JAC Advance Access published online on May 31, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm180
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Efficacy of ertapenem in the treatment of early ventilator-associated pneumonia caused by extended-spectrum ß-lactamase-producing organisms in an intensive care unit
1 Infectious Diseases Division, San Martino University Hospital, Genoa, Italy 2 ICU Division, San Martino University Hospital, Genoa, Italy 3 Microbiology Laboratory, San Martino University Hospital, Genoa, Italy
* Correspondence address. Clinica Malattie Infettive, Azienda Ospedaliera Universitaria San Martino, Largo R.Benzi 10, 16132 Genova, Italy. Tel: +39-010-5555132; Fax: +39-010-3537680; E-mail: mattba{at}tin.it matteo.bassetti{at}hsanmartino.it
Received 29 January 2007; returned 11 April 2007; revised 24 April 2007; accepted 27 April 2007
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Abstract |
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Objectives: Ventilator-associated pneumonia (VAP) is a frequent complication of patients admitted to intensive care units (ICUs). Ertapenem is a newer carbapenem with good in vitro activity against extended-spectrum ß-lactamase (ESBL)-producing organisms. However, there are no clinical data to support the use of ertapenem in VAP. Our purpose is to evaluate the usefulness and safety of ertapenem in the treatment of VAP caused by susceptible ESBL strains.
Methods: Ertapenem 1 g daily intravenously was given to adult patients with signs and symptoms of VAP beginning within 7 days of mechanical ventilation and caused by ESBL-producing Gram-negative organisms.
Results: From June 2005 to June 2006, we enrolled 20 adult patients hospitalized in an ICU and diagnosed with VAP due to Gram-negative ESBL strains. Causative organisms identified as ESBL producers susceptible to ertapenem were Klebsiella pneumoniae (alone in 10 cases and with methicillin-resistant Staphylococcus aureus in 4 cases), Enterobacter cloacae (2), Proteus mirabilis (2) and Citrobacter freundii (2). Clinical success was achieved in 16/20 (80%) of the clinically evaluable patients and in 15/20 (75%) of the microbiologically evaluable patients. The drug was well-tolerated; one patient presented a transient increase in liver enzymes.
Conclusions: We believe this is one of the first reports to demonstrate that ertapenem has clinical utility in treating serious infections caused by ESBL-producing organisms. Ertapenem appears to be suitable for ESBL VAP therapy. This pilot study suggests subsequent controlled randomized trials in this indication.
Key Words: carbapenems , hospital , Klebsiella pneumoniae , Enterobacter cloacae , Proteus mirabilis
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Introduction |
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Ventilator-associated pneumonia (VAP) remains an important and frequent complication of patients admitted to intensive care units (ICUs), despite advances in antimicrobial therapy and better supportive care modalities.1 Usually, incidences of VAP are sorted on the basis of timing of occurrence in relation to the onset of mechanical ventilation (MV): (i) early onset (<5–7 days MV); and (ii) late onset (>5–7 days MV).1 Early-onset VAP is most often caused by microorganisms (e.g. Streptococcus pneumoniae, enteric Gram-negative bacilli and methicillin-susceptible Staphylococcus aureus) usually susceptible to many ‘first-line’ antibiotics such as ß-lactams, macrolides and quinolones.2 However, many authors have reported that early-onset VAP may be associated with multiresistant pathogens, such as Pseudomonas aeruginosa and Gram-negative bacilli, characterized by the production of extended-spectrum ß-lactamases (ESBLs).2,3 ESBL producers show resistance to cephalosporins and aztreonam, and often carry resistance to aminoglycosides and other drugs, but ESBL-producing strains remain susceptible to carbapenems.4 Ertapenem is a new carbapenem, exhibiting antimicrobial activity against most Gram-positive and Gram-negative aerobic and anaerobic bacteria, including ESBL-producing pathogens.5 Ertapenem has recently been proposed by the American Thoracic Society as initial empirical therapy for hospital-acquired or early-onset VAP in patients with no known risk factors for multidrug-resistant pathogens.1 Although the efficacy of ertapenem has been studied in various in vitro models or in patients with community-acquired pneumonia and pharmacokinetic data demonstrated a very interesting lung penetration, no clinical data concerning critically ill patients on MV with early-onset VAP are available.6–8 Therefore, we conducted a study to evaluate the usefulness and safety of ertapenem in the treatment of early-onset VAP caused by susceptible ESBL strains.
