Cefazolin and Enterobacteriaceae: Rationale for Revised Susceptibility Testing Breakpoints

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1 INVITED ARTICLE MEDICAL MICROBIOLOGY L. Barth Reller and Melvin P. Weinstein, Section Editors Cefazolin and Enterobacteriaceae: Rationale for Revised Susceptibility Testing Breakpoints John D. Turnidge on behalf of the Subcommittee on Antimicrobial Susceptibility Testing of the Clinical and Laboratory Standards Institute Clinical and Laboratory Standards Institute breakpoints for cefazolin against Enterobacteriaceae that were published in January 2010 have been revised by the Subcommittee on Antimicrobial Susceptibility Testing, based on the examination of recent data about in vitro activity, pharmacokinetic-pharmacodynamic characteristics and published clinical outcome studies. The new breakpoints, to be formally published in January 2011, have increased the minimum inhibitory concentration interpretive criteria by one 2-fold dilution, linked to an adult dosing schedule of 2 g every 8 h intravenously. zone diameter correlates, shown to be impossible to define with the January 2010 interpretive criteria, have been able to be set for the new interpretive criteria. Diagnostic laboratories will continue to need to test cephalothin to predict susceptibility to the oral cephalosporins cefadroxil, cefpodoxime, cephalexin, and loracarbef. The advent of new knowledge, particularly emerging drug-resistance mechanisms and our understanding of antimicrobial pharmacodynamics, has led the Clinical and Laboratory Standards Institute (CLSI) to commence a program of re-evaluating some of its susceptibility testing breakpoints [1]. In January 2010, CLSI released new breakpoints for parenteral cephalosporins against Enterobacteriaceae [2]. This was the outcome of an exhaustive evaluation of data requested by and presented to the Subcommittee on Antimicrobial Susceptibility Testing (AST), including in vitro susceptibility data, pharmacokinetic-pharmacodynamic (PK-PD) analyses, and clinical outcome data. The review was triggered by publications documenting failures of treatment with cephalosporins of serious infections caused by Enterobacteriaceae that had tested in the laboratory as susceptible [3]. At the time of publication of the breakpoints in January 2010, concern was raised that the new Received 2 November 2010; accepted 5 January Correspondence: John D. Turnidge, SA Pathology at Women's and Children's Hospital, North Adelaide, 5006, and School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, Australia (john.turnidge@health.sa.gov.au). Clinical Infectious Diseases 2011;52(7): Ó The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please journals.permissions@oup.com /2011/ $37.00 DOI: /cid/cir031 breakpoints for cefazolin (susceptible, <1 lg/ml; intermediate, 2 lg/ml; and resistant, >4 lg/ml) would effectively eliminate cefazolin as a useful agent for the treatment and prevention of infections caused by some common Enterobacteriaceae that did not possess intrinsic AmpC b-lactamases (ie, Escherichia coli, Klebsiella species, and Proteus mirabilis). It was noted at the time that a susceptible breakpoint of 1 lg/ml falls within the wild-type minimum inhibitory concentration (MIC) distributions of these species, which had previously been considered to be susceptible in the wild-type (ie, have no acquired resistance mechanism). Implementation of the January 2010 breakpoints would, therefore, have resulted in the majority of the wild-type strains of these species being considered as intermediate or resistant. A likely consequence of a laboratory report listing cefazolin as intermediate or resistant and cefotaxime or ceftriaxone as susceptible is to steer prescribers toward the use of extended-spectrum cephalosporins. For laboratories that use cascaded reporting and do not list extended-spectrum cephalosporin results on reports if the strain is susceptible to the narrower spectrum cephalosporins, inadvertent endorsement of widespread extended-spectrum cephalosporin prescribing would be considered to be undesirable. The question, therefore, became is cefazolin an effective agent for the treatment for infections caused by Enterobacteriaceae that do not possess intrinsic chromosomal cephalosporinases and MEDICAL MICROBIOLOGY d CID 2011:52 (1 April) d 917

