β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options?

Review

β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? Patrick N A Harris, Paul A Tambyah, David L Paterson

The spread of extended-spectrum β-lactamase (ESBL) genes in Enterobacteriaceae such as Escherichia coli or Klebsiella spp is a major challenge to modern medical practice. Carbapenems are the treatment of choice for serious infections caused by ESBL producers; however, carbapenem resistance has increased globally. ESBL producers might be susceptible to β-lactam-β-lactamase inhibitor (BLBLI) combination antibiotics such piperacillin–tazobactam or amoxicillin–clavulanate. These drugs are frequently avoided in serious infections caused by ESBL producers because of the inoculum effect in-vitro (especially for piperacillin–tazobactam), animal data suggesting inferior efficacy when compared with carbapenems, concerns about pharmacokinetic–pharmacodynamic drug target attainment with standard doses, and poor outcomes shown in some observational studies. Prospective cohort data and a meta-analysis suggest that BLBLIs are non-inferior to carbapenems in the treatment of bloodstream infections caused by ESBL producers. We examine why BLBLIs are perceived as inferior in the treatment of infection with ESBL producers, and discuss data that suggest these concerns might not be strongly supported by clinical evidence.

Introduction Extended-spectrum β-lactamases (ESBLs) in Gramnegative bacteria have emerged as a major global public health concern in past decades.1 When first recognised, antibiotic-resistant isolates were usually encountered in nosocomially acquired infections or in outbreaks.2 Today ESBL producers are common in the community3–5 and especially in a health-care context, such as residential care facilities.6,7 If present trends in Europe continue, estimates are that bloodstream infections caused by third-generation cephalosporin-resistant Escherichia coli will be more common than those caused by meticillinresistant Staphylococcus aureus (MRSA).8 Some ESBL genes, such as blaCTX-M-15, have disseminated across the globe, facilitated by their location on plasmids harbouring multi-drug resistance elements and driven by epidemic strains such as E coli sequence type 131.9 A WHO global report on antimicrobial resistance surveillance showed that resistance to third-generation cephalosporins in Kleibsella pneumoniae or E coli is widespread.10 Surveillance data11 for Gram-negative bacteria isolated from patients with appendicitis in 39 countries showed the proportion of isolates that were positive for ESBL was highest in the Asia-Pacific region (28% of isolates) (excluding India), but lowest in Europe (4·4%) compared with a global mean of 16·3%. Reports on large surveillance studies of intra-abdominal infections show ESBLs are present in 67–79% of isolates in India, and 55–65% in China.12,13 In 225 K pneumoniae isolates of urinary specimens in south India, 96% expressed ESBLs, a figure that is even more striking in view of the fact that about 50% of isolates were from community samples.14 ESBL-producers are increasingly prevalent in Europe and the Americas.15–18 The Centers for Disease Control and Prevention reported 19% of all health-care-

related infections in the USA were caused by ESBLproducing Enterobacteriaceae, which translates into 26 000 infections and 1700 deaths every year, and 23% of Klebsiella spp and 14% of E coli are ESBL producers.19 Non-susceptibility to third-generation cephalosporins ranged from 11–25% in E coli and 45–52% in K pneumonia in Latin America.20 The European Union and European Economic Area population-weighted mean percentage of E coli isolates resistant to thirdgeneration cephalosporins in 2012 was 11·8%, ranging from 4·4% in Sweden to 38·1% in Bulgaria.21 Even in countries with a low prevalence of ESBLs international travel has been reported to increase the risk of colonisation and subsequent infection.22,23 A concomitant increase in the administration of carbapenems has ensued with increased incidence of ESBL-related infections worldwide. Increased use of carbapenems creates selection pressure for carbapenem resistance.24 A strong risk factor for infection with carbapenem-resistant bacteria is previous use of a carbapenem.25 Even brief exposure to a carbapenem increases the risk of colonisation with imipenem-resistant Gramnegative bacteria in patients under intensive care.26 A new challenge of carbapenem resistance is emerging largely mediated by the efficient spread of carbapenemases.27–31 With few new antibacterial drugs in development the targeted use of existing drugs is essential. The role of β-lactam-β-lactamase inhibitors (BLBLIs) are combination agents whereby a β-lactam is formulated with a β-lactamase inhibitor to extend the spectrum of activity and retain the activity of the β-lactam antibiotic despite the effect of hydrolysing β-lactamase enzymes, although β-lactamase inhibitors have little antibiotic activity of their own. However, the role of BIBLIs such as

www.thelancet.com/infection Published online February 23, 2015 http://dx.doi.org/10.1016/S1473-3099(14)70950-8

Lancet Infect Dis 2015 Published Online February 23, 2015 http://dx.doi.org/10.1016/ S1473-3099(14)70950-8 University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia (Prof P N A Harris MBBS, Prof D L Paterson PhD); Department of Infectious Diseases, National University Hospital, Singapore (P N A Harris, Prof P A Tambyah MD); and University Medicine Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (P N A Harris, P A Tambyah) Correspondence to: Dr Patrick N A Harris, University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital Campus, Herston, QLD 4029, Australia [email protected]

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amoxicillin–clavulanate, ticarcillin–clavulanate, and piperacillin–tazobactam is uncertain in the treatment of infections caused by ESBL producers.1 By definition,32 ESBLs are inhibited by clavulanate in vitro. Yet there are concerns that in-vitro susceptibility to clavulanate might not translate into clinical efficacy. In-vitro data and several retrospective clinical studies show efficacy of carbapenems over other drugs, including BLBLIs, because they are generally stable against a wide range of β-lactamases.33–39 Carbapenems, therefore, are usually recommended as first-line therapy for serious infections caused by ESBL producers.34,35,40 However, randomised controlled trials that specifically compare carbapenems with other drugs for the treatment of serious infections caused by ESBL producers have not been reported. Observational studies41,42 suggest that if the bacterial isolate is susceptible to BLBLIs in vitro then in definitive therapy BLBLIs are non-inferior to carbapenems, especially if the minimum inhibitory concentration (MIC; the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation) of the BLBLI combination antibiotic is low. This strategy might be a reasonable carbapenem-sparing option to treat infections caused by ESBL producers. In this Review we examine the basis of the caution associated with the use of BLBLIs for serious infections caused by ESBL producers and discuss whether the available clinical evidence might justify their use in specific circumstances.