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Patients and methods |
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This was a prospective, open-label, non-comparative pilot trial. The study was conducted between June 2005 and June 2006 in one of the ICUs of the San Martino University Hospital in Genoa, Italy. The ward has 18 beds and admits a mean of 500 medical and surgical patients every year. Adult patients with signs and symptoms of VAP beginning within 7 days of MV and caused by ESBL-producing Gram-negative organisms were eligible for this study. Patients were enrolled if hospitalized for >72 h and radiographic evidence of acute pulmonary infiltrate consistent with pneumonia was required. Exclusion criteria were an Acute Physiology and Chronic Health Evaluation II (APACHE II) scale score >35, to avoid cases difficult to evaluate for the study endpoints, terminal illness, and creatinine clearance <20 mL/min. Patients were treated with ertapenem 1 g daily intravenously for 14 days. In patients with suspected or documented infection caused by methicillin-resistant S. aureus (MRSA), adjunctive therapy with vancomycin or linezolid could be introduced but discontinued when the suspected infection was not confirmed by culture. The primary efficacy variables were clinical and microbiological response at the test-of-cure visit (14–21 days after the last dose of study medication). Clinical response was categorized as cure if there was resolution of signs and symptoms associated with nosocomial pneumonia, or failure if there was an inadequate response to therapy such that additional antimicrobial therapy was required for the treatment of the original infection. Each patient provided at least an endotracheal aspiration specimen for Gram's stain and culture. Further acceptable specimens included those obtained by bronchoscopy (bronchoalveolar lavage or protected-specimen brush) according to the literature.1 ESBL production in Gram-negatives was documented using CLSI (formerly NCCLS) criteria.9 Eradication rates included the pathogen eradication or persistence rates with or without acquisition of resistance, based on the susceptibility criteria of the CLSI.9 The study was approved by the Ethics Committee of our hospital and all patients signed an informed consent for participation in the study.
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Results |
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Twenty patients (12 men) [median age 67 (IQR 27)] were enrolled in the study. The demographic characteristics of the patients are summarized in Table 1. The overall mean APACHE II score was 23.2 (SD 3.5). Causative organisms identified as ESBL producers susceptible to ertapenem were Klebsiella pneumoniae (alone in 10 cases and with MRSA in 4 cases), Enterobacter cloacae (2), Proteus mirabilis (2) and Citrobacter freundii (2). The mean length of hospital stay before developing VAP (and study entry) was 10.2 days. The mean duration of antimicrobial therapy was 13.2 days. All out of the 20 patients who completed therapy were clinically and microbiologically evaluable at the test-of-cure visit. Clinical success was achieved in 16/20 (80%) of the clinically evaluable patients and in 15/20 (75%) of the microbiologically evaluable patients. Among patients with K. pneumoniae infection, eradication was achieved in 86% (12/14). Eradication rates in the microbiologically evaluable patients are shown in Table 2. Four patients failed therapy, three died of sepsis during third and fourth days of therapy respectively, while the other one relapsed with an ertapenem-resistant K. pneumoniae isolate. We observed two cases of respiratory superinfections caused by P. aeruginosa strains. The drug was well-tolerated; one patient presented a transient increase in liver enzymes.
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Discussion |
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Even though the number of treated patients was small, this is, to our knowledge, one of the first prospective pilot studies assessing the efficacy and safety of ertapenem in adult patients with ESBL-producing Gram-negative VAP. In our study, high rates of clinical (80%) and microbiological (75%) efficacy were reported. Comparable results for ertapenem in nosocomial pneumonia were reported in a previous study, even though the patients intubated were excluded.7 Cephalosporins, ß-lactam/ß-lactamase inhibitor combinations and quinolones are not currently recommended as first-line therapy for ESBL-producing organisms.4 Carbapenems should be regarded as the drugs of choice for serious infections caused by ESBL-producing organisms. The basis for this statement is not just the almost uniform in vitro susceptibility of these compounds, but also increasingly extensive clinical experience.4 The choice between imipenem, meropenem and ertapenem is difficult. Published experience is greatest with imipenem, but MICs are slightly lower for meropenem. Ertapenem shares the good in vitro activity of the other carbapenems.5 Ertapenem is not active against Pseudomonas spp. and therefore is not recommended for VAP caused by these bacteria. Ertapenem may be used in specific instances for nosocomial infections where Pseudomonas spp. are not deemed important pathogens, such as early nosocomial pneumonia acquired in the ICU. Ertapenem is ideal for directed therapy based on the results of microbiological testing, especially for the treatment of infections with isolates demonstrating ESBLs. In our study, ertapenem demonstrated a very high clinical and microbiological activity in the treatment of early VAP caused by susceptible organisms.
Ertapenem was also well tolerated. The type and frequency of ertapenem-related adverse events in this study resembled those observed in previous clinical trials.10
In our study, ertapenem was safe and both clinically and microbiologically efficacious in the treatment of ESBL-producing Gram-negative VAP.
These preliminary and limiting data need to be confirmed by further randomized, controlled studies before any definitive conclusions can be drawn.
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None to declare.
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References |
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1 . 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) 171:388–416.
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7 . Yakovlev SV, Stratchounski LS, Woods GL, et al. Ertapenem versus cefepime for initial empirical treatment of pneumonia acquired in skilled-care facilities or in hospitals outside the intensive care unit. Eur J Clin Microbiol Infect Dis (2006) 25:633–41.[CrossRef][Web of Science][Medline]
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Burkhardt O, Kumar V, Katterwe D, et al. Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration. J Antimicrob Chemother (2007) 59:277–84.
9 . National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing, Eleventh Informational Supplement, vol 21 (2001) Wayne, PA, USA: NCCLS.
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