2 either no b-lactamases or only narrow-spectrum b-lactamases? If so, what should the breakpoints of cefazolin be? RATIONALE FOR JANUARY 2010 CLSI BREAKPOINTS Before 2010, the breakpoints for parenteral cephalosporins and Enterobacteriaceae had been those that were set several decades ago. In the case of the first-generation cephalosporins cephalothin and cefazolin, the breakpoints had been in existence for.30 years. Since first publication of these breakpoints, the science of antimicrobial PK-PD emerged and matured to the point that it became an essential tool to assist breakpoint setting and revision [4], and PK-PD analyses were included in the essential data requirements by the CLSI Subcommittee [5]. When the AST Subcommittee of CLSI commenced its review of the cephalosporin breakpoints, it requested data in accordance with its own guidelines for setting and revising breakpoints [5]. This process ensured that the latest data on MIC distributions, PK-PD of cephalosporins, and outcome from published or regulator-submitted clinical studies were examined and factored into the decision making [4]. The most important influence on the potential revision of the breakpoints for these agents was the target attainment rate predicted by Monte Carlo simulations of the PK of standard adult dosing regimens. With use of a target percentage time of a MIC.50% for unbound cephalosporin agents [6], it became clear that cephalothin had no useful activity against Enterobacteriaceae, because the target attainment rates were extremely low. Therefore, the subcommittee agreed to delete breakpoints for cephalothin against Enterobacteriaceae, except as a test to predict the activity of certain oral first-generation cephalosporins, such as cephalexin, in urinary tract infection. For cefazolin, the Monte Carlo simulations predicted a satisfactory target attainment rate for a standard 1 g, 8-h dosing regimen if the breakpoints were set at susceptible (<1 lg/ml), intermediate (2 lg/ml), and resistant (>4 lg/ml). Data from a recent study comparing cefazolin MICs with zone diameters generated by a 30-lg disk were also reviewed. These data showed that no zone diameter criteria could be effectively selected using these new MIC breakpoints. The MIC breakpoints were duly accepted by the subcommittee and published by CLSI in January 2010, with the recognition that all newly published changes are tentative for 1 year. Reliable zone diameter interpretive criteria could not be set and were therefore not published. RE-EXAMINATION OF CEFAZOLIN DATA When it was recognized that the January 2010 published cefazolin breakpoints would fall within the wild-type MIC distributions of the most common Enterobacteriaceae, a review of available data and further analyses were commenced immediately. These are presented here. In Vitro Data Wild-Type Distributions. MIC distribution data for cefazolin are available for a range of Enterobacteriaceae on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Web site [7]. The data for the main target species are summarized in Table 1. Even wild-type P. mirabilis is less susceptible to cefazolin and first-generation cephalosporins in general [9]. The modal MIC of wild-type P. mirabilis is 4 mg/l, compared with 1 mg/l for E. coli and 2 mg/l for Klebsiella species. Effect of Narrow-Spectrum b-lactamases. A rather notable feature of the MIC distribution data is the longer upper tail, Table 1. Cefazolin Minimum Inhibitory Concentration (MIC) Distributions of the Common Enterobacteriaceae that Do Possess Chromosomal Cephalosporinases [7] MIC, lg/ml ECV a Species (cumulative %) (lg/ml) Escherichia coli b % 65.9% 80.4% 91.0% 95.7% 97.6% 99.2% 99.6% 100% Klebsiella pneumoniae b % 36.5% 76.0% 84.1% 88.0% 90.9% 96.6% 97.1% 99.5% 100% Klebsiella oxytoca b % 9.9% 43.8% 57.0% 71.1% 80.2% 83.5% 86.0% 95.9% 96.7% 100% Proteus mirabilis b % 75.3% 90.2% 95.8% 97.2% 97.6% 99.3% 99.7% 100% Salmonella species b % 33.2% 54.1% 97.7% 99.3% 99.6% 99.8% 99.8% 100% a Epidemiological (wild-type) cutoff value, estimated by the statistical method of Turnidge et al 2006 [8]. b Wild-type mode. 918 d CID 2011:52 (1 April) d MEDICAL MICROBIOLOGY

