1 Antibiotic Resistance Monitoring & Reference Laboratory, Central Public Health Laboratory, 61 Colindale Avenue, London NW9 5HT; 2 Department of Medical Microbiology, Barts and the London, Queen Marys School of Medicine and Dentistry, Turner Street, London E1 2AD; 3 Department of Clinical Microbiology, University College London Hospital, London WC1E 6DB, UK
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Abstract |
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Keywords: carbapenems, ß-lactamases, MK-0826, ß-lactams
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Introduction |
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Ertapenem will be promoted for wider and earlier use than imipenem and meropenem, which are mostly reserved for patients who are severely ill with multiresistant infections. If ceftriaxone is taken as a model for ertapenems future, its potential market is vast. Whether or not ertapenem achieves this level of usage, its launch raises questions about carbapenem therapy in general, not least because it comes at a time of growing concern about the spread of metallo-ß-lactamases.1,2 The purpose of this article is to review the properties of ertapenem and to open this debate, which will doubtless expand if oral carbapenems and penems such as faropenem ultimately reach the market.
For a compound already on the market, the literature on ertapenem is still remarkably scanty: a PubMed search on 1 March 2003 (http://www.ncbi.nlm.gov/PubMed/) gave just 42 hits, plus another six under the compounds previous code numbers. This compared with 170250 hits each for daptomycin, faropenem and gemifloxacin, none of which is yet licensed.
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Chemistry and target affinity of ertapenem |
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Inactivation of PBP-1a and -1b achieves rapid bactericidal action, without the prior filamentation that occurs with agents such as third-generation cephalosporins, which bind primarily to PBP-3. This means that the carbapenems allow a smaller increase in biomass before cell lysis, minimizing endotoxin release.9
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In vitro activity |
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NCCLS susceptibility and resistance breakpoints are 2 and
8 mg/L for non-fastidious Gram-negative bacteria and staphylococci,
4 mg/L and
16 mg/L for anaerobes, and
1 mg/L and
4 mg/L for Streptococcus pneumoniae. The NCCLS also has susceptibility breakpoints of
1 mg/L for ß-haemolytic streptococci, and
0.5 mg/L for Haemophilus influenzae. The British Society for Antimicrobial Chemotherapy has breakpoints of susceptible <2 mg/L and resistant >2 mg/L for all species except pneumococci, where it has values of
1mg/L and >1 mg/L, respectively (http://www.bsac.org.uk).
Enterobacteriaceae and other fermenters
With rare exceptions, the MICs of ertapenem for Enterobacteriaceae fall between 0.008 and 0.12 mg/L (Table 1). These values are similar to those of meropenem, and eight- to 16-fold below those of imipenem. Activity is maintained against Proteeae, which often have borderline susceptibility to imipenem.10 Among the 1611 Enterobacteriaceae isolates from 12 centres in Europe and Australia, just three organisms, all Enterobacter aerogenes, required ertapenem MICs 8 mg/L, whereas MICs of 24 mg/L were recorded for a few isolates of Enterobacter cloacae, Morganella morganii and Klebsiella spp.10 MICs
8 mg/L were also found in a few E. cloacae and klebsiellae among the 1563 Enterobacteriaceae collected from 11 American centres,11 with MICs of 24 mg/L seen for a few Citrobacter spp. and Proteeae. Most ertapenem-resistant isolates were cross-resistant to imipenem, or had reduced susceptibility.
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Non-fermenters
Ertapenem has only marginal activity against important non-fermenters.10,11 MICs for Pseudomonas aeruginosa isolates are from 216 mg/L, compared with 0.250.5 mg/L for meropenem and 12 mg/L imipenem. Curiously, the MIC distribution of ertapenem for P. aeruginosa is notably wider than that of imipenem, but the underlying reasons are unknown.10 Against Acinetobacter spp., ertapenem MICs generally exceed 4 mg/L, and imipenem remains the most active carbapenem, with MICs mostly from 0.120.5 mg/L, compared with 0.251 mg/L for meropenem. As with established carbapenems, ertapenem lacks activity against Stenotrophomonas maltophilia, which has a chromosomal metallo-ß-lactamase. Activity against Burkholderia cepacia is marginal, with an MIC50 of 8 mg/L, compared with 16 mg/L for imipenem and 48 mg/L for meropenem.
