-lactamase-producing Klebsiella Number of isolates inhibited MIC (mg ⁄ L)

Ertapenem

0.007 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8

8 49 71 39 9 2 1 1

Imipenem

14 125 22 15 4 1

1

Data from [12,13].

resistance, which has been conducted on a regular basis since 1975, reported, for the years 2001 and 2004, ESBL phenotypes in 1.8% and 5.1% of Escherichia coli, in 12.7% and 7.3% of Klebsiella pneumoniae, and in 5.3% and 12.4% of Klebsiella oxytoca isolates, respectively [9]. Imipenem, meropenem and ertapenem are generally considered to be equally active against most Gram-negative and Gram-positive pathogens [10–12]. However, there are subtle differences, depending partly on the b-lactamase produced by the organisms. In 2001, Livermore et al. reported differences in activity between ertapenem and imipenem against Klebsiella isolates in relation to b-lactamase profiles. The MIC50 and MIC90 of ertapenem for ESBL producers were 0.03 and 0.06 mg ⁄ L, respectively, whereas those of imipenem were 0.12 and 0.5 mg ⁄ L, respectively. Table 1 gives the distribution of strains inhibited at various concentrations [13]. Livermore et al. also investigated inoculum effects on MIC. They reported that the maximum inoculum effect with ertapenem for an ESBL producer was eight-fold and that most effects were four-fold or less; effects with imipenem were unrelated to ESBL production and were slightly greater than those with ertapenem. A K. pneumoniae strain that produced a carbapenemase (IMP-1 enzyme), but lacked an outermembrane porin, was highly resistant to both ertapenem and imipenem (MIC >32 mg ⁄ L). A variant of the same strain that retained the carbapenemase but regained porin expression was more susceptible to imipenem (MIC 2 mg ⁄ L) and ertapenem (MIC 6 mg ⁄ L). Ertapenem was

found to be slightly less stable in the presence of b-lactamase than imipenem. Kiffer et al. [14] compared the pharmacodynamic potencies of imipenem, meropenem and ertapenem—measured as percentage of dosing interval during which free drug was above the MIC and modelled via a 5000-subject Monte-Carlo simulation—against 133 ESBL-producing isolates. They also predicted that ertapenem was slightly less effective than imipenem or meropenem. Colodner et al. [29] from Israel reported that imipenem was the most active carbapenem against ESBL producers, followed by meropenem, with ertapenem being the least active. Resistance to carbapenems has been reported in many species of Gram-negative bacilli [15–29] In 1999, Martinez-Martinez et al. [15] reported that, in two clinical isolates of ESBL-producing K. pneumoniae, resistance to carbapenems was due to porin loss and the presence of these blactamases. Lee et al. claim to be the first to report reduced carbapenem susceptibility in K. pneumoniae strains due to combined DHA b-lactamases (discovered at Dhahran) production and porin loss [30]. Woodford et al. from the UK confirmed ertapenem resistance in 95 Klebsiella spp. and 76 Enterobacter spp. sent to their reference centre [31]. These had combinations of ESBLs or AmpC and impermeability. Only 8% of the Klebsiella spp.and 32% of the Enterobacter spp. were resistant to imipenem, and 26% of both species were resistant to meropenem. According to Woodford et al., the differential susceptibility to carbapenems warrants further investigation and ‘may reflect relative penetration rates through minor porins, differential susceptibility to efflux or relative susceptibility to slow hydrolysis by AmpC enzymes or ESBLs’ [31]. A report from Spain, where Hernandez et al. found 8% imipenem resistance in Salmonella enterica from chicken, is alarming [32]. All previously licensed carbapenems are clinically inactive against methicillin-resistant staphylococci, but a newer analogue (CS-023; Sankyo, Tokyo, Japan) is active in vitro against such isolates [33]. Of clinical interest is the selection of carbapenem non-susceptible mutants under treatment. The first report I am aware of was published from France by Mainardi et al. in 1997 [34]. They cultured an imipenem-resistant strain of Citrobacter freundii that did not produce carbapenemase, and the authors concluded that the resistance was

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Shah

associated with reduced porin-mediated permeability with high-level cephalosporinase production. Since then, similar anecdotal case reports of carbapenem resistance selected under carbapenem treatment have been published by several authors, concerning imipenem and meropenem [35], imipenem [36], meropenem [37], ertapenem and meropenem [38], imipenem and meropenem [39], and ertapenem [40].

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has a half-life of 4 h, permitting once-daily dosing. All carbapenems are widely distributed in the body and penetrate a broad range of body tissues and fluids. The usual daily dose for imipenem, meropenem and panipenem ranges from 1.5 to 3.0 g, depending on the pathogen and the site of infection. Biapenem was dosed at 300 mg twicedaily in the Japanese clinical trials; however, in the Swedish trials the dose selected was 500 mg three times daily [46].