3 Table 2. Cefazolin Minimum Inhibitory Concentrations (MICs) of Escherichia coli and Proteus mirabilis, Compared with Ampicillin MICs. A. Escherichia coli, n Cefazolin MIC, lg/ml AmpicillinMIC (mg/l) < >32 Total > < Amp S subset % Amp I or R subset % Table 2A. Cefazolin MICs of E. coli and P. mirabilis, compared to ampicillin MICs. B. Proteus mirabilis, n Cefazolin MIC (lg/ml) AmpicillinMIC (mg/l) < >32 Total > < Amp S subset % Amp I or R subset % suggesting that strains with acquired b-lactamases may have been included. To clarify the contribution that acquired b-lactamases may have on MIC distribution data, additional susceptibility data were collected from the SENTRY surveillance program, Asia- Pacific [10], for the period This surveillance program collected clinical isolates from.60 hospital laboratories in the region during the period. Only species that do not naturally harbor a b-lactamase of any type, namely E. coli and P. mirabilis, could be analyzed. Furthermore, data were selected for strains that did not have an extended-spectrum b-lactamase phenotype (ie, a ceftriaxone or aztreonam MIC of.1 mg/l or a ceftazidime MIC.2 mg/l). Results were analyzed using MIC and ampicillin susceptibility category and are present in Table 2. It is apparent that cefazolin has low-level vulnerability to the narrow-spectrum b-lactamases found in E. coli and P. mirabilis, such as TEM-1, resulting in an increase in the modal MIC by approximately half to one 2-fold dilution. PK-PD Data Theoriginaldecisionforthechangeinthecefazolinbreakpoints by CLSI was based largely on the Monte Carlo simulation analysis conducted by subcommittee member Dr Michael Dudley, using data from healthy volunteers in a study conducted by Nightingale et al. [11]. The decision was based on a conventional 1 g every 8 h dosing regimen. To validate this choice, an additional Monte Carlo simulation analysis was conducted using PK data from Scheld et al [12], also performed on healthy volunteers. The results of these 2 analyses are summarized in Table 3. The analysis using data from either study confirms the choice of breakpoints (susceptible, < 1 lg/ml) for the conventional dose of cefazolin (ie, 1 g every 8 h). However, the target attainment rates for 2 g every 8 h suggested that a breakpoint of susceptibility of < 2 lg/ml may be acceptable. Clinical Outcome Data Clinical outcome data were sought from published studies. Most published clinical studies of cefazolin have focused on its efficacy in surgical prophylaxis and infections in which staphylococci predominate, such as bone and joint, skin and skin structure, and continuous ambulatory peritoneal dialysis infections. For consideration by the subcommittee, only publications that included the cefazolin dosing regimen, Table 3. Target Attainment Rates Determined by Monte Carlo Simulation in 2 Pharmacokinetic Studies of Cefazolin Percentage of Target Attainment (50% T. MIC) (Nightingale et al [11]) Percentage of Target Attainment (50% T. MIC) (Scheld et al [12]) MIC (lg/ml) 1 g q8h 1 g q6h 1.5 g q6h 2 g q8h 1 g q8h 1 g q6h 1.5 g q6h 2 g q8h MEDICAL MICROBIOLOGY d CID 2011:52 (1 April) d 919