Haemophilus, Moraxella and Neisseria spp.
All the H. influenzae isolates examined in the European/Australian and American surveys were inhibited by ertapenem at 0.5 mg/L.10,11 MICs
0.5 mg/L were reported for isolates selected for ß-lactamase-independent amoxicillin resistance,24 but remain to be determined for those H. influenzae strains with high-level resistance to imipenem (MICs 3264 mg/L). Although nowhere prevalent, such organisms have been encountered on several occasions. 25,26 They typically are resistant to biapenem (a carbapenem ultimately marketed only in Japan) as well as imipenem, but not meropenem.
Ertapenem was active against >90% of Moraxella catarrhalis isolates at 0.016 mg/L, and against all at 0.25 mg/L.10,11 It was active at 0.016 mg/L against all Neisseria meningitidis isolates.10,11 Activity against Neisseria gonorrhoeae has not been reported, but may be worth investigating in view of increasing ciprofloxacin resistance.
Staphylococci
Like imipenem and meropenem, ertapenem is active against methicillin-susceptible Staphylococcus aureus (MSSA) but not against methicillin-resistant S. aureus (MRSA). The same rule applies for coagulase-negative staphylococci. MICs for methicillin-susceptible staphylococci are 0.25 to 0.5 mg/L; the higher top values in Table 1 almost certainly reflect the mistaken inclusion of a few methicillin-resistant isolates.10,11
Pneumococci, streptococci and enterococci
Ertapenem has good anti-pneumococcal activity although, as with all ß-lactams, sensitivity is reduced for penicillin-non-susceptible isolates (Figure 2).10,11 In general, MICs are equal to or two-fold below those of benzylpenicillin, but two- to four-fold above those of meropenem and imipenem. MICs up to 4 mg/L have been recorded for exceptional pneumococci, but most penicillin-resistant isolates are susceptible at 12 mg/L. Similar activity is seen against other - and non-haemolytic streptococci, but the European survey recorded one isolate with an MIC of 16 mg/L.10
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Gram-positive bacilli
Ertapenem has MIC90s of 0.25 to 0.5 mg/L for Propionibacterium acnes and most Corynebacterium spp., but MICs exceeding 16 mg/L are seen for a few coryneform isolates.11 Activity against Bacillus spp., including Bacillus anthracis, is likely to be constrained by their possession of chromosomal metallo-ß-lactamases.28
Activity against anaerobes
The American and European/Australian surveys10,11 showed that ertapenem has excellent anti-anaerobic activity,11 and this was confirmed in greater detail by a study of 1001 anaerobes from 17 centres worldwide.12 Each of these studies recorded an MIC90 of 12 mg/L for Bacteroides fragilis group isolates, with ertapenem about two-fold less active than imipenem. A few B. fragilis (<1%) isolates require ertapenem MICs >16 mg/L and it is likely (although unconfirmed) that these produce the CcrA (CfiA) metallo-ß-lactamase, which has been recorded in a tiny subset of B. fragilis strains for over 20 years.29,30 Its prevalence does not seem to be increasing, but surveillance is complicated because the encoding gene can remain silent unless there is appropriate mutation or migration of an insertion sequence.31,32
Virtually all Prevotella, Fusobacterium, Peptostreptococcus and Porphyromonas spp. are susceptible to ertapenem at 0.5 mg/L; most clostridia are susceptible at 12 mg/L, although one resistant Clostridium difficile isolate was recorded in the European survey.10 Resistance was seen in 12/61 isolates of Bilophila wadsworthia, an anaerobe often present in the mixed flora of appendicitis and peritonitis.12 The reasons for this resistance were not investigated, and the organism is rare as a single pathogen.
Susceptibility testing methods
MIC tests in the multicentre surveys10,11 were performed by broth microdilution but NCCLS agar dilution in MuellerHinton medium has also been used.33 MICs by Etest agreed, ±1 dilution, with those by broth microdilution in 80.8% of cases and ±2 dilutions in 93% of cases, based upon tests conducted at 12 centres in Europe and Australia.10 Similar agreement was found for imipenem in the same study (76.2% agreement ±1 dilution and 92.5% ±2 dilutions), and there was no bias for Etests to give higher or lower MICs for either carbapenem. NCCLS disc tests correlated well with broth MICs for non-fastidious bacteria;10 thus, using 10 µg discs against 3126 isolates, the rates of very major(susceptible by disc, resistant by MIC) and major (resistant by disc, susceptible by MIC) errors were 0.7% and 0.45%, respectively. Minor errors (intermediate by one method but resistant or susceptible by the other) arose for 3.45% of isolates.