ESBLs

For an updated listing of β-lactamases see http://www. lahey.org/studies

2

ESBLs are a family of proteins that hydrolyse β-lactams. The production of β-lactamase enzymes is the principal mechanism by which Gram-negative bacteria resist the action of β-lactam antibiotics.43 The genes that encode these enzymes are either chromosomally located, or, more commonly, acquired via mobile genetic elements such as plasmids. Historically, most β-lactamases hydrolysed only a narrow range of β-lactams (eg, penicillin). The first ESBL was described in a Klebsiella spp isolate producing sulfhydryl variable (SHV) β-lactamase that hydrolysed third-generation cephalopsorins and monobactams.44 An increase in the number and variety of β-lactamases has since occurred. From 2000 there has been a global increase in CTX-M-type ESBLs in both community-acquired E coli and nosocomial Klebsiella spp.45 The rapid evolution and dissemination of β-lactamases is believed to have occurred mainly via selection pressure because of the widespread use of antibiotics in human and veterinary medicine, and food production.46 Several classification schemes have been proposed for β-lactamases. The two most widely used are the Bush– Jacoby–Medeiros47 functional classification (ESBLs designated group 2be) and the Ambler48 molecular classification (ESBLs designated class A). ESBLs are defined by the capability to hydrolyse extended-spectrum

cephalosporins and monobactams, and their susceptibility to β-lactamase inhibitors (such as clavulanate), but yet do not hydrolyse cephamycins and carbapenems.49 Therapeutic strategies to combat the emergence and evolution of β-lactamases focused on the development of β-lactams that could resist hydrolysis and the use of β-lactamase inhibitors with high affinity for β-lactamase enzymes (so-called suicide substrates) to enable protection of the active enzyme.50 All of these drugs effectively inhibit β-lactamases, including ESBLs, although inhibitorresistant enzymes have been described.50 The key phenotypic property of ESBL enzymes is their ability to hydrolyse third-generation cephalosporins. However, other β-lactamases, such as AmpC, also mediate resistance to these antibiotics. AmpC is encoded by genes that are usually chromosomal in bacteria (such as Enterobacter cloacae), but can be mobilised by plasmids and transferred to other bacteria. Antibiotic resistance mediated by plasmid-derived AmpC is increasingly prevalent51 and these enzymes are not effectively inhibited by clavulanate or tazobactam. In the laboratory, a commonly used indicator of ESBL or AmpC expression in Enterobacteriaceae is resistance to third-generation cephalosporins. In the past the presence of an ESBL could not always be detected in this way because MIC breakpoints (used to predict the likelihood of therapeutic success with a particular antibiotic at concentrations achievable in patients with standard dosing, to detect resistant populations, or both) were fairly high. In the past 5 years, both the Clinical Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have lowered the MIC clinical breakpoints of third-generation cephalosporins and carbapenems in the treatment of Enterobacteriaceae infections to improve the detection of antibiotic resistance mediated by ESBLs, AmpC , and carbapenemase, and aid treatment recommendations. Low MIC breakpoints of antimicrobials have decreased the need for routine additional tests to confirm the presence of a β-lactamase and to guide therapy, although this information might still be useful for the purposes of epidemiological study and infection control. Confirmation of the presence, and characterisation, of a β-lactamase might be less important in laboratory reporting and clinical therapy than the MIC.52 When MIC values of drugs are high, but bacteria are still in the susceptible range, infection might be associated with worse clinical outcomes.53 New techniques are being developed to aid clinicians in the rapid detection and characterisation of ESBLs directly from blood cultures and might prove essential to the timely administration of appropriate empirical therapy in the future.54–56

BLBLIs in the treatment of ESBL producers In-vitro studies ESBL producers might frequently be susceptible in vitro to BLBLIs. However, clinicians might be hesitant to use

www.thelancet.com/infection Published online February 23, 2015 http://dx.doi.org/10.1016/S1473-3099(14)70950-8

Review

these drugs, especially for serious infections such as bacteraemia or pneumonia. Carbapenems have generally been recommended in such circumstances as the drug of choice.1,35,39 Yet the antimicrobial resistance landscape has changed since recommendations were formulated when carbapenem resistance was rare. So why is there reluctance to use a drug class when the bacteria are susceptible according to laboratory standards (panel)?

it has been argued that it is inconsistent to use BLBLIs against penicillinases (eg, amoxicillin–clavulanate against meticillin susceptible Staphyloccoccus aureus) or other narrow spectrum β-lactamases (such as TEM-1producing E coli), but dismiss their clinical efficacy against ESBLs.64

Multiple β-lactamase genes Co-resistant enzymes

Inoculum effect A major concern with the use of BLBLIs for infections caused by ESBL producers is the possibility of decreased efficacy in the presence of a high bacterial load. High inoculum infections might overwhelm the effect of β-lactamase inhibitors.57,58 In time-kill studies, piperacillin–tazobactam failed to maintain 99% bacterial killing against 1 × 10⁷ colony-forming units (CFU) per mL (a high inoculum) beyond 8 h, with regrowth occurring after this time, whereas carbapenems maintained 99·9% killing for 24 h.59 Piperacillin–tazobactam did not show equivalent bactericidal activity against ESBL producers and non-ESBL K pneumoniae, despite the same MIC.59 Time-kill studies of amoxicillin–clavulanate show this combination maintains killing of ESBL producing E coli for 24 h in the presence of a high bacterial load, by contrast with piperacillin–tazobactam, which showed a pronounced inoculum effect.60 However, the inoculum effect was evident for piperacillin–tazobactam in non-ESBL-producing E coli. The fact that amoxicillin–clavulanate is not subject to a substantial inoculum effect combined with the above results suggests that this phenomenon not only relates to β-lactamase.60 Because no additional drug doses are introduced into the testing system in these studies the inoculum effect could be a laboratory phenomenon of restricted clinical relevance.61 In a murine model of sepsis, the inoculum effect seen in-vitro for piperacillin–tazobactam seemed to be present in vivo, although to a lesser extent for amoxicillin–clavulanate. In mice infected with nonESBL-producing E coli, amoxicillin–clavulanate maintained bacterial killing independent of the bacterial inoculum, whereas piperacillin–tazobactam lost efficacy against high inoculum infections, as did imipenem. All three antibiotics had decreased efficacy against ESBLproducing E coli, although imipenem and amoxicillin clavulanate were more efficacious than piperacillin– tazobactam.62 In a murine model of pneumonia (there were three treatment groups: meropenem, piperacillintazobactam, and controls), higher concentration inoculations (106 CFU per mouse vs a standard 104 CFU per mouse) with ESBL producing K pneumoniae was associated with 100% mortality in the piperacillin– tazobactam treated group, but all mice treated with meropenem survived, and had lower bacterial loads in the lung and less bloodstream invasion than the piperacillin-tazobactam group.63 Despite these concerns,

Another concern is the complex setting in which ESBLmediated resistance might occur. ESBL genes are often acquired from plasmids that might contain other β-lactamases.9 Some β-lactamases might not be inhibited by clavulanate or tazobactam (such as plasmid-derived AmpC). For example, ESBL-producing E coli in some areas are commonly resistant to amoxicillin–clavulanate, largely due to colocalisation of clavulanate-resistant Panel: Reasons for and against the use of β lactam–β lactamase inhibitors for infections caused by extended-spectrum β-lactamase producers Arguments in favour • By definition, Ambler class A ESBL producers are inhibited by antimicrobials that inactivate β lactamases such as clavulanate or tazobactam • Emerging data from some large cohort studies and a meta-analysis support the safety and efficacy of BLBLIs • Drugs used regularly against Enterobacteriaceae expressing class A β lactamases (eg, TEM-1 in ampicillin-resistant Escherichia coli, SHV-1 in Klebsiella pneumoniae), and other β-lactamase-producing species (eg, Haemophilus influenzae, Staphyloccoccus aureus) without strong evidence for frequent clinical failure • ESBL producers are frequently susceptible in vitro to piperacillin–tazobactam (especially ESBL-producing E coli) in many parts of the world • Carbapenems should be reserved for specific situations in which no other drugs are available • Few clinical studies clearly show inferiority of BLBLIs when compared with carbapenems in the treatment of susceptible ESBL producers • Possible decreased selection pressure for carbapenem-resistant strains or Clostridium difficile might be more ecologically benign in some situations compared with third-generation cephalopsorins, carbapenems, or quinolones Arguments against • Carbapenems remain stable to ESBLs and are recommended as first-line therapy for serious infections • Scarce published clinical experience on the efficacy of BLBLIs against ESBL producers causing infections outside the urinary tract • An inoculum effect shown in mouse models, which might limit efficacy • Increasing resistance to BLBLIs in ESBL producers, especially K pneumoniae, thus limiting efficacy in empirical therapy • Overexpression of β lactamases (including by other non-ESBLs) that might overwhelm the inhibitor component • No head-to-head randomised trials to assess BLBLIs in comparison with carbapenems • Poor drug concentration attainment with standard doses of piperacillin–tazobactam for isolates with high minimum inhibitory concentrations but still within the Clinical Laboratory Standards Institute susceptible range (eg, 8–16 mg/L) • Complex co-resistance mechanisms, including other enzymes not well inhibited by tazobactam or clavulanate (eg, plasmid-derived AmpC) or development of inhibitor-resistant enzymes

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OXA-1 and CTX-M genes on the same plasmid, especially in ST131 E coli in the UK that carry blaCTX-M-15.65 Various CTX-M-type β-lactamases predominate across the world, and might result in variable MICs associated with BLBLIs. In a Spanish study66 of ESBL-producing E coli isolates from blood, 35·5% of the common CTX-M-9 isolates were susceptible to amoxicillin–clavulanate and 93·1% were susceptible to piperacillin–tazobactam compared with only 60·5% of CTX-M-1 (including CTX-M-15) isolates susceptible to both drugs. Variant genes encoding ESBL enzymes resistant to BLBIs can emerge with exposure to inhibitors in vitro.67 Bacteria might overexpress the non-ESBL parent enzymes (such as TEM-1) that overcomes the activity of β-lactamase inhibitors because there is not enough inhibitor present to effectively counteract their activity.68 Antibiotic resistance might arise from decreased membrane permeability or efflux mechanisms.64,69 All these factors might be difficult to detect or predict and could predispose some drug combinations to clinical failure.