4 Table 4. Clinical Studies Examining Outcomes of Cefazolin Treatment for Infections due to Enteric Gram-Negative Bacteria Study reference Madhavan et al, 1973 [13] Reller et al, 1973 [14] Turck et al, 1973 [15] Lus et al, 1977 [16] Hoyme and Madsen, 1978 [17] Iversen and Madsen, 1981 [18] Lea et al, 1982 [19] Millar et al, 1995 [20] Sanchez-Ramos et al, 1995 [21] Wing et al, 1998 [22] Dosing schedule(s) Infection type Organism (no.) 250 mg to 1 g q6h IM g per day I M or I V, most commonly 500 mg q8h g per day I M or I V 250 mg q12h IM 500 mg q12h IM Urinary tract Soft tissue Urinary tract Pneumonia E. coli (23)Klebsiella spp. (12)P. mirabilis (4)P. mirabilis (5)Klebsiella spp. (2) E. coli (6)Mixed, mainly E. coli or Klebsiella (7) E. coli (6)K. pneumoniae (5)P. mirabilis (1)K. pneumoniae (2) Mixed Gram-neg (4) No. bacteremic Pneumonia Klebsiella spp. (2) Cystis and Pyelonephritis 500 mg q8h IM Complicated urinary tract 1 g q8h IM Complicated urinary tract infection 1 g 12-hourly Acute urinary tract infection (pyelonephritis clinically) 1 g q8h IV Acute pyelonephritis in pregnancy 2 g q8h IV Acute pyelonephritis in pregnancy 1 g q8h IV Acute pyelonephritis in pregnancy E. coli (32) K. pneumoniae (5)P. mirabilis (5)(MICs mg/l) Escherichia and Citrobacter (6), Klebsiella and, Enterobacter (5) Proteus (9) E. coli (11) Klebsiella, Enterobacter (2) Proteus, Providencia (4) Serratia (1) E. coli (37) K. pneumoniae (2)P. mirabilis (2) E. coli, Proteus, Klebsiella, Enterobacter E. coli (47) Proteus (2) Klebsiella (5)(2 bacteremic) E. coli (48) Klebsiella pneumoniae Enterobacter spp. (n 5 not ) 5 patients 5 patients 2 patients 7 patients Susceptibility Test Method Agar dilution and disk Broth dilution and agar dilution Outcome Clinical response: Good a 23/23 (100%) Good 12/12 (100%) Good 4/4 (100%) Good 5/5 (100%) Good 2/2 (100%) Good 6/6 (100%) Good 7/7 (100%) Clinical response: Improved 6/6 (100%) Improved 5/5 (100%) Improved 1/1 (100%) Improved 2/2 (100%) Improved 2/4 (50%) Clinical response: Improved 2/2 Bacteriological response: Cure 33/42 Failure 1/42 Relapse 2/42 Reinfection 5/42 Superinfection 1/42 Bacteriological response: End of therapy eradication 91% 1w post therapy eradication 57% Bacteriological response end of treatment: Cure 17/18 Persistence, relapse 1/18 Bacteriological response: 18/20 uncomplicated 7/12 complicated Clinical response: Initial response 54/60 (90%)bacteremic subset 2/5 even though isolate tested as S Recurrence 3/60 (5%) Follow up 1ve urine 12/53 (23%) a Good outcome defined in the reference as the disappearance of most of the clinical symptoms and signs of infection within 3 days. Clinical response: Cure 83/88 (gentamicin added for 5 with poor response) Bacteriological response: Cure 51/60 Clinical response: Satisfactory 52/58 Prolonged fever 4/58 Antibiotic changed 2/58 described bacteriology that included Enterobacteriaceae, and contained data on clinical and/or bacteriological outcome were examined. Studies that fitted these criteria were few, and the majority were published before 1985 [13 26]. The qualifying studies in which at least 10 patients were treated with cefazolin are summarized in Table 4 [14 22]. Studies of pyelonephritis and other complicated urinary tract infections predominated. Three of the studies omitted from the Table 920 d CID 2011:52 (1 April) d MEDICAL MICROBIOLOGY

5 [23 25] mainly involved treatment of gram-positive infections and included only 5, 1, and 3 patients with infections caused by Enterobacteriaceae. A fourth involved the treatment of enteric fever [26], which is not considered to be an indication for the use of cefazolin. In the published studies, clinical and bacteriological outcomes were generally favorable. None of the treated Enterobacteriaceae was difficult to treat. However, there are uncertainties about the usefulness of these studies in the consideration of breakpoints. First, dosing regimens varied widely among the studies, and only regimens from the mid-1990s were similar to those recommended currently (1 2 g every 8 h). These regimens were used in 3 studies for a single indication, namely acute pyelonephritis during pregnancy. In studies in which.1 dosing schedule was used, it was not possible to determine how many patients were treated with each of the different regimens used. Second, only one of the studies recorded the clinical or bacteriological outcomes by MIC of the infecting pathogen [16]. This was a study published.30 years ago that examined lower urinary tract infections (n 5 26) and acute pyelonephritis (n 5 16)treatedwithlowerdoseregimensthat would not currently be used or recommended (250 mg or 500 mg