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Interactions with resistance mechanisms |
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More is known about ertapenems interactions with resistance mechanisms that compromise third-generation cephalosporins but which spare existing carbapenems. The European/Australian and American surveys10,11 both indicated that ertapenem remained active against the great majority of cephalosporin-resistant Enterobacteriaceae isolates, and further studies therefore directly tested its activity against strains known to produce extended-spectrum ß-lactamases (ESBLs) or to hyperproduce AmpC enzymes. Tests on 180 ESBL-positive klebsiellae from European ICUs indicated a modal MIC of 0.03 mg/L and an MIC90 of 0.12 mg/L.33 Corresponding values for 40 ESBL-non-producing control strains were lower, at 0.008 and 0.016 mg/L, respectively. By comparison, imipenem had modal MICs of 0.12 mg/L for both the ESBL producers and the controls (Figure 3). The highest ertapenem MIC for an ESBL producer was 8 mg/L compared with only 2 mg/L for imipenem, thus reversing the general pattern whereby ertapenem was the more active carbapenem against Klebsiella spp. Moreover, Paterson et al.36 recorded eight ESBL-positive Klebsiella pneumoniae from bloodstream infections in Argentina and South Africa that were resistant to ertapenem (MICs 16 mg/L) but still susceptible to imipenem and meropenem. These latter carbapenems were used successfully as therapy in seven of the cases. The isolates had various ESBL types, and except for one pair, were not clonally related. Such data all imply a slight effect by ESBLs against ertapenem. Nevertheless, the introduction of ESBL-encoding plasmids into recipient E. coli strains does not raise the MICs of ertapenem; nor, in contrast to cephalosporins, is there any substantial inoculum effect for ESBL-positive Klebsiella spp.33 It may be that the least-susceptible ESBL producers have further mechanisms, such as reduced permeability or increased efflux. This would explain why many also have reduced susceptibility to cefoxitin, another drug that is not a substrate for ESBLs.37
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A few acquired ß-lactamases hydrolyse carbapenems rapidly. These are loosely termed carbapenemases although most are broad-spectrum enzymes that hydrolyse all cephalosporins and penicillins. Acquired carbapenemases include (a) Class B metallo-ß-lactamases belonging to the IMP, VIM and SPM groups, (b) Class A enzymes belonging to the SME, NMC/IMI and KPC groups and (c) several Class D (OXA) enzymes recorded almost exclusively from Acinetobacter spp.1,2 There is an imperfect correlation between carriage of carbapenemase genes and expression of carbapenem resistance, perhaps because even the most potent Class B carbapenemases can protect Gram-negative organisms against carbapenems only if they function behind an increased permeability barrier. The interplay of permeability and a potent metallo-carbapenemase is well illustrated by work showing that ertapenem and imipenem MICs of >32 mg/L for a porin-deficient K. pneumoniae isolate with IMP-1 ß-lactamase fell to 6 mg/L and 2 mg/L, respectively, when porin expression was regained.40 The ertapenem MIC for an S. marcescens isolate with SME-1 (a Class A carbapenemase) was 2 mg/L, compared with 32 mg/L for imipenem, but the imipenem and ertapenem MICs for a K. pneumoniae isolate with a KPC-3 ß-lactamase (also Class A) were both >32 mg/L.33
Irrespective of susceptibility results, it seems unwise to use any carbapenem clinically against an infection suspected of harbouring a carbapenemase producer. Use against ESBL-producing and AmpC-derepressed strains seems reasonable, despite the small MIC effects seen for some producers.
Before leaving the topic of ß-lactamases it should perhaps be added that, although the studies outlined here illustrate the activity of ertapenem against ß-lactamase producers, kinetic studies are still awaited, and it is unclear how the meta-substituted benzoic acid (Figure 1) influences enzyme affinity.
