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Short communication

Ertapenem for the treatment of extended-spectrum ␤-lactamase-producing Gram-negative bacterial infections C.P. Teng a , H.H. Chen a , J. Chan b , D.C.B. Lye c,∗ b

a Department of Pharmacy, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, 308433 Singapore Department of Pathology and Laboratory Medicine, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, 308433 Singapore c Department of Infectious Diseases, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, 308433 Singapore

Received 23 April 2007; accepted 17 May 2007

Abstract Ertapenem is indicated for complicated intra-abdominal, skin and skin-structure, urinary tract and acute pelvic infections as well as community-acquired pneumonia, for which there are cheaper and more narrow-spectrum antibiotics. It is active against extended-spectrum ␤-lactamase (ESBL)-producing Gram-negative bacteria, but report of its clinical efficacy is lacking. We evaluated our experience with the use of ertapenem for ESBL-producing Gram-negative bacterial infections over 13 months. Forty-seven patients were treated with 50 courses of ertapenem. Thirty-nine courses were for ESBL-producing Gram-negative bacterial infections, 33% of which were bacteraemia. The clinical response rate was 92% and survival to hospital discharge was 94%. We propose that ertapenem has a role in the first-line treatment of these infections. © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Ertapenem; Extended-spectrum ␤-lactamase; Gram-negative infections

1. Introduction Ertapenem is a class 1 carbapenem with broad-spectrum antibacterial activity [1]. It is not active against Enterococcus, methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii and Pseudomonas aeruginosa [1]. It has comparable clinical efficacy with: ceftriaxone for the treatment of community-acquired pneumonia [2] and urinary tract infections (UTIs) [2]; ceftriaxone and metronidazole for treatment of intra-abdominal infections (IAIs) [2]; piperacillin/tazobactam in the treatment of IAIs [2], pelvic infections [2], skin and soft-tissue infections (SSTIs) [2] and diabetic foot infections [3]; and cefepime and metronidazole for treatment of healthcare-associated and hospital-acquired pneumonia [4]. However, its use in these settings is debatable as cheaper and potentially less broad-spectrum antibiotics can be used.

Ertapenem may select for carbapenem-resistant P. aeruginosa in vitro [5] although it has been associated with fewer secondary antibiotic-resistant bacterial infections in clinical studies [6]. Although ertapenem is active against extended-spectrum ␤-lactamase (ESBL)-producing Gramnegative bacteria in vitro [1,2], no study supporting its use in this context has been published. Ertapenem resistance has developed in vivo in two studies [7,8]. We aimed to audit retrospectively the use of ertapenem in Tan Tock Seng Hospital (TTSH) over 13 months to determine: (i) the infectious disease conditions for which ertapenem was used; (ii) its clinical efficacy in the treatment of ESBL-producing Gram-negative infections; and (iii) any relapse following treatment and any secondary bacterial infections.

2. Methods ∗

Corresponding author. Tel.: +65 6357 7925; fax: +65 6252 4056. E-mail address: david [email protected] (D.C.B. Lye).

Details of patients who were prescribed ertapenem over 13 months from 1 May 2005 to 31 May 2006 were retrieved

0924-8579/$ – see front matter © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2007.05.016

Please cite this article in press as: Teng CP, et al., Ertapenem for the treatment of extended-spectrum ␤-lactamase-producing Gram-negative bacterial infections, Int. J. Antimicrob. Agents (2007), doi:10.1016/j.ijantimicag.2007.05.016

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from the pharmacy dispensing database. A standardised data extraction form was created to collect demographic, epidemiological, clinical, laboratory, radiological and treatment response data from patients’ medical records. The infectious disease conditions for which ertapenem was prescribed were determined under categories of pneumonia, IAIs, pelvic infections, UTIs, SSTIs, and others. For one of these diagnoses to be made, the patient must have compatible signs or symptoms, with objective evidence of infection (e.g. fever, leukocytosis, raised C-reactive protein) and a positive microbiological culture from an appropriate anatomical site. For these conditions, it was ascertained whether there was an ESBL-producing Gram-negative bacterium requiring a carbapenem, a multidrug-resistant non-ESBL-producing bacterium requiring a carbapenem or a non-ESBL-producing bacterium susceptible to another non-carbapenem antibiotic. Clinical response was defined as the resolution of initial symptoms and signs. Relapse was defined as a positive microbiological culture from the same site with the same bacterium within the same admission or 3 months after the end of therapy. Secondary bacterial infection or colonisation with P. aeruginosa, A. baumannii, Enterococcus or MRSA following ertapenem use were sought within the same admission or 3 months after end of therapy. Survival at hospital discharge was noted. Gram-negative bacilli were identified by MicrobactTM Gram-negative Identification System (Oxoid, Basingstoke, UK). Antibiotic susceptibility was determined by disk diffusion test on Mueller–Hinton agar according to methodology and inhibition zone diameters recommended by the Clinical and Laboratory Standards Institute. ESBL was detected by modified double-disk synergy test with cefotaxime and ceftazidime disks (Becton Dickinson, Sparks, MD) on opposite sides of an amoxicillin/clavulanic acid disk at 25 mm apart.