intramuscularly every 12 h; regimen not specified by patient). Bacteriological cure was found in 22 of 29 patients whose gram-negative isolate had an MIC of <1.6 mg/l and in 9 of 14 patients whose isolate had an MIC of >3.1 mg/l. It is unclear how these data can be applied in the modern setting, where patients with infection receive higher and more frequent doses intravenously, although the study showed that only 8 of 16 patients with acute pyelonephritis experienced bacteriological cure with these low doses. Third, susceptibility testing was recorded as performed in most studies, and it is assumed that all of these studies would have defined susceptibility to cefazolin as an MIC <8 mg/l (or its disk zone diameter correlate), the susceptible breakpoint recommended by CLSI before January However, none of the studies specified the interpretive criteria used. Fourth, few patients had serious infection, such as bacteremia or septicaemia. Only 19 such cases were documented in the tabulated studies, and in many cases, the specific outcomes in these patients were not recorded. A very recent prospective study examined the efficacy of cefazolin in E. coli bacteremia secondary to acute pyelonephritis in obstetric patients [27]. This study was designed to assess the efficacy of cefazolin given as 2 g every 6 or 8 h against E. coli strains with MICs higher than the susceptibility breakpoint of <1 mg/l that was published by CLSI in January All 12 patients with bacteremia caused by isolates with MICs >2 mg/l were cured. Dosing Schedules The current US label for cefazolin is quite old but includes a wide range of dosing regimens, recommending doses as low as 250 mg every 8 h to 12 g per day in adults [28]. For severe or lifethreatening infections, such as endocarditis or septicemia, the recommended dosing regimen is g every 6 h. As can be seen in Table 3, a regimen of 1.5 g every 6 h gives equivalent target attainment rates to that of 2 g every 8 h. Diffusion Correlates For the determination of disk (30 lg disk)zone diameter correlates with the MIC interpretive criteria, data were provided to the subcommittee by Dr Ronald Jones from work performed in his laboratory in When initial attempts to establish correlates to the January 2010 MIC interpretive criteria were undertaken, it had not been possible to establish zone correlates for cefazolin. With the revised criteria, satisfactory correlates were found using the standard error-rate bounded methods prescribed by CLSI [5]. The results are summarized in Figure 1. Although there were a moderate number of minor errors (as defined by CLSI [5]), correlations were good with use of the zone diameter interpretive criteria of >23 mm for susceptible, mm for intermediate, and <19 for resistant. NEW CLSI RECOMMENDATIONS On the basis of consideration of all the available data, the AST Subcommittee agreed in June 2010 to revise the cefazolin breakpoints for Enterobacteriaceae to those detailed in Table 5. CAVEATS The revised breakpoints for cefazolin were derived mainly from Monte Carlo simulations of PK-PD data and recent laboratory data. Like many older agents, it has not been possible to find recent high-quality clinical data to support the PK-PD and laboratory data. Nevertheless, the best available evidence from the accessible older published studies generated no adverse signal. The revised breakpoints are linked to the dosing schedule of 2 g every 8 h in adults. This is a frequently recommended dose for serious infections in standard treatment guidelines, such as the Sanford Guide [29]. CLSI recognizes that only regulators can enforce changes to dosing schedules but is obliged to provide users with the dosing schedule data on which changes in breakpoints were based. It is recognized that a 2 g, 8-h adult dosing regimen represents a doubling of the doses that many clinicians prescribe for infections due to gram-negative bacteria. It is widely believed that MEDICAL MICROBIOLOGY d CID 2011:52 (1 April) d 921