Inadequate conventional dosing Concerns exist that conventional dosing with BLBLIs might not always achieve adequate pharmacokinetic– pharmacodynamic indices (the quantitative relationship between achievable drug concentrations over time and microbiological parameters of the infecting organism, such as the MIC).70 By Monte Carlo simulation, the probability of target attainment (the probability of achieving exposure to the drug at an adequate concentration relative to the MIC for a specific proportion of the dosing interval; 30–70% t>MIC [a key measure for determining the efficacy of β-lactams—ie, the peak concentration is less critical than the duration of exposure to the drug at a concentration above the MIC]) was established for ESBL-producing isolates from the SENTRY surveillance programme in the USA71. For example, according to this model in a patient given 3·375 g of piperacillin–tazobactam every 4 h or 6 h the probability of achieving 30–40% t>MIC for E coli was greater than 0·86. The probability of achieving the same target for K pneumoniae with piperacillin–tazobactam CLSI MIC breakpoints (mg/L)

EUCAST MIC breakpoints (mg/L)

Susceptible

Susceptible

Resistant

Resistant

Amoxicillin–clavulanate*

≤8/4†

>32/16†

≤8‡

≥ 8‡

Piperacillin–tazobactam

≤16/4§

>128/4§

≤8§

≥ 16§

Ampicillin–sulbactam

≤8/4†

>32/16†

≤8§

≥ 8§

Ticarcillin–clavulanate

≤16/2‡

>128/2‡

≤8‡

≥ 16‡

CLSI=Clinical Laboratory Standards Institute. MIC=minimum inhibitory concentration. EUCAST=European Committee on Antimicrobial Susceptibility Testing. *EUCAST have defined MIC breakpoint of amoxicillin–clavulanate in the treatment of uncomplicated urinary tract infection as susceptible ≤32 mg/L and resistant >32 mg/L. †Fixed ratio of β-lactam to β-lactamase inhibitor of 2:1. ‡Fixed β-lactamase inhibitor concentration 2 μg/mL. §Fixed β-lactamase inhibitor concentration 4 μg/mL.

Table: CLSI and EUCAST breakpoints for β-lactam-β-lactamase inhibitors in the treatment of Enterobacteriaceae infections

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3·375 g every 4 h, however, was 0·72–0·77 but decreased to 0·57–0·69 at dose intervals of 3·375 g every 6 h.71 Prolonged infusions of piperacillin–tazobactam may be necessary in critically ill patients,72 and were shown to decrease mortality in a retrospective study of patients with Gram-negative infections.73 Continuous infusions of β-lactams improved drug target attainment (plasma antibiotic concentration above the MIC on days 3 and 4) and the chance of a clinical cure in patients with sepsis compared with intermittent dosing.74 Whether this strategy will enhance the activity of BLBLIs against ESBLproducers is not clear, but has been recommended by some researchers, largely based on pharmacokinetic– pharmacodynamic considerations.70

Bacterial resistance to BLBLIs MICs of BLBLIs might vary according to ESBL, the membrane permeability of strains, the amount of β-lactamase produced, and the rate of enzyme resynthesis.75 There is surprising variation in the in-vitro methods used to test susceptibility of bacteria to BLBLIs. The breakpoints set for MICs differ between CLSI and EUCAST, as do fixed concentrations or fixed ratios of the the β-lactamase inhibitor (table).76,77 A move from CLSI to EUCAST standards increases the chance of E coli being reported as resistant to amoxicillin–clavulanate, but might correlate better with clinical outcomes.78 The in-vitro activity of piperacillin–tazobactam against various ESBL producers is less predictable than that of carbapenems. In a US study79 of 300 E coli isolates with resistance to third-generation cephalosporins, in which CTX-M type ESBLs predominated, piperacillin– tazobactam had good in-vitro activity (>90% of isolates susceptible). Data for the 2009–10 SMART programme in North America and Europe show that 83·6% of ESBLproducing E coli isolates from urinary tract were susceptible to piperacillin–tazobactam compared with 96·6% of non-ESBL-producing isolates.80 Similarly, 580 (86.8%) of 668 ESBL-producing E coli isolates from intraabdominal infected individuals in the Asia-Pacific region were susceptible to piperacillin–tazobactam, but only 85 (47%) of 181 ESBL-producing K pneumoniae isolates were susceptible.13 In the North American SMART programme between 2010 and 2011, 106 (78%) of 138 ESBL-producing E coli isolates were susceptible to piperacillin–tazobactam compared with only 21 (34%) of 62 ESBL K pneumoniae isolates.81 In the SENTRY surveillance programme from 2009 to 2012 in Europe and the USA, 48 (69·6%) of 69 ESBL-producing E coli isolates from patients with pneumonia were susceptible to piperacillin–tazobactam, but only 35 (26·9%) of 130 ESBL-producing Klebsiella spp isolates were susceptible.82 The CANWARD surveillance data for Canadian hospitals during 2007–2011 reported 144 (62·3%) of 231 ESBL-producing E coli isolates and 23 (47·7%) of 48 K pneumoniae isolates were susceptible to amoxicillin–clavulanate, and 215 (93·1%) of 231 E coli isolates and 66·7% of K pneumoniae isolates were

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susceptible to piperacillin–tazobactam.83 A reduction in susceptibility to BLBLIs in some parts of the world clearly has implications for empirical therapy in areas where ESBL producers are common, especially in view of the high incidence of piperacillin–tazobactam resistance in ESBL-producing Klebsiella spp. Variation in the prevalence of some ESBL producers can affect their susceptibility to BLBLIs. For example, in a survey including isolates of Enterobacteriaceae with an ESBL phenotype from 72 US hospitals, only 67·2% of isolates with CTX-M-15-like enzymes were susceptible to piperacillin–tazobactam compared with 92·9% of isolates with CTX-M-14-like enzymes, 81·5% of isolates with CMY-like enzymes, and only 45·8% of isolates with SHV-type enzymes.84 Knowledge of local antibiotic resistance patterns, and molecular epidemiology of the enzymes responsible, might be essential to guide empirical therapy.

Clinical studies of antimicrobial therapy for ESBL producers Despite the efficacy of carbapenems in the treatment of infections with ESBL-producing Enterobacteriaeae, this approach has not yet been assessed in randomised controlled trials. Data are largely derived from observational studies.1 Even a well designed observational study will be prone to bias and confounding factors, weakening the conclusions that can be drawn from the analyses. Several studies35,39,85,86 have established that third-generation cephalosporins are inferior to carbapenems in the treatment of infections with ESBL producers. Before the introduction of lowered susceptibility MIC breakpoints by CLSI, there was a high incidence of clinical failure when infections caused by ESBL producers that tested susceptible were treated with third-generation cephalosporins.87 Large epidemiological surveys11,80,81,82,83,88–90 showed that carbapenems have in-vitro efficacy against ESBLproducing E coli (about 97–100% of isolates susceptible), although increased resistance to carbapenems in ESBLproducing K pneumoniae has been shown (about 61–100% of isolates susceptible).

Clinical studies of BLBLIs for ESBLs Despite changes in interpretative criteria for thirdgeneration cephalosporins in the past years, CLSI and EUCAST have continued to report BLBLI susceptibility of bacteria according to their MIC breakpoints, irrespective of the presence or not of an EBSL. In view of the scarce clinical experience with BLBLIs against ESBL producers, carbapenems have remained the treatment of choice for many clinicians. Few early studies directly examined the efficacy of BLBLIs against ESBL producers when the efficacy of third-generation cephalosporins was the main focus. In the past 3 years larger cohorts and a meta-analysis have provided a greater depth of evidence (appendix). Some case reports and a small series reported on the use of BLBLIs for infections with ESBL producers.

Amoxicillin–clavulanate was successful in the treatment of a lower urinary tract infection caused by E coli producing a CTX-M-15 ESBL.91 A 93% cure rate was reported for uncomplicated cystitis caused by ESBLproducing E coli when treated with amoxicillin– clavulanate, if susceptible in vitro (MIC ≤8 μg/mL), compared with a 56% cure rate with intermediately susceptible or resistant bacteria in vitro.92 Piperacillin– tazobactam was successful in the treatment of ten of 11 patients with non-urinary infections with ESBLproducing E coli or Klebsiella spp with MIC of 16 μg/mL or less, but treatment was only successful in one of five patients with with MIC greater than 16–4 μg/mL. All six patients with urinary infection had a good outcome irrespective of the MIC.93 However, clinical failures with piperacillin–tazobactam have been reported,94,95 such as in the treatment of spontaneous bacterial peritonitis caused by ESBLproducing E coli94 or endocarditis caused by ESBLproducing K pneumoniae, whereby antibiotic resistance developed during therapy.95 Burgess and co-workers38 collected all ESBL-positive clinical isolates detected during a 2-year period and analysed outcomes of 18 patients. Three (17%) of 18 patients died and six (33%) of 18 had failed treatment. All three patients treated with a carbapenem had clinical cure, whereas only six (55%) of 11 patients treated with piperacillin–tazobactam in combination had a successful outcome, and only five (56%) of nine patients were successfully treated despite susceptible isolates in vitro.38 However, the study was small, lacked any control group, included isolates from a range of clinical samples, and made no adjustment for co-morbidities.1 Authors of a retrospective study96 in Canada analysed 79 episodes of bacteraemia caused by ESBL-producing E coli or K pneumoniae and showed empirical treatment with a BLBLI increased mortality (six [38%] of 16 patients vs ten [16%] of 63 patients, p=0·063), whereas the empiric use of a carbapenem decreased mortality (none of ten patients vs 16 [24%] of 69 patients; p=0·09), but neither result was significant.96 Notably, five of six patients who died after piperacillin–tazobactam treatment had ESBL isolates with MICs defined, according to CLSI standards, as susceptible, leading the authors to question the safety of using piperacillin–tazobactam in this context. Although 42 (53%) of 79 patients received inadequate therapy96 (defined in this study as receipt of a drug to which bacteria were subsequently shown to be resistant), mortality was not increased, perhaps a reflection of the use of a broader spectrum antibiotics in patients who were most ill.96 Other studies suggested a worse outcome with BLBLIs compared with carbapenems. In 74 episodes of bacteraemia caused by ESBL-producing E coli, K pneumonia, or Proteus mirabilis, eight (14%) of 57 patients treated with carbapenem monotherapy had not survived at 21 days, compared with two (25%) of eight

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in the BLBLI-treated group, although not all patients were dosed adequately.97 Carbapenems were superior to non-carbapenem β-lactams (mainly broad spectrum cephalosporins, piperacillin-tazobactam or ticarcillinclavulanate) in the treatment of ESBL-K pneumoniae bacteraemia (mortality at 14 days odds ratio [OR] 0·48, 95% CI 0·0009–0·688; p=0·009), especially versus BLBLI monotherapy, which showed 50% mortality (two of four patients).39 The use of a BLBLI for definitive treatment of ESBL-producing P mirabilis bacteraemia had a low response rate (one [25%] of four) compared with a carbapenem (two [100%] of two) or treatment for non-ESBL-producers (five [100%] of five).33 In many of these early studies, only a handful of patients were treated with BLBLIs. Furthermore, many of these studies did not use multivariate analyses and so were unable to adjust for confounders—a substantial weakness in observational studies of this type. Later studies show more favourable results with BLBLIs. Tumbarello and co-workers98 examined the role of initial empirical therapy with BLBLIs in a study of 186 bloodstream infections caused by ESBL-producing E coli, K pneumonia, and P mirabilis. Although best outcomes were with carbapenems (one death in 38 patients when in-vitro susceptibility was shown), BLBLIs (mainly piperacillin–tazobactam) had comparable outcomes (four deaths in 33 patients) and no significant increase in mortality (OR 0·55, 95% CI 0·19–1·55; p=0·24).98 The authors conclude, however, that there were insufficient data to recommend BLBLIs as therapy. In a multicentre study of 387 ESBL-producing E coli bloodstream infections, empirical therapy with piperacillin–tazobactam (after susceptibility of isolates was proven) showed lower mortality than carbapenems (13·1% [11 of 84] vs 24·6%; [17 of 69] p=0·05).99 The authors of a prospective observational study100 in India examined the use of non-carbapenem alternatives (such as cefoperazone-sulbactam, piperacillin-tazobactam, fluouroquinolones, aminoglycosides, chloramphenicol or co-trimoxazole) for the treatment of ESBL producers, in an area where the prevalence of ESBLs in Gram-negative bacteria is 60–70%.100 They analysed 522 consecutive patients with infections caused by ESBL producers. Similar clinical success rates were seen with carbapenems and non-carbapenems (126 [85·7%] of 147 vs 270 [79·6%] of 339; p=0·152) when BLBLIs (especially cefoperazone–sulbactam) were predominantly used. In a small study101 of 36 patients in Thailand with community onset bacteraemia due to ESBL-producing E coli or K pneumoniae predictors of mortality were examined in comparison with matched patients with non-ESBL bacteraemia. Empirical therapy with either a carbapenem or BLBLI given alone was associated with increased survival compared with a cephalosporin or quinolone given alone (14 [93%] of 15 vs nine [43%] of 21; p=0·637). In the multivariate analysis the failure to receive initial empirical treatment with a carbapenem or BLBLI 6

(adjusted OR 2·1, 95% CI 1·09–17·1; p=0·04) was a predictor of mortality.101 However all patients in this study101 were subsequently switched to a carbapenem after ESBL status was confirmed. In a study102 from China, definitive treatment of ESBL-producing E coli bacteraemia with cefoperazone–sulbactam had an equivalent outcome to treatment with imipenem (no deaths, clinical success 71·4% vs 87·5%; p=0·637). In a retrospective study103 of 114 patients with ESBL-producing E coli or K pneumoniae bacteraemia there was no difference in mortality between those empirically treated with a BLBLI or carbapenem at 3, 7, or 30 days. Much of the evidence to support BLBLIs in the treatment of infections with ESBL producers comes from a large prospective study4 of ESBL-producing E coli bloodstream infections in a Spanish cohort, in whom CTX-M β-lactamases were predominant and community acquisition was common. In a study of 43 episodes, only one of 11 patients died when treated with amoxicillin– clavulanate, and one of six patients died when treated with piperacillin–tazobactam.4 No patients died when the isolate was susceptible to piperacillin–tazobactam at MIC 1 mg/L or lower (n=5). Mortality was lower when patients received a BLBLI or a carbapenem given alone than either a cephalosporin or fluoroquinolone (two [9%] of 23 vs seven [35%] of 20; p=0·05).4 A post-hoc analysis42 of six prospective studies of the same Spanish cohort examined BLBLIs for both the empirical and definitive treatment of ESBL-producing E coli bacteraemia. Mortality was not increased with either empirical (hazard ratio [HR] 1·14, 95% CI 0·29–4·40; p=0·84) or definitive therapy (HR 0·76, 95% CI 0·28–2·07; p=0·5) with BLBLIs.42 The MIC of piperacillin–tazobactam seemed to be linked to outcome in this study,42 with only 4·5% mortality at 30 days (one of 22) if MIC was 4 μg/mL or less, or 23% (three of 13) mortality at 30 days if the MIC was or 4 μg/mL or more.69 Notably, most isolates produced CTX-M-type β-lactamases, which are efficiently inhibited by tazobactam, and there was a predominance of urinary and biliary tract infections—all potentially associated with low mortality. A subsequent study on the Spanish cohort104 reported outcomes of 39 patients with bloodstream infection caused by ESBL-producing E coli and treated empirically with piperacillin–tazobactam. All 11 patients with a urinary focus of infection survived, irrespective of MIC, and in patients with a non-urinary focus mortality was significantly decreased with MIC 2 mg/L or less compared with MIC higher than 2 mg/L or (none [0%] of 18 vs seven [41·1%] of 17; p=0·02). A meta-analysis86 of 21 studies comparing carbapenems with other drugs for the treatment of bloodstream infection caused by ESBL-producing Enterobacteriaeae and including 1584 patients has been done. Mortality did not differ between patients treated with carbapenems and BLBLIs as definitive (relative risk [RR] 0·52, 95% CI 0·23–1·13) or empirical therapy (RR 0·91, 95% CI 0·66–1·25). Mortality was lower in patients treated with

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carbapenems alone than in those treated with other nonBLBLIs in definitive (RR 0·65, 95% CI 0·47–0·91) and empirical (RR 0·50, 95% CI 0·33–0·77) therapy.86 However, several patients who were treated empirically with a BLBLI in these studies subsequently received a carbapenem. Furthermore, several studies included in the metaanalysis86 reported mortality data unadjusted for potential confounders. A large international retrospective observational study105 of 656 patients with bloodstream infection caused by ESBL-producing Enterobacteriaceae reported no difference in mortality between patients who received definitive therapy with BLBLI versus carbapenems given alone even after adjustment for comorbidity (adjusted HR 0·97, 95% CI 0·48–2·03).

Effects of BLBLIs on microbial resistance A major reason to consider BLBLIs in the treatment of infections with ESBL producers is the potential advantage of the decrease in selection pressure on ESBL producers in terms of microbial ecology. In an analysis106 of K pneumoniae bacteraemia in Taiwan, previous exposure to piperacillin–tazobactam or an aminoglycoside was associated with a decreased risk of isolates positive for ESBL producers compared with previous exposure to oxyimino-β-lactam. During periods of antibiotic cycling in four Australian intensive care units the use of antipseudomonal BLBLIs was associated with lower rates of MRSA and Pseudomonas aeruginosa infection or colonisation than cefepime.107 The use of piperacillin– tazobactam, as opposed to carbapenems, was associated with a decreased incidence of carbapenem-resistant Enterobacteriaceae at a hospital in Illinois.24 In the UK, a shift in prescribing away from the use of third-generation cephalosporins and towards BLBLIs (largely reflecting concerns with Clostridium difficile infections), has led to a decrease in cephalosporin non-susceptibility in Enterobacteriaceae isolated from bloodstream infections, but without clear increases in piperacillin–tazobactam resistance.108 Although there is a belief that piperacillin–tazobactam might have less of an effect on antimicrobial resistance, overuse of this drug will probably exert evolutionary selection pressure for strains expressing inhibitorresistant TEM genes, OXA β-lactamases, or carbapenemases, all of which confer piperacillin–tazobactam resistance.109 An association between previous piperacillin–tazobactam exposure and susequent colonisation or infection with CTX-M β-lactamase-producing E coli has been reported.110 The risk remains that excessive use of piperacillin–tazobactam might create selection pressure for carbapenemase producers and other antimicrobial-resistant organisms.108

New BLBLI combinations Interest has grown in the development of novel β-lactamase inhibitors111 or new combinations of existing drugs. Cefepime–tazobactam and ceftriaxone–sulbactam

combinations have been developed and marketed in India.64 Cefepime–tazobactam had the highest in-vitro efficacy (90·6% of isolates were susceptible) of six BLBLIs in a survey112 of 384 Gram-negative bacteria in India (compared with 4·7% for amoxicillin–clavulanate or ampicillin–sulbactam) including susceptibility of all ESBL isolates tested. Ceftriaxone–sulbactam has in-vitro efficacy against 54 CTX-M-15 producing E coli strains in India.113 Avibactam is a novel synthetic β-lactamase inhibitor against Ambler class A and C β-lactamases, and some class D enzymes. Combined with ceftazidime, avibactam seems to be as effective as carbapenems in the treatment of complicated urinary and abdominal infections including those with isolates resistant to thirdgeneration cephalosporins.114 Ceftazidime–avibactam has in-vitro activity against many resistant Gram-negative bacteria including ESBL-producing E coli or Klebsiella spp, ceftazidime-resistant E cloacae, and K pneumoniae carbapenemase (KPC) producing K pneumoniae.89 Ceftaroline–avibactam shows activity against Enterobacteriaceae expressing ESBLs (such as CTX-M β-lactamases), KPCs, and AmpCs (chromosomal derepression or plasmid expression) including strains expressing several β-lactamases.115 Avibactam in combination with imipenem, ceftazidime or cefepime showed in-vitro activity against carbapenem-resistant OXA-48-producing K pneumoniae and E coli or K pneumoniae expressing CTX-M-15 β-lactamase.116 Ceftolozane is a novel cephalosporin with improved stability against AmpC β-lactamases, and combined with tazobactam has efficacy against ESBL producers and is currently in phase 3 trials.117 Ceftolozane–tazobactam combined with metronidazole showed comparative efficacy against meropenem in a phase 2 trial of treatment for intra-abdominal infections.118 At the time of writing none of these new drugs are registered for clinical use.111

Conclusions In the past three decades there has been a plethora of studies on the investigation of diversity, global expansion, and the activity spectrum of β-lactamases in Gramnegative bacteria.119 Despite advances in the understanding of the basic science of resistance, the clinical evidence to guide treatment decisions for infections caused by resistant bacteria is surprisingly scarce. We urgently need well designed, prospective, and randomised trials to address treatment options for infections with ESBL producers. In view of the fact that ESBL producers are common in many areas of the world, a concerted international research effort could tackle the dilemma and provide clinicians with robust data to inform therapeutic strategies. An international multicentre randomised trial comparing meropenem with piperacillin–tazobactam in the definitive treatment of bloodstream infection caused by E coli or K pneumoniae spp non-susceptible to ceftriaxone is currently recruiting (NCT02176122).

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Search strategy and selection criteria We identified references for this Review through a search of articles in PubMed published from Jan 1, 1980 to Aug 1, 2014 using the terms, “extended-spectrum beta-lactamase OR ESBL”, AND “bacteremia OR bacteraemia OR bloodstream infection” and yielded 556 articles. The search was then narrowed to 392 articles with the combined search terms, “Escherichia coli”, OR “Klebsiella pneumoniae”, OR “Proteus”. Finally, articles were filtered using the terms, “drug therapy OR treatment”, OR “beta-lactamase inhibitor”, OR “piperacillin-tazobactam”, OR “amoxicillin-clavulanate”, to a final total of 262 articles. Only articles in English or translated into English or with abstracts translated into English were included. Further relevant articles were identified through cited references and Google Scholar. Abstracts were reviewed and papers for inclusion selected on the basis of relevance to the aims of this Review. Articles mainly on carbapenemase-producers or nonEnterobacteriaceae spp were not included.

Some studies from 201470 support the notion that BLBLIs might have a role in the treatment of infections with ESBL producers, which might reflect the changing epidemiology. In the early years studies on ESBL producers were of inpatients, often during nosocomial outbreaks, and many patients had co-morbidities or more complex infections (eg, ventilator-associated pneumonia). Today, more community infections are caused by ESBL producers, and the predominant sources of infection are changing (eg, urinary or biliary tract). In this context, the efficacy of BLBLIs might be at least adequate. On the basis of available evidence, although limited by increasing antimicrobial resistance, BLBLIs might provide a reasonable carbapenem-sparing option for ESBL producers, especially in less serious infections. Data are more robust for infections of the urinary tract (including with bacteraemia), non-urinary infections in which the isolate is susceptible at a low MIC, and when adequate source control has been achieved (panel). Empirical use of BLBLIs might be compromised in areas where resistance to BLBLIs is common, especially where ESBL-producing K pneumoniaeare are prevalent; knowing the local susceptibility patterns for common Gram negatives is important to guide such decisions. When piperacillin–tazobactam is used for serious infections it should be dosed to maximise pharmacokinetic–pharmacodynamic parameters, which is likely to be of greater importance when the MIC is at the higher end of the susceptible range.74,120 Changing perceptions toward the efficacy of BLBLIs in this context (the use of BLBLIs against ESBL-producers that test susceptible in vitro) might provide opportunities to decrease the use of carbapenems. Further evidence from trials is needed for clinicians to confidently recommend such an approach 8

in broad range of clinical situations. Whether BLBLIs are safe and effective in the context of critically ill patients with a complex focus of infection or with severe sepsis remains uncertain. Declaration of interests PAT has received research support from Baxter, ADAMAS, Merlion Pharmaceuticals, Sanofi Pasteur, Fabentech, and Inviragen. He has received honoraria from Novartis and AstraZeneca. DLP has participated in advisory boards and received honoraria from AstraZeneca, Merck, Pfizer, Bayer, Cubist, and Leo Pharmaceuticals. PNAH declares no competing interests. Contributors DLP and PAT initiated the idea for the Review. PNAH did the literature search, selected relevant articles, and wrote the first and final drafts. All authors contributed to writing of the manuscript, and approved the final version. References 1 Pitout JD, Laupland KB. Extended-spectrum β-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis 2008; 8: 159–66. 2 Medeiros AA. Nosocomial outbreaks of multiresistant bacteria: extended-spectrum β-lactamases have arrived in North America. Ann Intern Med 1993; 119: 428–30. 3 Doi Y, Park YS, Rivera JI, et al. Community-associated extended-spectrum β-lactamase-producing Escherichia coli infection in the United States. Clin Infect Dis 2013; 56: 641–48. 4 Rodríguez-Baño J, Navarro MD, Romero L, et al. Bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli in the CTX-M era: a new clinical challenge. Clin Infect Dis 2006; 43: 1407–14. 5 Ben-Ami R, Rodríguez-Baño J, Arslan H, et al. A multinational survey of risk factors for infection with extended-spectrum β-lactamase-producing enterobacteriaceae in nonhospitalized patients. Clin Infect Dis 2009; 49: 682–90. 6 Stuart RL, Kotsanas D, Webb B, et al. Prevalence of antimicrobial-resistant organisms in residential aged care facilities. Med J Aust 2011; 195: 530–33. 7 Rooney PJ, O’Leary MC, Loughrey AC, et al. Nursing homes as a reservoir of extended-spectrum β-lactamase (ESBL)-producing ciprofloxacin-resistant Escherichia coli. J Antimicrob Chemother 2009; 64: 635–41. 8 de Kraker ME, Davey PG, Grundmann H, BURDEN study group. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe. PLoS Med 2011; 8: e1001104. 9 Coque TM, Novais A, Carattoli A, et al. Dissemination of clonally related Escherichia coli strains expressing extended-spectrum β-lactamase CTX-M-15. Emerg Infect Dis 2008; 14: 195–200. 10 WHO. Antimicrobial resistance global report on surveillance. Geneva: World Health Organization, 2014. 11 Lob SH, Badal RE, Bouchillon SK, Hawser SP, Hackel MA, Hoban DJ. Epidemiology and susceptibility of gram-negative appendicitis pathogens: SMART 2008–2010. Surg Infect (Larchmt) 2013; 14: 203–08. 12 Hawser SP, Bouchillon SK, Hoban DJ, Badal RE, Hsueh PR, Paterson DL. Emergence of high levels of extended-spectrum-βlactamase-producing gram-negative bacilli in the Asia-Pacific region: data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program, 2007. Antimicrob Agents Chemother 2009; 53: 3280–84. 13 Chen YH, Hsueh PR, Badal RE, et al. Antimicrobial susceptibility profiles of aerobic and facultative gam-negative bacilli isolated from patients with intra-abdominal infections in the Asia-Pacific region according to currently established susceptibility interpretive criteria. J Infect 2011; 62: 280–91. 14 Muzaheed DY, Doi Y, Adams-Haduch JM, et al. High prevalence of CTX-M-15-producing Klebsiella pneumoniae among inpatients and outpatients with urinary tract infection in Southern India. J Antimicrob Chemother 2008; 61: 1393–94. 15 Babinchak T, Badal R, Hoban D, et al. Trends in susceptibility of selected gram-negative bacilli isolated from intra-abdominal infections in North America: SMART 2005–2010. Diagn Microbiol Infect Dis 2013; 76: 379–81.

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