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Pharmacokinetics and pharmacodynamics |
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Elimination follows non-linear kinetics, partly owing to the concentration dependence of protein binding.41 About 80% of excretion is via the kidneys, with half as native compound and half as the open-ring derivative; a further 10% is eliminated via the faeces. As with any renally excreted drug, the AUC alters with renal insufficiency, increasing 1.5-fold with creatinine clearance (CLCR) rates 6090 mL/min/1.73 m2; 2.3-fold with CLCR 3159 mL/min/1.73 m2; 4.4-fold with CLCR 530 mL/min/1.73 m2 and 7.6-fold with CLCR <5 mL/min/1.73 m2. A halving of the dose is suggested in the USA if the CLCR is
30 mL/min/1.73 m2, whereas the EU licence suggests that the drug should be avoided. Since ertapenem does not undergo hepatic metabolism or significant biliary excretion, no adjustment is needed for hepatic insufficiency.
Little has been published on tissue penetration, which is difficult to measure for protein-bound agents. Studies showed ertapenem concentrations in blister fluid rising to 24 mg/L by 4 h after a third days 1 g iv dose, and then remaining >20 mg/L for over 12 h.44 Concentrations in breast milk were measured in women in a pelvic infection trial (see below) and were <0.38 mg/L within 24 h of the last dose and below the detection limit of 0.13 mg/L by 120 h after the last dose.45
Whether one should review the MICs of protein-bound antibiotics against free or total drug levels is a long-standing debate, unlikely to be settled here. A 1 g dose of ertapenem gives a total serum level >1 mg/L (i.e. >MICs for >90% isolates, see Table 1) throughout the 24 h dosage interval. The serum level of free drug remains >1 mg/L for about 8 h, corresponding to one-third of the inter-dosage interval.41,46 This seems acceptable based on the view that carbapenem levels must be kept above the MIC for rather less than the 40% of the inter-dose interval required for other ß-lactams.47 Nevertheless, the free drug levels do signal caution if, for example, treating infections caused by pneumococci with MICs >1 mg/L. The pneumonia trials outlined below allowed the ertapenem dosage to be increased to 2 g daily in patients with such pathogens, although this option was rarely exercised.
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Clinical trials and clinical use |
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Major clinical trials in these settings are outlined below and in Tables 38. As with most drug evaluations, these were powered to demonstrate equivalence, not superiority. Ceftriaxone, with or without metronidazole, or piperacillin/tazobactam served as a comparator, according to the setting. Dosages were those normally used in the USA; thus piperacillin/tazobactam was used at 3.375 g four times daily rather than at 4.5 g three times daily, as normally given in the UK. All the trials were randomized, multicentre and double-blinded and/or double dummy. General exclusions included a history of allergy to ß-lactams, AIDS (though not HIV-positive status), a resistant baseline pathogen (although this did not preclude patients with mixed infections including enterococci and pseudomonads), underlying diseases expected to be rapidly progressive or fatal, and more than 24 h antibiotic therapy in the preceding 72 h. Specific exclusions are shown in Tables 38. Those trials with ceftriaxone as the comparator allowed a step-down to oral antibiotics after 72 h if the response was good; other trials allowed discharge on home iv therapy. Vancomycin could be added if MRSA or enterococci were confirmed to be present. Test-of-cure assessments varied among the trials according to regulatory requirements.
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Two trials in intra-abdominal sepsis have been published. The first and smaller (Merck Protocol 004, Phase IIA, Table 3) enrolled 114 patients and randomized them to receive ertapenem 1 g once daily or ceftriaxone 2 g once daily plus metronidazole 500 mg three times daily.48 A further arm received ertapenem 1.5 g once daily, but these will not be discussed, since this regimen gave no advantage and was not pursued. The patients all had complicated infections that necessitated hospitalization and surgery, but which were judged not to be life-threatening. Over 70% had appendicitis, mostly with perforation. Appropriate surgery and drainage was undertaken, together with intravenous antibiotic treatment for 314 days, as clinically appropriate. Therapy could be stepped-down to oral ciprofloxacin (500 or 750 mg twice daily) plus metronidazole (500 mg three times daily) after 3 full days of iv treatment, if clinically warranted. Early assessment was made 710 days after the end of therapy, with a final test-of-cure assessment after 46 weeks. Favourable clinical and microbiological outcomes were obtained at early assessment in 90% of the ertapenem patients, in 88% of those receiving ceftriaxone/metronidazole and in 84% and 85%, respectively, at test-of-cure. Few microbiologically evaluable patients were, however, available for final assessment: 41 in the ceftriaxone/metronidazole arm and just 31 in the ertapenem arm. Several patients yielded a mixed infective flora including enterococci and, although none of the study agents had significant anti-enterococcal activity, these were eradicated in 6/7 ertapenem patients and 12/15 ceftriaxone/metronidazole patients. A few patients had pathogen persistence or super-infection, but there was no pattern to the organisms involved.
The second trial (Merck Protocol 017, Phase III, Table 4) was much larger, with 633 patients randomized between the two arms.49 In general, these patients were more seriously ill than those in Protocol 004, with moderate to severe intra-abdominal infection extending into the peritoneal cavity and requiring surgical intervention. About half had a primary diagnosis of complicated appendicitis; the remainder had infections originating from other sites along the alimentary tract, including diverticulitis, gastric, intestinal or duodenal perforation, or intra-peritoneal abscesses. The patients underwent surgery and drainage and were randomized to receive ertapenem 1 g once daily or piperacillin/tazobactam 3.375 g four times daily for 314 days, with follow-up as in Protocol 004. No switch to oral therapy was allowed. The results indicated equivalence; ertapenem tended to give higher response rates than in the non-appendicitis groups, but this difference was not significant once corrected for the multiple comparisons. Many patients had P. aeruginosa or enterococci within a mixed infective flora. Although these species are more susceptible to piperacillin/tazobactam than to ertapenem, favourable responses were obtained in 19/26 ertapenem patients who had P. aeruginosa among their baseline pathogens compared with 23/26 in the piperacillin/tazobactam arm. Similarly, 50/65 patients with enterococci had a favourable response to ertapenem compared with 24/37 receiving piperacillin/tazobactam.
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Two trials in severe community-acquired pneumonia requiring hospitalization have been published, both comparing ertapenem 1 g once daily with ceftriaxone 1 g once daily. Each allowed step-down to oral co-amoxiclav 875 + 125 mg twice daily after 3 full days of iv therapy, if clinically appropriate. Each also allowed the ertapenem or ceftriaxone dosage of the primary treatment to be doubled if penicillin-resistant pneumococci were isolated. Although many clinicians would routinely use ceftriaxone 2 g once daily, trials suggest that this is no more effective than 1 g once daily50 (a conclusion that might, however, vary with the local prevalence of resistant pneumococci).
The first and larger trial (Phase III, Merck Protocol 018, Table 5) enrolled 502 patients, randomizing them equally between the two arms.51 Favourable clinical outcomes were achieved for 92.3% of the ertapenem patients and for 91% in the ceftriaxone arm. Just over 90% of patients in each arm were switched to oral therapy after a median of 4 days iv treatment. Cure rates were similarly high in both arms irrespective of the severity of the disease and the pathogen. S. pneumoniae accounted for >40% of all pathogens, and ertapenem cured 11/11 pneumonias caused by penicillin-non-susceptible (MIC 0.12 mg/L) S. pneumoniae, compared with 12/13 for ceftriaxone. However, only three patients in the ceftriaxone arm and one in the ertapenem arm had pneumococci with penicillin MICs
2 mg/L, and conclusions about efficacy against such organisms must therefore be tentative. The second trial (Phase III, Merck Protocol 020) gave similar results: 364 patients were randomized, in a 2:1 ratio, to receive ertapenem or ceftriaxone 1 g once daily.20 Cure rates for clinically evaluable patients were 91.8% for ertapenem and 93.5% for ceftriaxone; those for microbiologically evaluable patients were 91.0% and 91.8%, respectively. Mean durations of parenteral therapy were similar (5.5 and 5.6 days) in both arms, as were the total durations of therapy (11.5 and 11.7 days). S. pneumoniae was again the main pathogen, and ertapenem achieved favourable clinical and microbiological outcomes in 28/33, 9/9 and 2/2 patients infected with penicillin-susceptible, -intermediate and -resistant strains, respectively, compared with 14/14, 5/5 and 0/0 for ceftriaxone.
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Skin and skin structure infections
One trial of ertapenem in complicated skin and skin structure infections has been published (Phase III, Merck Protocol 016, Table 6). This recruited 540 patients and used piperacillin/tazobactam 3.375 g four times daily as the comparator.54 Oral switch therapy was not allowed, but patients could be discharged on home iv treatment after a minimum of 2 days hospitalization (more practicable with ertapenem than for piperacillin/tazobactam). The patients were stratified depending on whether they had underlying decubitus ulcers, diabetes mellitus, or other neuropathic conditions. Based on clinical assessments 1021 days after the end of therapy, cure was achieved in 82.4% of the ertapenem group and 84.4% of the piperacillin/tazobactam group, indicating equivalence.
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Acute gynaecological infections
One trial has been published comparing ertapenem 1 g once daily with piperacillin/tazobactam 3.375 g four times daily in acute pelvic infections (Phase III, Merck Protocol 023).45 Four hundred and twelve women, of whom 316 remained clinically evaluable (Table 7), were stratified according to whether they had obstetric/post-partum or gynaecological/post-operative infections. Over 80% were in the former category, and 75% had endometritis. Eighty percent of the patients remained microbiologically evaluable and. 60% had polymicrobial infections, with E. coli and peptostreptococci as the predominant pathogens. Favourable clinical responses were recorded 24 weeks post-therapy in 93.9% of patients in the ertapenem arm, and in 91.5% of those in the piperacillin/tazobactam arm. Equivalence in outcome was also seen in subset analysis for those patient groups with moderate or severe infection, and for those with endometritis. In each treatment arm, the eradication rates exceeded >90% for a wide range of pathogens. Enterococci were isolated from mixed infections in 23 women in the ertapenem arm and, despite the lack of in vitro activity, were eradicated from all of them, as compared with 30/31 in the piperacillin/tazobactam arm. Non-fermenters were isolated from only four patients in each arm.
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Two trials of ertapenem 1 g once daily in complicated urinary tract infections have been published, both with ceftriaxone 1 g once daily as the comparator. The larger trial (Merck Protocol 014, Phase III)57 is summarized in Table 8. It randomized 592 patients equally between the study arms and allowed a switch to oral ciprofloxacin after at least 3 days if the patient became afebrile. The patients were stratified according to whether they had pyelonephritis or other complicated urinary tract infections. The predominant pathogens were E. coli (69%) and Klebsiella spp. (13%). Microbiological cure rates 59 days after the end of therapy were 91.8% among evaluable patients who had received ertapenem, and 93.0% among those who received ceftriaxone. Success rates were similar between the arms when compared by stratum and severity of disease. Persistence of baseline pathogens was observed in 7%8% of patients, but was not associated with the development of resistance, except that one E. coli strain became ciprofloxacin resistant during the step-down regimen. Relapse rates at late follow-up, 46 weeks post-therapy, were 5.4% and 7.9% in the ertapenem and ceftriaxone arms, respectively. New infections, often with enterococci, occurred in 17% and 12.3% of ertapenem and ceftriaxone patients, respectively.
The second trial (Phase III, Merck Protocol 021) randomized 258 patients in a 2:1 ratio in favour of the ertapenem arm.58 The patients received iv antibiotics for at least 3 full days, but could then be switched to oral ciprofloxacin. E. coli accounted for 79% of all pathogens and Enterobacteriaceae for 95%. By completion of iv therapy, a favourable clinical response was seen in 97%98% of patients in each arm. At test-of-cure, 59 days after the end of all therapy, 85.6% of ertapenem patients and 84.9% of ceftriaxone patients had favourable clinical and microbiological outcomes, indicating equivalence. Reasons for the lower success rates than in Protocol 01457 (Table 8) are unclear. Recurrence occurred by late follow-up (46 weeks post-treatment) in 7/63 evaluable patients from the ertapenem arm and in 2/37 from the ceftriaxone arm. Twelve ertapenem-treated patients and six ceftriaxone patients developed new infections, many of them caused by Enterococcus spp.
Bacteraemia
Sizeable numbers of trial patientsmostly in the pneumonia and urinary evaluationhad secondary bacteraemia.59 The predominant pathogens were E. coli and S. pneumoniae. Primary efficacy (clinical, microbiological or both, according to the trial) was achieved in 69/86 patients treated with ertapenem, in 44/51 treated with ceftriaxone and in 28/35 treated with piperacillin/tazobactam, indicating equivalence. No patient had persistent bacteraemia.
Safety and tolerability in clinical trials
Side effects were assessed in the Phase III trials summarized above. These recorded diarrhoea in 1.7%7% of ertapenem patients, nausea in 0.8%7.0% and headache in 0.4%6.5%. Between 3.2% and 15.3% of patients experienced at least one local reaction at the infusion site, although three-quarters of these amounted to no more than local erythema. Increased alanine amino-transferase levels were seen in 3.3%9.0% of patients, increased aspartate amino-transferase in 2.1%8.0%, and increased alkaline phosphotransferase in 1.4%7.0%. The platelet count was increased in 1.8%3.2% of patients. None of these rates was significantly different from those found for the comparator agents.
There is concern about the seizure risk for ß-lactams in general and carbapenems in particular.60 One 89-year-old patient receiving ertapenem 1 g once daily in the pneumonia trial 018 had a seizure, which the investigator believed to be probably drug related.51 This occurred on day 10, when treatment was already scheduled to cease. Two brief seizures also occurred on day 10 of therapy in a 76-year-old man in the other pneumonia trial (020).20 He was a patient with a high risk of fits, with a recent change in his anti-epileptic treatment and a resected frontal meningioma; moreover, he had received ertapenem 2 g once daily from the previous day of therapy, having responded poorly to the standard 1 g regimen. Both these patients recovered without sequelae. A third patient had a seizure in the larger intra-abdominal sepsis trial, but no details are given (017).49 There were no seizures in a Phase II intra-abdominal sepsis trial arm that routinely used ertapenem 1.5 g once daily.48 Two patients in the ertapenem arm of the larger intra-abdominal sepsis trial (017, Table 4) developed C. difficile-associated diarrhoea;49 pseudomembranous colitis was also reported in two patients in each arm of the skin and soft tissue infection trial.54
Further potential settings for ertapenem use
The antimicrobial spectrum and pharmacokinetics of ertapenem suggest several potential applications, not yet explored by clinical trials. Some readers may think that ertapenem is tailor-made for purposes other than those for which it is licensed.
Critical here is a potential role in outpatient/home iv therapy, where ceftriaxone has been favoured because of its long serum half-life. Ertapenem might be used on the same rationale, although the need for infusion, rather than bolus injection, would be an inconvenience in those countries where the intramuscular formulation is not licensed. Many patients can benefit from home iv therapy, often as a step-down following hospital discharge.61 The strategy has cost advantages, and most patients would prefer to be at home. Patients with osteomyelitis involving Gram-negative pathogens are a particular group who might benefit, and who often receive ceftriaxone.62 Ertapenem would have a potential advantage if the pathogens included those organisms, principally Enterobacter spp., that are prone to develop mutational cephalosporin resistance63 and which show a rising prevalence of ciprofloxacin resistance.64 A caution is that there are no published data on the toxicity of ertapenem over the 6 week treatment periods likely to be needed, or on its bone penetration. There is also interest in ceftriaxone for the home management of infections in neutropenic patients, and ertapenem might be investigated in this setting too, although the lack of cover against non-fermenters is a concern with either agent.65
Ertapenem, because of its broad spectrum and once-daily regimen, might also prove useful in the treatment of military personnel in combat zones, especially those in transit to larger bases or to specialist care in their home country.
Ertapenems activity against AmpC-derepressed strains and ESBL producers suggests that it might be used as directed therapy once these organisms have been identified in an infection. Advantages over existing carbapenems include a more convenient regimen and, in many countries, a lower acquisition cost. Using the same logic, ertapenem might be considered as empirical therapy in a nosocomial outbreak involving ESBL producers, but any general role in nosocomial infections would be constrained by the lack of activity against non-fermenters.
A final, and controversial, use might be as single-dose prophylaxis in abdominal or gynaecological surgery. The potential lies in the spectrum and long half-life, affording cover against both anaerobes and aerobes even if surgery is delayed or protracted. Clinical trials are, however, needed with ecological follow-up to check for stool carriage of a resistant flora in recipients.
Public health and resistance risks
Ertapenems launch comes at a time of concern about resistance, and when acquired metallo-ß-lactamases are reported in increasing numbers of isolates and countries. Until 1997, IMP-1 was the sole acquired metallo-ß-lactamase known, and was reported only from P. aeruginosa, Serratia and one Klebsiella spp. isolated in Japan. By 2000, however, there were three IMP and two VIM carbapenemase types recorded66 and, at the time of writing, 12 VIM types, 10 VIM types and SPM-1, with these enzymes reported from continental East Asia, Japan, the Middle East, mainland Europe, the UK, andmore rarelythe Americas.67 In addition, there has been an erosion of the anti-acinetobacter activity of imipenem in the USA, with the proportion of non-susceptible isolates at 250 hospitals rising steadily from 2.4% in 1996 to 13.5% in the first 9 months of 2002, although the extent to which this depends on carbapenemases is unclear.68
Carbapenem resistance is serious because imipenem and meropenem are often the last useful resort against infections caused by multi-resistant Gram-negative bacteria. Their loss would mean an increasing need to treat severe infections with long-abandoned, toxic antibiotics, such as polymyxins. Whether it is right to fear ertapenem as a major selector is less certain. Most carbapenem resistance is in non-fermenters, which lie outside ertapenems spectrum. It might be argued, therefore, that the use of a carbapenem without anti-non-fermenter activity should mitigate selection pressure for carbapenemases in non-fermenters. Likewise, it is reasonable to suggest that ertapenem, lacking activity against P. aeruginosa in general, is unlikely to select specifically for strains with porin (OprD) deficiency or up-regulated efflux. However, these arguments are more relevant to the question of which carbapenem to use, rather than whether to use a carbapenem at all.
What is more relevant to ertapenem use is the sheer difficulty of obtaining carbapenem resistance in Enterobacteriaceae, as illustrated by its continued rarity 17 years after the launch of imipenem. Among 1.42 million Enterobacteriaceae from 250 hospitals reported to the TSN surveillance in the USA during 1 January 199630 November 2002, just 59 (0.005%) were resistant to imipenem.67 This is despite the fact that even hyperproduced AmpC ß-lactamases and ESBLs can confer carbapenem resistance if they are combined with extreme impermeability.66,68 Since permeability mutations emerge readily in vitro, it follows that such mutants must be counter-selected in vivo, perhaps because their impermeability impedes nutrition. More surprisingly, impermeability also seems to be necessary for the IMP and VIM metallo-carbapenemases to confer carbapenem resistance in Enterobacteriaceae.69 Since these latter enzymes confer cephalosporin resistance without permeability lesions, it is plausible (though speculative) that cephalosporins may be more selective for carbapenemases than the carbapenems themselves.
Nevertheless, one cannot wholly be sanguine about bringing carbapenems into first-line use, and the effects of ertapenem on microbial ecology need careful monitoring. In particular, studies are needed to investigate changes in the gut flora of individual patients receiving ertapenem, and studies of ertapenems effects at the hospital level. Since carbapenemase genes can be carried without phenotypic resistance being obvious,69 it will be essential that this surveillance incorporates gene detection methods.
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There is concern as to whether it is wise to widen the use of carbapenem when carbapenemases are beginning to spread. The worst situation would be if using ertapenem, where there are alternatives, were to undermine the value of imipenem and meropenem in settings where there are no good alternatives. The arguments seem finely balanced. On the one hand, repeated experience shows that antibiotics select resistance to themselves and to their analogues; on the other, it is naive to suppose that carbapenems are the sole selectors of carbapenemases, most of which are much more effective at conferring resistance to cephalosporins than to carbapenems. When the debate relates to what carbapenem to use, ertapenem may have an advantage since, lacking activity against non-fermenters in general, it seems unlikely to select specifically for those variants with increased resistance.
For the time being the best advice is to carefully monitor the institutional ecology where ertapenem enters use. Trials (e.g. the Merck SMART Program) have been established for this purpose. In the future, the spread of cephalosporin resistance into community isolates may drive clinicians to use compounds such as ertapenem. TEM and SHV-type ESBLs have not yet become widely established outside hospitals, but there is some evidence from Spain that CTX-M type ESBLs are beginning to disseminate into the community.70
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