6 Figure 1. zone diameter correlates for cefazolin using revised breakpoints. the conventional dosing schedule of 1 g every 8 h has been performing satisfactorily for decades. This belief may be wellfounded for the treatment of noninvasive infections, especially those involving the urinary tract, where the drug is concentrated. Whether the conventional dosing regimen would perform well in bacteremic infections is much less clear. Unfortunately, the published clinical data were not able to answer the dosing question, and only a prospective clinical dose ranging study can confidently resolve this dilemma. Such a study is challenging to perform, and there is an ethical issue about whether patients with bacteremia would agree to participate when PD analyses suggest a potential risk of failure with currently used doses. With these difficulties in mind, the CLSI Subcommittee took a cautious approach to the signal generated by the Monte Carlo simulations and linked the revised cefazolin breakpoints to the higher dosing schedule. The breakpoints have been set using data from species of Enterobacteriaceae that lack chromosomal b-lactamases of the AmpC or related type. The potential routine laboratory impact has been examined on 3 species in this category by Dien Bard et al [30]. These investigators examined routine laboratory test data from their own laboratory and showed that an elevation of the susceptible breakpoint to 2 lg/ml increases the percentage of susceptible E. coli from 24.2% to 43.1%, K. pneumoniae from 41.3% to 59.1%, and P. mirabilis from 0.6% to 13%. A significant proportion of the last species (71.6%) would be interpreted as intermediate with the new breakpoints. During their deliberations, the subcommittee considered the possibility of cefazolin as a test surrogate for the oral cephalosporins cefadroxil, cefpodoxime, cephalexin, and loracarbef. Currently, the test agent surrogate for many members of this Table 5. Revised Clinical and Laboratory Standards Institute Breakpoints Test/Report group Antimicrobial Agent content Zone Diameter Breakpoints, nearest whole mm MIC Interpretive Standard (lg/ml) Comments S I R S I R A a Cefazolin 30 lg/ml > <19 <2 4 >8 Interpretive criteria are based on a dosage regimen of 2 g every 8 h a Primary test and report. 922 d CID 2011:52 (1 April) d MEDICAL MICROBIOLOGY

7 drug class is cephalothin. In figures generously supplied by the Dr Tsai-Ling Yang Lauderdale from Taiwan, MIC data from an ongoing surveillance program in that country permitted a comparison of MIC distributions between cefazolin and cephalothin. Unfortunately, the MIC correlations between these 2 agents for the combined data for E. coli, K. pneumonia, and P. mirabilis were insufficient (categorical agreement,,75%) to allow cefazolin to replace cephalothin for surrogate testing at this time. Further work will be required to address this problem. The EUCAST has thus far elected not to set breakpoints for cefazolin and Enterobacteriaceae. In addition, they have not yet selected an epidemiological cutoff value for members of the Enterobacteriaceae family. Acknowledgments I thank the members and advisors of the Subcommittee on AST of CLSI, for the discussion and input into the decision making, and in particular, Drs Michael Dudley, Paul Ambrose, Ronald Jones, and Tsai-Ling Yang Lauderdale, for assisting with the data analyses that were presented to the Subcommittee. Financial support. This work was supported by CLSI and the Australian Society for Antimicrobials. Potential conflicts of interest. J.D.T. has been a board member for Johnson & Johnson, Novartis (Australia), Pfizer (Australia), Wyeth (Australia), and Cerexa; has received institutional grant support from National Health and Medical Research Council and JMI Laboratories; and has received travel, accommodations, and/or meeting expenses from American Society for Microbiology, Western Pacific Society for Chemotherapy, International Symposium on Antimicrobials and Antimicrobial Resistance, and BioMerieux. References 1. Ferraro MJ. Should we reevaluate antibiotic breakpoints? 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8 30. Dien Bard J, Hindler JA, