REVIEW

Parenteral P. M. Shah

J. W. Goethe Universitaet, Arzt fuer Innere Medizin, Mikrobiologie und Infektion sepidemiologie, Frankfurt, Germany

ABSTRACT Among the many different structurally distinct classes of b-lactams, the 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. , and are licensed in the European Community and 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 Espan˜ola de la panipenem and biapenem are also available. Penicillinia y Antibioticos [2] but was extremely Other carbapenems, e.g., 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 ). 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

2008 The Author Journal Compilation 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- , 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 -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 ), 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

2008 The Author Journal Compilation 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 produc- ing. 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, 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, biapenem and panipenem, ertapenem from dehydropeptidase-I. is less active against Pseudomonas species and Table 2 gives the pharmacokinetic parameters enterococci, and is thus not indicated in clinical of the compounds. The urinary excretion rates situations where a nosocomial infection is sus- varies from 30% for panipenem to 70% for pected. Whether the minor differences in activity imipenem and meropenem [41–45]. The lowest against ESBL producers are of clinical relevance rates of protein binding, namely 4%, are reported remains to be determined. Owing to its longer for panipenem and biapenem; it is also low for elimination half-life and once-daily dosing regi- imipenem and meropenem, whereas ertapenem men, ertapenem could be an ideal carbapenem for has a high binding rate of 95%. The elimination the treatment of community-acquired ESBL infec- half-life is c. 1 h for all except ertapenem, which tions, whereas the other carbapenems should

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

C ⁄ % c % Dose (mg) max (mg L) Half-life (h) Protein binding ( ) Urinary recovery ( )

Imipenema 500 12–20 0.95 13–20 70 Meropenem 500 23 0.95 10 70 Panipenemb 500 28 1.2 4 30 Biapenem 600 32 1.0 4 60 Ertapenem 1000 155 (i.v.) 4.0 95 38 67 (i.m.) i.v., intravenous infusion; i.m., intramuscular injection. aIn combination with cilastatin. bIn combination with betampiron. cUnchanged compound.

Table 3. Classification of carbapenemsa

Group 1 Group 2 Group 3

Limited activity against non-fermentative Active also against non-fermentative In addition to group 2 Gram-negative bacilli, suitable for Gram-negative bacilli, suitable for spectrum, also active against community-acquired infections nosocomial infections methicillin-resistant Ertapenem and panipenem Imipenem, meropenem and CS-023 (investigational) biapenem Doripenem (investigational) aAdapted from [4].

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 1), 175–180 178 Clinical Microbiology and Infection, Volume 14, Supplement 1, January 2008

Table 4. Influence of inoculum on MIC and MBC for as the therapy of choice for treating Klebsiella pneumoniae severe infections with ESBL-producing organ- Ciprofloxacin Imipenem isms’ [48].