3. Results Over 13 months, 47 patients were prescribed 50 courses of ertapenem (3 patients received two courses of treatment). The mean patient age was 64 years and 45% were male. The baseline demographic and clinical data and infectious disease conditions requiring ertapenem are given in Table 1. Prior antibiotic use preceded ertapenem in 42 courses. Prior antibiotics comprised: broad-spectrum penicillins (amoxicillin/clavulanic acid, piperacillin/tazobactam and ampicillin/sulbactam), n = 17; broad-spectrum cephalosporins (ceftriaxone, ceftazidime and cefepime), n = 23; aminoglycosides, n = 6; fluoroquinolones, n = 19; imipenem, n = 17; and meropenem, n = 7. In 40 of 42 courses, ertapenem was initiated after microbiological cultures became available. Ertapenem replaced empirical antibiotics shown to be resistant in vitro in 16 courses and was ‘step-down’ therapy from imipenem or meropenem in 24 courses. Forty-four courses of ertapenem were for

Table 1 Baseline demographic and clinical data of 47 patients prescribed 50 courses of ertapenem Characteristic

No. (%) of patientsa

Mean age (range) (years) Male Mean total length of hospital stay (days) Diabetes mellitus Cardiac disease Pulmonary disease Liver disease Renal disease Cancer Corticosteroid therapy HIV Seizure Antibiotic allergy Infection within 48 h of admission

64 (23–89) 21 (45) 45 22 (47) 8 (17) 6 (13) 5 (11) 10 (21) 6 (13) 1 (2) 2 (4) 5 (11) 14 (30) 24/50 (48)

Proven infections needing ertapenem (n = 44) Pneumonia Abdominal infections Urinary tract infections Skin and soft tissue infections Others

1 (2.3) 6 (14) 31 (70) 3 (7) 3 (7)

HIV, human immunodeficiency virus. a Data are no. (%) of patients unless otherwise stated.

positive microbiological culture, whilst six had no positive microbiological culture. The median time from a positive microbiological culture to initiation of ertapenem was 5 days, whilst the median time of switching from imipenem or meropenem to ertapenem was 5.5 days. The median duration of ertapenem therapy was 9 days. Of 44 courses of definitive ertapenem use, it was used to treat an ESBL-producing Gram-negative bacterial infection in 39 (Group 1). Ertapenem was used for a multidrug-resistant bacterial infection in three, although ESBL screening by double-disk test was negative (Group 2). Ertapenem was used in two cases even though the bacterial infection would have been adequately treated by another ␤-lactam antibiotic without contraindication due to allergy (Group 3). The clinical response rates were 92% (36/39) in Group 1, 67% (2/3) in Group 2 and 50% (1/2) in Group 3. In Group 1, there were 12 Escherichia coli, 26 Klebsiella pneumoniae and 7 other Gram-negative bacteria (including 3 Proteus mirabilis and 3 Enterobacter cloacae); all were susceptible to ertapenem in vitro. There were 13 cases of bacteraemia (12 of which were urinary infections). Of the ESBL-producing Gram-negative bacterial infections without bacteraemia, 16 were urinary infections, 4 were IAIs, 1 was pneumonia, 3 were SSTIs and 2 were others. Ninety-four percent of patients survived to hospital discharge. One of the three deaths was attributable to the infection requiring ertapenem. Twelve (92%) of 13 patients with ESBL-producing Gram-negative bacteraemia and 100% of 26 patients with ESBL-producing Gram-negative infections in other sites survived to hospital discharge. Ertapenem