PHARMACOKINETIC PROPERTIES Imipenem and panipenem are subject to degradation by dehydropeptidase-I, a renal tubular enzyme, and are thus co-administered with a dehydropeptidase-I inhibitor, cilastatin or betamipron. Meropenem, biapenem and ertapenem are more stable and do not require protection from dehydropeptidase-I. Table 2 gives the pharmacokinetic parameters of the compounds. The urinary excretion rates varies from 30% for panipenem to 70% for imipenem and meropenem [41–45]. The lowest rates of protein binding, namely 4%, are reported for panipenem and biapenem; it is also low for imipenem and meropenem, whereas ertapenem has a high binding rate of 95%. The elimination half-life is c. 1 h for all except ertapenem, which

CLASSIFICATION OF CARBAPENEMS Based on antimicrobial activity, as well as experience from clinical use and clinical trials, a classification of carbapenems is proposed (Table 3) [4]. In comparison to imipenem, meropenem, biapenem and panipenem, ertapenem is less active against Pseudomonas species and enterococci, and is thus not indicated in clinical situations where a nosocomial infection is suspected. Whether the minor differences in activity against ESBL producers are of clinical relevance remains to be determined. Owing to its longer elimination half-life and once-daily dosing regimen, ertapenem could be an ideal carbapenem for the treatment of community-acquired ESBL infections, whereas the other carbapenems should

Table 2. Pharmacokinetic parameters of the licensed carbapenems after intravenous infusion Antibiotic

Dose (mg)

Cmax (mg ⁄ L)

Half-life (h)

Protein binding (%)

Urinary recoveryc (%)

500 500 500 600 1000

12–20 23 28 32 155 (i.v.) 67 (i.m.)

0.95 0.95 1.2 1.0 4.0

13–20 10 4 4 95

70 70 30 60 38

Imipenema Meropenem Panipenemb Biapenem Ertapenem

i.v., intravenous infusion; i.m., intramuscular injection. In combination with cilastatin. b In combination with betampiron. c Unchanged compound. a

Table 3. Classification of carbapenemsa Group 1

Group 2

Group 3

Limited activity against non-fermentative Gram-negative bacilli, suitable for community-acquired infections

Active also against non-fermentative Gram-negative bacilli, suitable for nosocomial infections

Ertapenem and panipenem

Imipenem, meropenem and biapenem Doripenem (investigational)

In addition to group 2 spectrum, also active against methicillin-resistant Staphylococcus aureus CS-023 (investigational)

a

Adapted from [4].

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Table 4. Influence of inoculum on MIC and MBC for Klebsiella pneumoniae Ciprofloxacin

Imipenem

Inoculum

MIC

MBC

MIC

MBC

5 · 105 5 · 107

0.38 1.52

0.76 3.04

0.19 0.38

0.19 0.38

Data adapted from [47].

be used in hospital-acquired infections. Thus, newer drugs can be easily included in the present scheme. CLINICAL EFFICACY OF CARBAPENEMS IN THE TREATMENT OF INFECTIONS CAUSED BY ESBL PRODUCERS Endmiani et al. [47] investigated 35 cases of bloodstream infections caused by TEM-52 ESBLproducing K. pneumoniae. Twenty-eight cases classified as ‘non-fatal disease’ were investigated with regard to response to treatment with ciprofloxacin or imipenem. Seven strains were resistant to ciprofloxacin in vitro. Ten patients were treated with imipenem, two of whom failed to respond. In the ciprofloxacin group, only two of seven patients had even a partial response, and five failed, although the bacteria were classified as susceptible to ciprofloxacin. The authors noted that the MIC and MBC of ciprofloxacin were markedly influenced by inoculum, whereas there was no effect for imipenem (Table 4). In an international study involving 12 hospitals in seven countries over a period of 2 years, Paterson et al. [48] prospectively collected data on 455 episodes of K. pneumoniae bacteraemia. Eighty-five episodes were caused by ESBL-producing strains. All strains were susceptible to imipenem or meropenem; 47% were resistant to piperacillin–tazobactam, 71% to gentamicin and 19% to ciprofloxacin. Treatment with a carbapenem (primarily imipenem) was associated with significantly lower 14-day mortality than was treatment with other in-vitro active antibiotics. The authors concede that ‘unforeseen bias may occur in any non-randomised study with a design similar to ours’ and that ‘optimally, a large, multicentre, randomised, controlled trial should be performed that compares the efficacy of carbapenems with that of other antibiotic classes. Until such a trial is performed, we recommend carba-

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