Inoculum MIC MBC MIC MBC CONCLUSION · 5 5 10 0.38 0.76 0.19 0.19 Infections caused by ESBL-producing Gram-neg- 5 · 107 1.52 3.04 0.38 0.38 ative bacteria complicate therapy and are increas- Data adapted from [47]. ingly reported both in hospitals and in the community. Antibiotic options are extremely lim- be used in hospital-acquired infections. Thus, ited, with carbapenems the treatment of choice for newer drugs can be easily included in the present serious infections. Disturbingly, case of isolates scheme. acquiring resistance under treatment have been reported. Clinical microbiologists need to be aware of the subtle differences in in-vitro activity CLINICAL EFFICACY OF CARBAPENEMS IN among the few carbapenems available, though it THE TREATMENT OF INFECTIONS CAUSED has not been determined whether these are of BY ESBL PRODUCERS clinical relevance. In order to preserve this group Endmiani et al. [47] investigated 35 cases of of compounds, they should not be used indis- bloodstream infections caused by TEM-52 ESBL- criminately. Other alternatives, for which very producing K. pneumoniae. Twenty-eight cases limited clinical experience is available, are classified as ‘non-fatal disease’ were investigated and tigecycline. with regard to response to treatment with cipro- floxacin or imipenem. Seven strains were resistant REFERENCES to ciprofloxacin in vitro. Ten patients were treated with imipenem, two of whom failed to respond. 1. Shah PM. In vitro activity of thienamycin. Methods Find In the ciprofloxacin group, only two of seven Exp Clin Pharmacol 1981; 3: 387–390. 2. Spratt BG, Jobanputra V, Zimmermann W. Binding of patients had even a partial response, and five thienamycin and to the -binding failed, although the bacteria were classified as proteins of Escherichia coli K-12. Antimicrob Agents Chemo- susceptible to ciprofloxacin. The authors noted ther 1977; 12: 406–409. that the MIC and MBC of ciprofloxacin were 3. Bryskier A. Carbape´ne`mes. In: Bryskier A, ed. Antibiotiques markedly influenced by inoculum, whereas there agents antibacte´s et antifongiques, 2nd edn. Paris: Ellipses E´dition Marketing S.A, 1999; 305–350. was no effect for imipenem (Table 4). 4. Shah PM, Isaacs RD. Ertapenem, the first of a new group In an international study involving 12 hospitals of carbapenems. J Antimicrob Chemother 2003; 52: 538–542. in seven countries over a period of 2 years, 5. Bush K. New b-lactamases in gram-negative bacteria: Paterson et al. [48] prospectively collected data diversity and impact on the selection of antimicrobial therapy. Clin Infect Dis 2001; 32: 1085–1089. on 455 episodes of K. pneumoniae bacteraemia. 6. Witte W, Mielke M. b-Laktamasen mit breitem Wir- Eighty-five episodes were caused by ESBL-pro- kungsspektrum. Bundesgesundheitsbl - Gesundheitsforsch - ducing strains. All strains were susceptible to Gesundheitschutz 2003; 46: 881–890. imipenem or meropenem; 47% were resistant to 7. Jacoby GA, Munoz-Price LS. The new beta-lactamases. % N Engl J Med 2005; 352: 380–391. –, 71 to gentamicin and b % 8. Paterson DL, Bonomo RA. Extended-spectrum -lacta- 19 to ciprofloxacin. Treatment with a carbape- mases: a clinical update. Clin Microbiol Rev 2005; 18: 657– nem (primarily imipenem) was associated with 686. significantly lower 14-day mortality than was 9. Kresken M, Hafner D, Schmitz F-J, Wichelhaus TA. Re- treatment with other in-vitro active . sistenz bei ha¨ufig isolierten Enterobacteriaceae gegenu¨ber Breitspektrum-Antibiotika. Chemother J 2006; 15: 179–190. The authors concede that ‘unforeseen bias may 10. King A, Boothman C, Phillips I. Comparative in-vitro occur in any non-randomised study with a design activity of meropenem on clinical isolates from the United similar to ours’ and that ‘optimally, a large, multi- Kingdom. J Antimicrob Chemother 1989; 24 (suppl A): 31–45. centre, randomised, controlled trial should be 11. Hoban DJ, Jones RN, Yamane N, Frei R, Trilla A, Pignatari performed that compares the efficacy of carba- AC. In vitro activity of three carbapenem antibiotics. Comparative studies with biapenem (L-627), imipenem, penems with that of other antibiotic classes. Until and meropenem against aerobic pathogens isolated such a trial is performed, we recommend carba- worldwide. Diagn Microbiol Infect Dis 1993; 17: 299–305.

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 1), 175–180 Shah Parenteral carbapenems 179

12. Livermore DM, Carter MW, Bagel S et al. In vitro activities 26. Henrichfreise B, Wiegand I, Wagner J, Wiedemann B. of ertapenem (MK-0826) against recent clinical bacteria VIM-metallo-beta-lactamase bei . collected in Europe and Australia. Antimicrob Agents Che- Chemother J 2006; 15: 17–19. mother 2001; 45: 1860–1867. 27. Wang CY, Jerng JS, Cheng KY et al. Pandrug-resistant 13. Livermore DM, Oakton KJ, Carter MW, Warner M. Pseudomonas aeruginosa among hospitalised patients: clin- Activity of ertapenem (MK-0826) versus Enterobacteriaceae ical features, risk-factors and outcomes. Clin Microbiol with potent b-lactamases. Antimicrob Agents Chemother Infect 2006; 12: 63–68. 2001; 45: 2831–2837. 28. Lee C-H, Chu C, Liu J-W, Chen Y-S, Chiu C-J, Su L-H. 14. Kiffer CR, Kuti JL, Eagye KJ, Mendes C, Nicolau DP. Collateral damage of flomoxef therapy: in vivo devel- Pharmacodynamic profiling of imipenem, meropenem opment of porin deficiency and acquisition of blaDHA- and ertapenem against clinical isolates of extended-spec- 1 leading to ertapenem resistance in clinical isolate trum beta-lactamase-producing Escherichia coli and Klebsi- of Klebsiella pneumoniae producing CTX-M-3 and ella spp. from Brazil. Int J Antimicrob Agents 2006; 28: 340– SHV-5 b-lactamases. J Antimicrob Chemother 2007; 60: 344. 410–413. 15. Martinez-Martinez L, Pascual A, Hernandez-Alles S et al. 29. Colodner R, Samra Z, Keller N et al. First national sur- Roles of b-lactamases and porins in activities of carba- veillance of susceptibility of extended-spectrum b-lac- penems and against Klebsiella pneumoniae. tamase-producing Escherichia coli and Klebsiella spp. to Antimicrob Agents Chemother 1999; 43: 1669–1673. antimicrobials in Israel. Diagn Microbiol Infect Dis 2007; 57: 16. MacKenzie FM, Forbes KJ, Dorai-John TS, Amyes SGB, 201–205. Gould IM. Emergence of a carbapenem-resistant Klebsiella 30. Lee K, Yong D, Choi YS et al. Reduced imipenem sus- pneumoniae. Lancet 1997; 350: 783. ceptibility in Klebsiella pneumoniae clinical isolates with 17. Ahmad M, Urban C, Mariano N et al. Clinical character- plasmid-mediated CMY-2 and DHA-1 b-lactamases istics and molecular epidemiology associated with imipe- co-mediated by porin loss. Int J Antimicrob Agents 2007; nem-resistant Klebsiella pneumoniae. Clin Infect Dis 1999; 29: 29: 201–206. 352–355. 31. Woodford N, Dallow JW, Hill RL et al. Ertapenem resis- 18. Cao VTB, Arlet G, Ericsson BM, Tammelin A, Courvalin P, tance among Klebsiella and Enterobacter submitted in the Lambert T. Emergence of imipenem resistance in Klebsiella UK to a reference laboratory. Int J Antimicrob Agents 2007; pneumoniae owing to combination of plasmid-mediated 29: 456–459. CMY-4 and permeability alteration. J Antimicrob Chemother 32. Hernandez T, Rodriguez-Alvarez C, Arevalo MOP, Torres 2000; 46: 895–900. A, Sierra A, Arias A. Antimicrobial-resistant Salmonella 19. Nordmann P, Poirel L. Emerging carbapenemases in enterica serovars isolated from chickens in Spain. J Che- Gram-negative aerobes. Clin Microbiol Infect 2002; 8: 321– mother 2002; 14: 346–350. 331. 33. Thomson KS, Moland ES. CS-023 (R-115685), a novel 20. Gales AC, Biedenbach DJ, Winokur P, Hacek DM, Pfaller carbapenem with enhanced in vitro activity against oxa- MA, Jones RN. Carbapenem-resistant Serratia marcescens cillin-resistant staphylococci and Pseudomonas aeruginosa. isolates producing Bush Group 2f b-lactamase (SME-1) in J Antimicrob Chemother 2004; 54: 557–562. the United States: results from the MYSTIC Programme. 34. Mainardi JL, Mugnier P, Coutrot A, Buu-Hoi A, Collatz E, Diagn Microbiol Infect Dis 2001; 39: 125–127. Gutmann L. Carbapenem resistance in a clinical isolate of 21. Yamasaki K, Komatsu M, Yamashita T et al. Production of Citrobacter freundii. Antimicrob Agents Chemother 1987; 41: CTX-M-3 extended-spectrum beta-lactamase and IMP-1 2352–2354. metallo beta-lactamase by five Gram-negative bacilli: sur- 35. Hong T, Moland ES, Abdalhamid B et al. Escherichia coli: vey of clinical isolates from seven laboratories collected in development of carbapenem resistance during therapy. 1998 and 2000, in the Kinki region of Japan. J Antimicrob Clin Infect Dis 2007; 40: e84–e86. Chemother 2003; 51: 631–638. 36. Thiolas A, Bollet C, La Scola B, Raoult D, Pages JM. Suc- 22. Bradford PA, Bratu S, Urban C et al. Emergence of carba- cessive emergence of Enterobacter aerogenes strains -resistant Klebsiella species possessing the class A resistant to imipenem and colistin in a patient. Antimicrob carbapenem-hydrolyzing KPC-2 and inhibitor-resistant Agents Chemother 2005; 49: 1354–1358. TEM-30 beta-lactamases in New York City. Clin Infect Dis 37. Albert-Braun S, Wichelhaus TA. Nachweis von zwei 2004; 39: 55–60. Carbapenem-resistenten Enterobacteriaceae-Isolaten in ei- 23. Galani I, Souli M, Chryssouli Z, Katsala D, Giamarellou H. nem deutschen Krankenhaus. Chemother J 2006; 15: 13–16. First identification of an Escherichia coli clinical isolate 38. Pillay DG, De P, Merard R et al. Therapy-driven selection producing both metallo-beta-lactamase VIM-2 and of carbapenem resistance in CTX-M-producing Klebsiella extended-spectrum beta-lactamase IBC-1. Clin Microbiol pneumoniae. Clin Microbiol Infect 2006; 12 (suppl 4): P1621. Infect 2004; 10: 757–760. 39. Mena A, Plasencia V, Garcia L et al. Characterization of a 24. Wang CX, Mi ZH. IMP-1 metallo-beta-lactamase-produc- large outbreak by CTX-M-1-producing Klebsiella pneumo- ing Pseudomonas aeruginosa in a university hospital in the niae and mechanisms leading to in vivo carbapenem People’s Republic of China. J Antimicrob Chemother 2004; resistance development. J Clin Microbiol 2006; 44: 2831– 54: 1159–1160. 2837. 25. Hirakata Y, Yamaguchi T, Nakano M et al. Clinical and 40. Elliott E, Brink AJ, van Greune J et al. In vivo development bacteriological characteristics of IMP-type metallo-beta- of ertapenem resistance in a patient with pneumonia lactamase-producing Pseudomonas aeruginosa. Clin Infect caused by Klebsiella pneumoniae with an extended-spec- Dis 2003; 37: 26–32. trum beta-lactamase. Clin Infect Dis 2006; 42: e95–e98.

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 1), 175–180 180 Clinical Microbiology and Infection, Volume 14, Supplement 1, January 2008

41. Perry CM, Ibbotson T. Biapenem. Drugs 2002; 62: 2221– 46. Brismar B, Akerlund JE, Sjostedt S et al. Biapenem versus 2234. imipenem ⁄ cilastatin in the treatment of complicated intra- 42. Ku¨ mmel A, Schlosser V, Petersen E, Daschner FD. Phar- abdominal infections: report from a Swedish Study Group. macokinetics of imipenem–cilastatin in serum and tissue. Scand J Infect Dis 1996; 28: 507–512. Eur J Clin Microbiol Infect Dis 1985; 4: 609–610. 47. Endimiani A, Luzzaro F, Perilli M et al. Bacteremia due to 43. Unertl KE, Adam D, Sunder-Plassmann L, Koller H, Klebsiella pneumoniae isolates producing the TEM-52 Martin ES III. Konzentrationen von Imipenem im Lun- extended-spectrum beta-lactamase: treatment outcome of gengewebe. FAC Fortschr Antimikrob Antineopl Chemother patients receiving imipenem or ciprofloxacin. Clin Infect 1986; 2: 321–327. Dis 2004; 38: 243–251. 44. Tomaselli F, Maier A, Matzi V, Smolle-Juttner FM, Dittrich 48. Paterson DL, Ko WC, Von Gottberg A et al. Antibiotic P. Penetration of meropenem into pneumonic human lung therapy for Klebsiella pneumoniae bacteremia: implications tissue as measured by in vivo microdialysis. Antimicrob of production of extended-spectrum beta-lactamases. Clin Agents Chemother 2004; 48: 2228–2232. Infect Dis 2004; 39: 31–37. 45. Mouton JW, Touzw DJ, Horrevorts AM, Vinks AA. Comparative pharmacokinetics of the carbapenems: clini- cal implications. Clin Pharmacokinet 2000; 39: 185–201.

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