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Keywords:

  • Carbapenems;
  • β-lactams;
  • multidrug resistance;
  • review

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References

Antibiotic resistance among Gram-negative pathogens in hospitals is a growing threat to patients and is driving the increased use of carbapenems. Carbapenems are potent members of the β-lactam family of antibiotics, with a history of safety and efficacy for serious infections that exceeds 20 years. Original and review articles were identified from a Medline search (1979–2008). Reference citations from identified publications, abstracts from the Interscience Conferences on Antimicrobial Agents and Chemotherapy and package inserts were also used. Carbapenems are effective in treating severe infections at diverse sites, with relatively low resistance rates and a favourable safety profile. Carbapenems are the β-lactams of choice for the treatment of infections caused by multidrug-resistant organisms. Optimized dosing of carbapenems should limit the emergence of resistance and prolong the utility of these agents. The newly approved doripenem should prove to be a valuable addition to the currently available carbapenems: imipenem, meropenem and ertapenem.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References

β-Lactams comprise more than half of all antibiotics.

They are among the most widely prescribed antimicrobial agents in both community and hospital settings, because they have a long history of efficacy and safety [1]. The use of β-lactams for more than 60 years has, however, resulted in a dramatic increase in the rates of resistance that now threatens the utility of the majority of this large drug family. Enzymes have appeared with potent hydrolytic activity against penicillins, cephalosporins, cephamycins, β-lactam–β-lactamase inhibitor combinations, and even carbapenems [2,3]. Several bacterial species have acquired these enzymes, thus becoming multidrug-resistant, and leaving clinicians with few therapeutic options [4]. Within the β-lactam family, carbapenems have historically been the drugs of choice for the treatment of severe infections caused by multidrug-resistant organisms [5].

Antimicrobial resistance continues to evolve, and presents serious challenges concerning the therapy of both nosocomial and community-acquired infections; 50–60% of the more than two million nosocomial infections in the USA each year are caused by antimicrobial-resistant bacteria [6]. Although carbapenems retain nearly universal activity against Enterobacteriaceae, rates of resistance to carbapenems are increasing in Pseudomonas and Acinetobacter spp. [7].

On the other hand, reports of Enterobacteriaceae harbouring enzymes such as metallo-β-lactamases and carbapenemases are increasingly being recognized [8–12]. Such bacteria can develop resistance to all β-lactam antibiotics, including carbapenems.

Resistance to antimicrobial agents is mediated by many factors, including β-lactamases, porin loss, efflux pumps, and target modifications.

β-Lactamases are enzymes that hydrolyze β-lactam agents. They are ubiquitous in Gram-negative bacilli, and are the major cause of resistance to β-lactams in Gram-negative bacteria. The genes of these enzymes can be either chromosome- or plasmid-borne. The latter pose a significant threat in the context of controlling bacterial resistance, because plasmid-borne β-lactamase genes are readily transferable among bacteria, allowing an effective and rapid spread of resistance. The β-lactamases with the greatest impact in the nosocomial setting are mainly extended-spectrum β-lactamases (ESBLs), AmpC-type β-lactamases and carbapenemases.

Carbapenemases (metallo-β-lactamases and active-site serine carbapenemases) are fairly uncommon, although they are a source of considerable concern, due to a spectrum of activity that encompasses almost all known β-lactams, from penicillins to the carbapenems, and they are generally not susceptible to current class A β-lactamase inhibitors [6]. The most clinically important bacteria harbouring carbapenemases are Pseudomonas and Acinetobacter, although sporadic reports of carbapenemase-mediated resistance to carbapenems in Enterobacteriaceae have appeared [3,13–16]. Historically, carbapenems have retained stability to almost all clinically relevant β-lactamases, but some class B β-lactamases (IMP, VIM, SPM, GIMs), along with some rare class A (SPE, NMC-A, IMI-1, KPC) and class D enzymes (OXAs), are able to hydrolyze these antibiotics (Kattan JN, Guzman AM, Correa A et al. Evidence for widespread dissemination of OXA-23-like carbapenemases in Acinetobacter baumannii in Colombia. Programs and Abstracts of the American Society for Microbiology’s 46th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, 2006, Abstract C2-598) [3,17,18]. Although class B enzymes are generally chromosome-encoded, plasmid-carbapenems have been reported in Bacteroides fragilis [19], Pseudomonas aeruginosa, Acinetobacter baumannii and members of the Enterobacteriaceae family [1,20–22].

These β-lactamases have emerged as significant threats to treatment with all β-lactams by becoming epidemic and endemic in the Far East [23], Europe [10] and South America [22,24]. For perspective, it is worth noting that despite the occurrence of carbapenemases, the most common means by which bacteria become carbapenem-resistant in most of the world is via loss of permeability, or through loss of porins, increased efflux of the drug, by increased efflux pump, and target modifications activity [25].

In porin loss, the loss of a membrane protein channel decreases the rate of entry of antibiotics into the periplasm, thus raising the MIC. If combined with β-lactamase production, porin loss may confer resistance to one or many antibiotics simultaneously. An example of this mechanism is the loss of a specific porin known as OprD in P. aeruginosa along with simultaneous production of AmpC, which confers resistance to carbapenems, particularly imipenem [26]. Many Gram-negative bacteria are able to expel antibiotics after entry by utilizing energy-dependent efflux mechanisms. The best studied and described efflux mechanisms are those of P. aeruginosa, in which four multidrug efflux pumps have been well characterized (MexAB–OprM, MexCD–OprJ, MexEF–OprN and MexXY–OprM) [27–29]; each has a preferential set of antimicrobial substrates, including meropenem and ertapenem, which are pumped out of the cell by OprM.

Resistance in Pseudomonas and Acinetobacter is more likely to affect carbapenems because of low membrane permeability and simultaneous expression of multiple resistance mechanisms. With Gram-negative organisms having a plethora of resistance mechanisms at their disposal, carbapenems emerge as the last line of defence in many cases [30,31]. The development of new drugs and the more rational use of currently available antibiotics should help to limit the problem of multidrug-resistant pathogens and prevent the loss of carbapenems as antibiotics of last resort in clinical practice.

Carbapenems occupy a unique position in the β-lactam family of antibacterials. As a class, carbapenems are innately stable to most β-lactamases of Ambler classes A, C and D. Their broad spectrum of activity and their stability in the presence of this wide range of β-lactamases make them important therapeutic options for treating serious infections involving resistant Enterobacteriaceae (including ESBL-producing and AmpC-overproducing isolates), anaerobes, P. aeruginosa, and Acinetobacter spp. [1]. Carbapenems are recommended for the empirical treatment of a variety of severe infections, e.g. nosocomial pneumonia, complicated intra-abdominal infection, septicaemia, complicated skin and skin structure infection, complicated urinary tract infection, meningitis, and acute exacerbations of cystic fibrosis [32–36].

The first carbapenems discovered were olivanic acids produced by Streptomyces olivaceus. This was followed by the discovery of thienamycin in 1976 [37]. The latter was found in the course of a soil-screening programme to identify inhibitors of peptidoglycan synthesis [37,38]. It was produced by a previously unknown Streptomyces spp. that received the name Streptomyces cattleya, as the pigment in its aerial mycelium resembled the colour of the cattleya orchid [20]. These compounds were chemically unstable, so they were not used clinically.

Years later, a more stable thienamycin derivative, N-formimidoyl thienamycin (known as imipenem), was synthesized and approved for use in 1984 [39]. This compound was therapeutically useful, as it was more stable in the solid state and in concentrated solution. However, an additional instability to a mammalian hydrolase from the renal brush border, dehydropeptidase-I (DHP-I), led to the decrease of imipenem levels in urine and the production of a potentially nephrotoxic metabolite [40,41]. The development of an additional compound, cilastatin, to be co-administered in a 1 : 1 ratio with imipenem, prevented hydrolysis by DHP-I and reduced nephrotoxicity [40]. Meropenem was the first carbapenem with a 1-β-methyl group and 2-thiopyrrolidinyl moiety, which renders this antibiotic stable to DHP-I. Other carbapenems, for parenteral administration, were discovered later, and include biapenem, panipenem, ertapenem, lenapenem, E-1010, S-4661 and BMS-181139. Carbapenems that are orally administered include sanfetrinem, DZ-2640, CS-834 and GV-129606 [20].

A recently proposed classification system for carbapenems divides them into two groups [42]. Group 1 carbapenems, e.g. ertapenem, are defined as broad-spectrum agents that have limited activity against non-fermentative Gram-negative bacilli and are most suited for use in community-acquired infections, whereas group 2 carbapenems, e.g. imipenem, meropenem and doripenem, are broad-spectrum agents that are active against non-fermentative Gram-negative bacilli and are particularly useful in treating nosocomial infections. A third group of carbapenems has also been suggested. This category includes agents with activity against methicillin-resistant Staphylococcus aureus, such as PZ-601, a carbapenem under development (Lolans K, Quinn JP. PZ-601 susceptibility against Gram-negative pathogens with known resistance mechanisms. Programs and Abstracts of the American Society for Microbiology’s 47th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, 2007). Table 1 lists each group of carbapenems and the pathogens typically covered by each.

Table 1.   Carbapenem groups and spectrum of activity for each compound
Carbapenem group Group 1 ErtapenemGroup 2 Imipenem Meropenem Doripenem Group 3 PZ-601
Gram-negative aerobes
 AcinetobacterResistantSusceptibleResistant
 Burkholderia cepaciaResistantVariableResistant
 EnterobacteriaceaeSusceptibleSusceptibleSusceptible
 HaemophilusSusceptibleSusceptibleSusceptible
 MoraxellaSusceptibleSusceptibleSusceptible
 NeisseriaSusceptibleSusceptibleSusceptible
 Pseudomonas aeruginosaResistantSusceptibleResistant
 Stenotrophomonas maltophiliaResistantResistantResistant
Gram-positive aerobes
 Enterococcus faecalisResistantVariableVariable
 Enterococcus faecium  (ampicillin-resistant)ResistantResistantResistant
 ListeriaResistantSusceptibleNot reported
 Staphylococcus aureus  (methicillin-susceptible)SusceptibleSusceptibleSusceptible
 S. aureus (methicillin-resistant)ResistantResistantSusceptible
 Streptococcus pneumoniae  (penicillin-susceptible)SusceptibleSusceptibleSusceptible
 Streptococcus pneumoniae  (penicillin-resistant)SusceptibleSusceptibleSusceptible
 Streptococcus pyogenesSusceptibleSusceptibleSusceptible
 Viridans group streptococciSusceptibleSusceptibleSusceptible
Anaerobes
 BacteroidesSusceptibleSusceptibleSusceptible
 Clostridium difficileSusceptibleSusceptibleNot reported
 EubacteriumSusceptibleSusceptibleNot reported
 FusobacteriumSusceptibleSusceptibleNot reported
 PeptostreptococcusSusceptibleSusceptibleNot reported
 PropionibacteriumNot reportedSusceptibleNot reported

Carbapenem Activities

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References

β-Lactam antibiotics share a common structure, the four-membered lactam ring. Carbapenems differ from other β-lactam antibiotics in that they possess a carbon instead of a sulphone in the four-position of the thyazolidinic moiety of the β-lactam ring [20]. They have a broad spectrum of antimicrobial activity that exceeds that of most other classes of antimicrobials [43]. Carbapenems are rapidly bactericidal agents because they bind with high affinity to most high molecular weight penicillin-binding proteins of Gram-negative and Gram-positive bacteria [44]. Carbapenems (except ertapenem) are active against clinically significant Gram-negative non-fermenters such as P. aeruginosa, Burkholderia cepacia and Acinetobacter spp. [45,46]. They also retain activity against streptococci, methicillin-sensitive staphylococci, Neisseria and Haemophilus [39]. Unlike most other broad-spectrum antibiotics, carbapenems are active against most Gram-positive and Gram-negative anaerobes, including subspecies of B. fragilis, Bacteroides thetaiotaomicron, Prevotella bivia, Fusobacterium nucleatum, Fusobacterium mortiferum, Peptostreptococcus asaccharolyticus and Clostridium perfringens [36,39]. Carbapenem-resistant bacteria include: ampicillin-resistant Enterococcus faecium, methicillin-resistant staphylococci, Stenotrophomonas maltophilia and some isolates of Clostridium difficile [47,48].

The enhanced activity of carbapenems is due to several factors: (i) they are smaller molecules than cephalosporins and are zwitterions (i.e. they have both positive and negative charges in solution), both of which properties facilitate rapid penetration across the Gram-negative outer membrane [39]; (ii) they have high affinity for essential penicillin-binding proteins (PBP-2, PBP-4, PBP-3 and PBP-1b) from a broad range of bacteria [20]; and (iii) they are resistant to a broad range of β-lactamases from Gram-positive and Gram-negative bacteria. Table 2 lists the current CLSI and EUCAST breakpoints for carbapenems [49,50].

Table 2.   Breakpoints for carbapenems as published by CLSI and EUCAST
Antibacterial agentGeneral breakpoints, MIC (mg/L)Species-specific breakpoints
GroupSusceptibleIntermediateResistant Enterobacteriaceae Pseudomonas Acinetobacter Staphylococcus EnterococcusStreptococcus A, B, C, GaStreptococcus pneumoniaeHaemophilus influenzae, Moraxella catarrhalisaNeisseria meningitidisaAnaerobes
  1. IMP, imipenem; MER, meropenem; ETP, ertapenem; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antibiotic Susceptibility Testing.

  2. aStrains with MIC values above the S/I breakpoint are rare or not yet reported.

IMPCLSI4/164/164/164/160.12/14/44/16
IMPEUCAST≤2>2 to ≤8>82/84/82/84/82/22/22/22/8
MERCLSI4/164/164/164/160.5/0.50.25/10.5/0.50.25/0.254/16
MEREUCAST≤2>2 to ≤8>82/82/82/82/22/22/20.25/0.252/8
ETPCLSI2/82/81/11/40.5/0.54/16
ETPEUCAST≤0.5>0.5 to ≤1>10.5/10.5/0.50.5/0.50.5/0.51/1a

Safety Advantages of Carbapenems

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References

One reason why β-lactams are the most frequently prescribed class of antibiotics is their superior safety profile, as compared with other antibiotics [45]. Carbapenems are generally well tolerated. Allergic reactions to β-lactam compounds are the most common adverse events in treatment with carbapenems; these include rash, urticaria and immediate hypersensitivity. Major adverse effects such as diarrhoea, pseudomembranous colitis, coagulation abnormalities, nephrotoxicity and hepatotoxicity occur with frequencies similar to those of comparators [44].

Differences Among Individual Carbapenems

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References

As the oldest of the carbapenems, imipenem is still used considerably, although it has several disadvantages as compared with newer carbapenems [39]. It is not approved by the US Food and Drug Administration (FDA) for meningitis, and should be avoided in the treatment of central nervous system infections because of its propensity to cause seizures in patients with elevated risk factors, e.g. renal failure or structural brain disease [44]. It is typically very active against P. aeruginosa and Acinetobacter spp. However, resistance to imipenem during therapy has been described since 1986 [52]. Downregulation of the carbapenem-specific OprD porin in P. aeruginosa can lead to this type of resistance [53–55]. Mutational loss of OprD is frequent during imipenem therapy, reaching 25% or more in strains causing difficult infections [56,57]. Loss of OprD does not confer reduced susceptibility to other β-lactams; however, it does affect all carbapenems. Similar to Paeruginosa, Enterobacter spp. can also become resistant during therapy with imipenem, although this is much less common and appears to require a combination of porin loss and increased activity of a β-lactamase-like AmpC [55,58,59]. Imipenem is slightly more active against Gram-positive bacteria than are other carbapenems. Imipenem is excreted renally, with 70% of imipenem recovered in the urine within 10 h and no detectable urinary excretion after that time. Accumulation is not observed in plasma or urine, even with regimens administered as frequently as every 6 h. Imipenem is distributed extensively in tissues and fluids [60]. The recommended adult dose of imipenem for patients with normal renal function is 250 mg to 1 g intravenously every 6–8 h. The paediatric dose is 15–25 mg/kg every 6–8 h. Dose adjustment is required for patients with creatinine clearance of less than 50 mL/min or body weight of less than 70 kg [44]. Unfortunately, the low stability of imipenem (10% degradation at 25°C after 3.5 h) limits the possible duration of infusion of this carbapenem; it must therefore be dosed as 30–60-min infusions [51].

Panipenem (RS-533), introduced into clinical practice in Japan in 1993, was the second approved carbapenem. It is susceptible to hydrolysis by DHP-I and thus requires the co-administration of an inhibitor of this enzyme, betamipron [20]. This drug, which is not discussed further in this article, is approved in Japan, China and South Korea [44].

The discovery that stability to human renal DHP-I can be achieved by introducing a 1-β-methyl substituent at C-1 led to the synthesis and introduction of meropenem (SM7338) in 1995 [39,61,62]. Meropenem is primarily excreted by the kidneys, with c. 50–75% of the dose being excreted unchanged in the urine and a further 25% being excreted as a microbiologically inactive open β-lactam metabolite [63]. Meropenem has a spectrum of activity similar to that of imipenem (including P. aeruginosa and Acinetobacter spp.) and is slightly more active against Gram-negative aerobic bacteria. This agent is a substrate for the multidrug efflux system MexAB–OprM, present in P. aeruginosa [54,64]. Overexpression of this efflux system raises the MIC of meropenem and other substrate antibiotics, but not of imipenem. Downregulation of the porin OprD also raises the MIC of meropenem, but usually not to the degree of outright resistance, as defined by conventional breakpoints [56]. Rather, the combination of a β-lactamase and downregulation of outer membrane proteins, like OprD, and an efflux system, such as MexAB–OprM, are needed for outright resistance to meropenem to occur.

Meropenem is approved by the US FDA for the treatment of bacterial meningitis in children aged 3 months and older, and is efficacious in adults [44]. The recommended adult dose of meropenem for patients with normal renal function is 500–1000 mg intravenously every 8 h, although daily doses of 6 g seem to be safe [65]. The paediatric dose is 20–40 mg/kg every 6–8 h. Dose adjustment is required for patients with creatinine clearance of less than 50 mL/min [44]. Some investigators have dosed meropenem as a 3-h infusion in an attempt to improve efficacy against resistant pathogens [21,39,66].

Ertapenem (MK-0826) is a 1-β-methyl carbapenem developed in 2001 [67] to be more resistant than imipenem to DPH-I inactivation, and therefore, does not require the addition of a DPH-I inhibitor such as cilastatin or betamipron [20]. Elimination follows non-linear kinetics, partly owing to the concentration dependence of protein binding. Approximately 80% of excretion is via the kidneys, with half as the native compound and half as the open-ring derivative; a further 10% is eliminated via the faeces [68]. Ertapenem possesses a longer apparent elimination half-life than imipenem and meropenem. This longer half-life allows for a convenient, once-daily administration schedule [69]. Ertapenem is an important option for the empirical treatment of complicated community-acquired bacterial infections, where a mixed flora of anaerobes and aerobes is likely, e.g. community-acquired pneumonia, complicated skin and skin structure infection, complicated urinary tract infection, or community-acquired complicated intra-abdominal infection, in both children and adults [69]. Ertapenem is now an option for the treatment of some nosocomial infections, but it lacks antimicrobial activity against non-fermenting Gram-negatives such as P. aeruginosa and Acinetobacter spp., and thus cannot be used when they are suspected pathogens [21]. A recent study demonstrated the greater efficacy of ertapenem in comparison with cefotetan for elective colorectal procedures, making this drug a potential option for prophylaxis of surgical site infection following abdominal surgery [70]. Despite its being generally effective against infections caused by ESBL-producing pathogens, ertapenem has decreased in vitro activity as compared with other carbapenems against some bacteria that produce ESBLs [71]. The most common form of ertapenem resistance in Enterobacteriaceae is the combination of AmpC production and porin loss. This type of resistance has been reported during therapy in an ESBL-producing Klebsiella pneumoniae strain [72]. Similar to imipenem and meropenem, ertapenem has anti-anaerobic activity and is thus especially useful in a single daily dose regimen for polymicrobial infections [44]. Although it penetrates into cerebrospinal fluid, ertapenem is not approved for the treatment of bacterial meningitis.

One concern that has limited the use of ertapenem is the fear that its use will select for imipenem, meropenem or doripenem resistance in P. aeruginosa. This appears unlikely, on the basis of in vitro studies [73]. Furthermore, a comprehensive study of gut-colonized patients with intra-abdominal infections treated with one of two comparators, ceftriaxone–metronidazole or piperacillin–tazobactam, not only showed no increase in imipenem-resistant P. aeruginosa in ertapenem-treated patients, but also showed less emergence of resistance in enterics in these patients than in those treated with either comparator [74,75].

The recommended adult dose of ertapenem for patients with normal renal function is 1000 mg, intravenously or intramuscularly, once daily, and 500 mg once daily for patients with creatinine clearance of less than 30 mL/min or on dialysis [44]. Paediatric dosing is 15 mg/kg every 12 h for patients between the ages of 3 months and 12 years.

Doripenem (S-4661) is a parenteral 1-β-methyl carbapenem that has completed phase 3 trials for nosocomial pneumonia (including ventilator-associated pneumonia), complicated intra-abdominal infection, and complicated urinary tract infection. Doripenem is licensed for adults for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, in the USA.

It is undergoing regulatory review for the treatment of complicated urinary tract infections and intra-abdominal infections in Europe, and for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia, in both the USA and Europe. A recent clinical trial comparing doripenem and imipenem for the treatment of ventilator-associated pneumonia showed less emergence of resistance among P. aeruginosa isolates in the doripenem arm, although the numbers were modest and the clinical outcomes were the same in both groups [76]. This carbapenem has stability against human DPH-I [77] and a wide spectrum of activity [78]. It combines the in vitro activity of imipenem against Gram-positive pathogens and of meropenem against Gram-negative pathogens [1,78]. Its renal elimination is similar to that of meropenem, with a mean urinary recovery, of doripenem, of 75% over 24 h [79]. Doripenem retains activity against ESBL- and AmpC-producing Enterobacteriaceae [80]. The MICs of doripenem are lower for P. aeruginosa than are those of other antipseudomonal agents, and it inhibits a great proportion of otherwise carbapenem-resistant P. aeruginosa at ≤4 mg/L [80–83].

When compared with several other antipseudomonal agents, including other carbapenems, doripenem was associated with the lowest rate of spontaneous resistance in vitro [84]. When it was combined with an aminoglycoside in vitro, doripenem resistance selection in P. aeruginosa was decreased even further [85]. Against a wide range of bacteria, doripenem can be safely combined with various antimicrobial agents (amikacin, co-trimoxazole, levofloxacin, daptomycin and linezolid) without risk of antagonism [86] (Mushtaq S, Warner M, Ge Y, Kaniga K, Livermore DM. In-vitro interactions of doripenem with other antibacterial agents. Programs and Abstracts of the American Society for Microbiology’s 45th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, 2005). Unlike treatment with imipenem, treatment with doripenem is expected to carry a low risk of seizures [87]. Its enhanced stability in solution makes it suitable for extended infusions (3 h), thus potentially minimizing resistance development and improving efficacy [88] (Floren L, Wikler M, Kilfoil T, Ge Y. A phase I, double-blind, placebo-controlled study to determine the safety, tolerability, and pharmacokinetics (PK) of prolonged-infusion regimens of doripenem (DOR) in healthy subjects. Programs and Abstracts of the American Society for Microbiology’s 46th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, 2004, Abstract A16). Doripenem at doses of 500 mg every 8 h was shown to be non-inferior, in terms of safety and efficacy, to meropenem at doses of 1 g every 8 h in a phase 3 trial for complicated intra-abdominal infections (Malafaia O, Umeh O, Jang J. Doripenem versus meropenem for the treatment of complicated intra-abdominal infections. Programs and Abstracts of the American Society for Microbiology’s 46th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA, 2006, Poster E-0221). Likewise, the compound met non-inferiority criteria for efficacy as compared with piperacillin–tazobactam (Rea-Neto A, Niederman M, Prokocimer P, Lee M, Kaniga K, Friedland I. Efficacy and safety of intravenous doripenem vs piperacillin/tazobactam in nosocomial pneumonia. Programs and Abstracts of the American Society for Microbiology’s 47th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, 2007, Abstract L-731) for the treatment of hospital-acquired pneumonia and as compared with imipenem for the treatment of ventilator-associated pneumonia [76,89].

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References

The progressive rise of broad resistance among non-fermenters, as well as an ever-increasing prevalence and diversity of β-lactamases in Enterobacteriaceae, is driving the increased use of carbapenems. Although the development of bacterial resistance to carbapenems largely parallels its use, the rate of emergence of resistance has been relatively low. Twenty-three years after the first release of a carbapenem into wide use, carbapenems remain invaluable, with low resistance rates and favourable safety profiles [32,33,35,36,90]. The newest member, doripenem, should prove to be a valuable addition to the carbapenem class.

Transparency Declaration

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References

J. P. Quinn has received grants from and is a consultant for Merck & Co., Inc. and Johnson & Johnson. M. V. Villegas is a consultant for Merck & Co., Inc. J. P. Quinn and M. V. Villegas have received reimbursements for attending congresses, fees for speaking, and funds for research other than directly for this work from various pharmaceutical companies (including Merck & Co., Inc. and Johnson & Johnson). J. N. Kattan has no conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Carbapenem Activities
  5. Safety Advantages of Carbapenems
  6. Differences Among Individual Carbapenems
  7. Conclusion
  8. Transparency Declaration
  9. References
  • 1
    Fritsche TR, Stilwell MG, Jones RN. Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003). Clin Microbiol Infect 2005; 11: 974984.
  • 2
    Bush K. The impact of beta-lactamases on the development of novel antimicrobial agents. Curr Opin Investig Drugs 2002; 3: 12841290.
  • 3
    Villegas MV, Lolans K, Correa A et al. First detection of the plasmid-mediated class A carbapenemase KPC-2 in clinical isolates of Klebsiella pneumoniae from South America. Antimicrob Agents Chemother 2006; 50: 28802882.
  • 4
    American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: 388416.
  • 5
    Naas T, Levy M, Hirschauer C, Marchandin H, Nordmann P. Outbreak of carbapenem-resistant Acinetobacter baumannii producing the carbapenemase OXA-23 in a tertiary care hospital of Papeete, French Polynesia. J Clin Microbiol 2005; 43: 48264829.
  • 6
    Suarez CJ, Lolans K, Villegas MV, Quinn JP. Mechanisms of resistance to beta-lactams in some common Gram-negative bacteria causing nosocomial infections. Expert Rev Anti Infect Ther 2005; 3: 915922.
  • 7
    Livermore DM. The threat from the pink corner. Ann Med 2003; 35: 226234.
  • 8
    Deshpande LM, Rhomberg PR, Sader HS, Jones RN. Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in the United States Medical Centers: report from the MYSTIC Program (1999–2005). Diagn Microbiol Infect Dis 2006; 56: 367372.
  • 9
    Deshpande LM, Jones RN, Fritsche TR, Sader HS. Occurrence and characterization of carbapenemase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program (2000–2004). Microb Drug Resist 2006; 12: 223230.
  • 10
    Luzzaro F, Docquier JD, Colinon C et al. Emergence in Klebsiella pneumoniae and Enterobacter cloacae clinical isolates of the VIM-4 metallo-beta-lactamase encoded by a conjugative plasmid. Antimicrob Agents Chemother 2004; 48: 648650.
  • 11
    Sader HS, Castanheira M, Mendes RE, Toleman M, Walsh TR, Jones RN. Dissemination and diversity of metallo-beta-lactamases in Latin America: report from the SENTRY Antimicrobial Surveillance Program. Int J Antimicrob Agents 2005; 25: 5761.
  • 12
    Scoulica EV, Neonakis IK, Gikas AI, Tselentis YJ. Spread of bla(VIM-1)-producing E. coli in a university hospital in Greece. Genetic analysis of the integron carrying the bla(VIM-1) metallo-beta-lactamase gene. Diagn Microbiol Infect Dis 2004; 48: 167172.
  • 13
    Yigit H, Queenan AM, Anderson GJ et al. Novel carbapenem-hydrolyzing betalactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 2001; 45: 11511161.
  • 14
    Woodford N, Tierno PM Jr, Young K et al. Outbreak of Klebsiella pneumoniae producing a new carbapenem-hydrolyzing class A beta-lactamase, KPC-3, in a New York Medical Center. Antimicrob Agents Chemother 2004; 48: 47934799.
  • 15
    Smith ME, Hanson ND, Herrera VL et al. Plasmid-mediated, carbapenem-hydrolysing beta-lactamase, KPC-2, in Klebsiella pneumoniae isolates. J Antimicrob Chemother 2003; 51: 711714.
  • 16
    Naas T, Nordmann P, Vedel G, Poyart C. Plasmid-mediated carbapenem-hydrolyzing beta-lactamase KPC in a Klebsiella pneumoniae isolate from France. Antimicrob Agents Chemother 2005; 49: 44234424.
  • 17
    Lolans K, Rice TW, Munoz-Price LS, Quinn JP. Multicity outbreak of carbapenem-resistant Acinetobacter baumannii isolates producing the carbapenemase OXA-40. Antimicrob Agents Chemother 2006; 50: 29412945.
  • 18
    Villegas MV, Lolans K, Correa A, Kattan JN, Lopez JA, Quinn JP. First identification of Pseudomonas aeruginosa isolates producing a KPC-type carbapenem-hydrolyzing {beta}-lactamase. Antimicrob Agents Chemother 2007; 51: 15531555.
  • 19
    Nakano V, Padilla G, Do Valle Marques M, Avila-Campos MJ. Plasmid-related beta lactamase production in Bacteroides fragilis strains. Res Microbiol 2004; 155: 843846.
  • 20
    Bonfiglio G, Russo G, Nicoletti G. Recent developments in carbapenems. Expert Opin Investig Drugs 2002; 11: 529544.
  • 21
    Jones RN, Sader HS, Fritsche TR. Comparative activity of doripenem and three other carbapenems tested against Gram-negative bacilli with various beta-lactamase resistance mechanisms. Diagn Microbiol Infect Dis 2005; 52: 7174.
  • 22
    Villegas MV, Lolans K, Del Rosario OM et al. First detection of metallo-beta-lactamase VIM-2 in Pseudomonas aeruginosa isolates from Colombia. Antimicrob Agents Chemother 2006; 50: 226229.
  • 23
    Nishio H, Komatsu M, Shibata N et al. Metallo-beta-lactamase-producing gram-negative bacilli: laboratory-based surveillance in cooperation with 13 clinical laboratories in the Kinki region of Japan. J Clin Microbiol 2004; 42: 52565263.
  • 24
    Gales AC, Menezes LC, Silbert S, Sader HS. Dissemination in distinct Brazilian regions of an epidemic carbapenem-resistant Pseudomonas aeruginosa producing SPM metallo-beta-lactamase. J Antimicrob Chemother 2003; 52: 699702.
  • 25
    Livermore DM. Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 1992; 36: 20462048.
  • 26
    Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 2002; 34: 634640.
  • 27
    Okamoto K, Gotoh N, Nishino T. Alterations of susceptibility of Pseudomones aeruginosa by overproduction of multidrug efflux systems, MexAB-OprM, MexCD-OprJ, and MexXY/OprM to carbapenems: substrate specificities of the efflux systems. J Infect Chemother 2002; 8: 371373.
  • 28
    Sobel ML, Hocquet D, Cao L, Plesiat P, Poole K. Mutations in PA3574 (nalD) lead to increased MexAB-OprM expression and multidrug resistance in laboratory and clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49: 17821786.
  • 29
    Sobel ML, Neshat S, Poole K. Mutations in PA 2491 (mexS) promote Mex’1’-dependent MexEF-oprN expression and multidrug resistance in a clinical strain of Pseudomonas aeruginosa. J Bacteriol 2005; 187: 12461253.
  • 30
    Schwaber MJ, Navon-Venezia S, Schwartz D, Carmeli Y. High levels of antimicrobial coresistance among extended-spectrum-beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2005; 49: 21372139.
  • 31
    Zhanel GG, Hisanaga TL, Laing NM et al. Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents 2006; 27: 468475.
  • 32
    Colardyn F. Appropriate and timely empirical antimicrobial treatment of ICU infections—a role for carbapenems. Acta Clin Belg 2005; 60: 5162.
  • 33
    Sun HK, Kuti JL, Nicolau DP. Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: a report from the OPTAMA Program. Crit Care Med 2005; 33: 22222227.
  • 34
    Ong CT, Kuti JL, Nightingale CH, Nicolau DP. Emerging Pseudomonas aeruginosa resistance: implications in clinical practice. Conn Med 2004; 68: 1115.
  • 35
    Richards GA. The therapeutic challenge of gram-negative sepsis: prolonging the lifespan of a scarce resource. Clin Microbiol Infect 2005; 11 (suppl): 1822.
  • 36
    Tellado JM, Wilson SE. Empiric treatment of nosocomial intra-abdominal infections: a focus on the carbapenems. Surg Infect (Larchmt) 2005; 6: 329343.
  • 37
    Kahan JS, Kahan FM, Goegelman R et al. Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties. J Antibiot (Tokyo) 1979; 32: 112.
  • 38
    Kahan FM, Kropp H, Sundelof JG, Birnbaum J. Thienamycin: development of imipenen–cilastatin. J Antimicrob Chemother 1983; 12 (suppl): 135.
  • 39
    Hellinger WC, Brewer NS. Carbapenems and monobactams: imipenem, meropenem, and aztreonam. Mayo Clin Proc 1999; 74: 420434.
  • 40
    Kropp H, Sundelof JG, Hajdu R, Kahan FM. Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase. Antimicrob Agents Chemother 1982; 22: 6270.
  • 41
    Birnbaum J, Kahan FM, Kropp H, MacDonald JS. Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin. Am J Med 1985; 78: 321.
  • 42
    Shah PM, Isaacs RD. Ertapenem, the first of a new group of carbapenems. J Antimicrob Chemother 2003; 52: 538542.
  • 43
    Moellering RC Jr, Eliopoulos GM, Sentochnik DE. The carbapenems: new broad spectrum beta-lactam antibiotics. J Antimicrob Chemother 1989; 24 (suppl): 17.
  • 44
    Chambers HF. Other B-lactam antibiotics. In: MandellGL, BennettJE, DolinR, eds. Principles and practice of infectious diseases. Philadelphia, PA: Elsevier Churchill Livingstone, 2005; 311317.
  • 45
    Quale J, Bratu S, Gupta J, Landman D. Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 2006; 50: 16331641.
  • 46
    Unal S, Garcia-Rodriguez JA. Activity of meropenem and comparators against Pseudomonas aeruginosa and Acinetobacter spp. isolated in the MYSTIC Program, 2002–2004. Diagn Microbiol Infect Dis 2005; 53: 265271.
  • 47
    Livermore DM, Carter MW, Bagel S et al. In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia. Antimicrob Agents Chemother 2001; 45: 18601867.
  • 48
    John R, Brazier JS. Antimicrobial susceptibility of polymerase chain reaction ribotypes of Clostridium difficile commonly isolated from symptomatic hospital patients in the UK. J Hosp Infect 2005; 61: 1114.
  • 49
    CLSI Breakpoints: CLSI Performance Standards for Antimicrobial Susceptibility Testing; Eighteeth Informational Supplement. CLSI document M100-S18. Wayne, PA: Clinical and Laboratory Standards Institute, 2008.
  • 50
    Carbapenems-EUCAST clinical MIC breakpoints 2008-06-19 (v.2.0), http://www.srga.org/eucastwt/MICTAB/MICcarbapenems.html. Last accessed 13 November 2008.
  • 51
    Karran SJ, Sutton G, Gartell P, Karran SE, Finnis D, Blenkinsop J. Imipenem prophylaxis in elective colorectal surgery. Br J Surg 1993; 80: 11961198.
  • 52
    Quinn JP, Dudek EJ, DiVincenzo CA, Lucks DA, Lerner SA. Emergence of resistance to imipenem during therapy for Pseudomonas aeruginosa infections. J Infect Dis 1986; 154: 289294.
  • 53
    Ballestero S, Fernandez-Rodriguez A, Villaverde R, Escobar H, Perez-Diaz JC, Baquero F. Carbapenem resistance in Pseudomonas aeruginosa from cystic fibrosis patients. J Antimicrob Chemother 1996; 38: 3945.
  • 54
    Kohler T, Michea-Hamzehpour M, Epp SF, Pechere JC. Carbapenem activities against Pseudomonas aeruginosa: respective contributions of OprD and efflux systems. Antimicrob Agents Chemother 1999; 43: 424427.
  • 55
    Vurma-Rapp U, Kayser FH, Hadorn K, Wiederkehr F. Mechanism of imipenem resistance acquired by three Pseudomonas aeruginosa strains during imipenem therapy. Eur J Clin Microbiol Infect Dis 1990; 9: 580587.
  • 56
    Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. Clin Infect Dis 2006; 43 (suppl): S49S56.
  • 57
    Zanetti G, Bally F, Greub G et al. Cefepime vs. imipenem for treatment of nosocomial pneumonia in ICU patients: a multicenter, evaluator-blind prospective, randomized study. Antimicrob Agents Chemother 2003; 47: 34423447.
  • 58
    Bornet C, Vin-Regli A, Bosi C, Pages JM, Bollet C. Imipenem resistance of Enterobacter aerogenes mediated by outer membrane permeability. J Clin Microbiol 2000; 38: 10481052.
  • 59
    Lee EH, Nicolas MH, Kitzis MD et al. Association of two resistance mechanisms in a clinical isolate of Enterobacter cloacae with high-level resistance to imipenem. Antimicrob Agents Chemother 1991; 35: 10931098.
  • 60
    Rodloff AC, Goldstein EJ, Torres A. Two decades of imipenem therapy. J Antimicrob Chemother 2006; 58: 916929.
  • 61
    Fukasawa M, Sumita Y, Harabe ET et al. Stability of meropenem and effect of 1-beta-methyl substitution on its stability in the presence of renal dehydropeptidase  I. Antimicrob Agents Chemother 1992; 36: 15771579.
  • 62
    Edwards SJ, Emmas CE, Campbell HE. Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infections. Curr Med Res Opin 2005; 21: 785794.
  • 63
    Drusano GL, Hutchison M. The pharmacokinetics of meropenem. Scand J Infect Dis 1995; 96 (suppl): 1116.
  • 64
    Li XZ, Zhang L, Poole K. Interplay between the MexA–MexB–OprM multidrug efflux system and the outer membrane barrier in the multiple antibiotic resistance of Pseudomonas aeruginosa. J Antimicrob Chemother 2000; 45: 433436.
  • 65
    Schmutzhard E, Williams KJ, Vukmirovits G, Chmelik V, Pfausler B, Featherstone A. A randomised comparison of meropenem with cefotaxime or ceftriaxone for the treatment of bacterial meningitis in adults. Meropenem Meningitis Study Group. J Antimicrob Chemother 1995; 36 (suppl): 8597.
  • 66
    Dandekar PK, Maglio D, Sutherland CA, Nightingale CH, Nicolau DP. Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion. Pharmacotherapy 2003; 23: 988991.
  • 67
    Gill CJ, Jackson JJ, Gerckens LS et al. In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345). Antimicrob Agents Chemother 1998; 42: 19962001.
  • 68
    Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. J Antimicrob Chemother 2003; 52: 331344.
  • 69
    Keating GM, Perry CM. Ertapenem: a review of its use in the treatment of bacterial infections. Drugs 2005; 65: 21512178.
  • 70
    Itani KM, Wilson SE, Awad SS, Jensen EH, Finn TS, Abramson MA. Ertapenem versus cefotetan prophylaxis in elective colorectal surgery. N Engl J Med 2006; 355: 26402651.
  • 71
    Moczygemba LR, Frei CR, Burgess DS. Pharmacodynamic modeling of carbapenems and fluoroquinolones against bacteria that produce extended-spectrum beta-lactamases. Clin Ther 2004; 26: 18001807.
  • 72
    Elliot E, Brink AJ, Van Greune ZEls J et al. In vivo development of ertapenem resistance in a patient with pneumonia caused by Klebsiella pneumoniae with an extended-spectrum beta-lactamase. Clin Infect Dis 2006; 42: e95e98.
  • 73
    Livermore DM, Mushtaq S, Warner M. Selectivity of ertapenem for Pseudomonas aeruginosa mutants cross-resistant to other carbapenems. J Antimicrob Chemother 2005; 55: 306311.
  • 74
    Dinubile MJ, Friedland I, Chan CY et al. Bowel colonization with resistant gram-negative bacilli after antimicrobial therapy of intra-abdominal infections: observations from two randomized comparative clinical trials of ertapenem therapy. Eur J Clin Microbiol Infect Dis 2005; 24: 443449.
  • 75
    DiNubile MJ, Chow JW, Satishchandran V et al. Acquisition of resistant bowel flora during a double-blind randomized clinical trial of ertapenem versus piperacillin–tazobactam therapy for intraabdominal infections. Antimicrob Agents Chemother 2005; 49: 32173221.
  • 76
    Chastre J, Wunderink R, Prokocimer P, Lee M, Kaniga K, Friedland I. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study. Crit Care Med 2008; 36: 10891096.
  • 77
    Mori M, Hikida M, Nishihara T, Nasu T, Mitsuhashi S. Comparative stability of carbapenem and penem antibiotics to human recombinant dehydropeptidase-I. J Antimicrob Chemother 1996; 37: 10341036.
  • 78
    Jones RN, Huynh HK, Biedenbach DJ, Fritsche TR, Sader HS. Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations. J Antimicrob Chemother 2004; 54: 144154.
  • 79
    Doripenem: S 4661. Drugs R D 2003; 4: 363365.
  • 80
    Jones RN, Huynh HK, Biedenbach DJ. Activities of doripenem (S-4661) against drug-resistant clinical pathogens. Antimicrob Agents Chemother 2004; 48: 31363140.
  • 81
    Tsuji M, Ishii Y, Ohno A, Miyazaki S, Yamaguchi K. In vitro and in vivo antibacterial activities of S-4661, a new carbapenem. Antimicrob Agents Chemother 1998; 42: 9499.
  • 82
    Ge Y, Wikler MA, Sahm DF, Blosser-Middleton RS, Karlowsky JA. In vitro antimicrobial activity of doripenem, a new carbapenem. Antimicrob Agents Chemother 2004; 48: 13841396.
  • 83
    Traczewski MM, Brown SD. In vitro activity of doripenem against Pseudomonas aeruginosa and Burkholderia cepacia isolates from both cystic fibrosis and non-cystic fibrosis patients. Antimicrob Agents Chemother 2006; 50: 819821.
  • 84
    Mushtaq S, Ge Y, Livermore DM. Doripenem versus Pseudomonas aeruginosa in vitro: activity against characterized isolates, mutants, and transconjugants and resistance selection potential. Antimicrob Agents Chemother 2004; 48: 30863092.
  • 85
    Huynh HK, Biedenbach DJ, Jones RN. Delayed resistance selection for doripenem when passaging Pseudomonas aeruginosa isolates with doripenem plus an aminoglycoside. Diagn Microbiol Infect Dis 2006; 55: 241243.
  • 86
    Kobayashi Y. Study of the synergism between carbapenems and vancomycin or teicoplanin against MRSA, focusing on S-4661, a carbapenem newly developed in Japan. J Infect Chemother 2005; 11: 259261.
  • 87
    Horiuchi M, Kimura M, Tokumura M, Hasebe N, Arai T, Abe K. Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics. Toxicology 2006; 222: 114124.
  • 88
    Drusano GL. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin Infect Dis 2003; 36 (suppl): S42S50.
  • 89
    Merchant S, Gast C, Nathwani D et al. Hospital resource utilization with doripenem versus imipenem in the treatment of ventilator-associated pneumonia. Clin Ther 2008; 30: 117.
  • 90
    Ong CT, Kuti JL, Nicolau DP. Pharmacodynamic modeling of imipenem–cilastatin, meropenem, and piperacillin-tazobactam for empiric therapy of skin and soft tissue infections: a report from the OPTAMA Program. Surg Infect (Larchmt) 2005; 6: 419426.