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was well tolerated, with an adverse drug event (diarrhoea) reported in only one case. Six (15%) of the 39 ESBL-producing Gram-negative bacterial infections treated with ertapenem suffered a relapse at a mean of 54 days (range 17–85 days). All had urinary infections (three had indwelling urinary catheters). Underdosing of ertapenem was noted in one patient. Two of these relapses were not treated because it was clinically assessed to be colonisation, whilst four cases were treated with an alternative antibiotic tested susceptible in vitro. Only in one case was ertapenem resistance noted in an E. coli from urine culture. Secondary bacterial infection or colonisation was noted in 14 cases from all groups. This occurred at a mean of 41 days (range 16–67 days) for P. aeruginosa (7 cases, 5 of which were colonisation), 11 days (range 3–16 days) for A. baumannii (5 cases, 2 of which were colonisation), 24 days (range 4–54 days) for Enterococcus (5 cases, 4 of which were colonisation) and 46 days (range 5–85 days) for MRSA (6 cases, 3 of which were colonisation). Of these, 11 received other broad-spectrum antibiotics prior to ertapenem use.

4. Discussion Therapy of ESBL-producing Gram-negative bacteraemia with carbapenems is associated with improved survival [9,10]. However, increased use of carbapenems is associated with carbapenem resistance in A. baumannii [11] and P. aeruginosa [12]. In our hospital, 67.1% of A. baumannii and 13.1% of P. aeruginosa were resistant to imipenem in 2005 (Department of Pathology and Laboratory Medicine, TTSH). Ertapenem is not active against A. baumannii and P. aeruginosa. Whilst ertapenem may select for A. baumannii and P. aeruginosa, it may not select for carbapenem resistance in these organisms [2]. We showed excellent efficacy of ertapenem for ESBLproducing Gram-negative bacterial infections, comparable with treatment of ESBL-producing Gram-negative bacteraemia with either imipenem or meropenem. Mortality was 3.7% in a prospective K. pneumoniae bacteraemia study treated primarily with imipenem [9], 12.9% in a retrospective K. pneumoniae and E. coli bacteraemia study treated with carbapenem [13] and 26% in a retrospective Enterobacter aerogenes infection study (61% were pneumonia and 22% were bacteraemia) treated with either imipenem or meropenem [14]. Twenty percent of patients in another retrospective K. pneumoniae bacteraemia study had no response to imipenem [10]. However, given the possibility of ertapenem resistance, especially in K. pneumoniae [2], its in vitro activity should be proven by laboratory testing before clinical use. In addition, as ertapenem is not active against P. aeruginosa, a virulent nosocomial bacterial pathogen, its use in empirical therapy of nosocomial infections should be discouraged [2]. Of note,

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six courses of ertapenem treatment in our study were for empirical use, against our institutional guidelines. Although concern regarding selection of resistant bacteria by ertapenem has not been confirmed in clinical studies [6], indiscriminate use of ertapenem for bacterial infections susceptible to more narrow-spectrum antibiotics (e.g. community-acquired pneumonia and UTIs) may result in resistance. Cautious monitoring of this is warranted. Our retrospective study is unable to prove that ertapenem predisposed to secondary bacterial infection or colonisation because 11 of the 14 cases had precedent broad-spectrum antibiotic use before ertapenem. In addition, the six cases that relapsed after treatment were urinary infections where factors other than efficacy of antibiotic therapy may play a part, such as presence of a urinary catheter in one-half of the cases. In our hospital, the cost of ertapenem 1 g daily is 82.11 Singapore dollars (SGD) compared with 118.92 SGD for imipenem 500 mg every 6 h and 212.01 SGD for meropenem 1 g every 8 h. Imipenem and meropenem costs increased from 525 619 SGD in 2002 to 1 222 655 SGD in 2005 (Department of Pharmacy, TTSH). Cost saving without compromising patient outcome is a potential advantage of replacing imipenem and meropenem with ertapenem for proven bacterial infections. The retrospective observational design of our study does not allow us to compare ertapenem with imipenem or meropenem because ertapenem was used to replace imipenem or meropenem once microbiological culture was available. In addition, the number of patients with ESBLproducing Gram-negative bacteraemia was small (33%), whilst 41% had UTIs. A larger study involving more cases of bacteraemia and patients with greater severity of illness will give greater support to the clinical efficacy of ertapenem. We believe this is the first report of the clinical efficacy of ertapenem for ESBL-producing Gram-negative bacterial infections. Ertapenem has a useful role in the first-line treatment of proven ESBL-producing Gram-negative bacterial infections. Funding: None. Competing interests: None reported. Ethical approval: Exemption for ethical approval was obtained from the Institutional Review Board of the National Healthcare Group, Singapore.

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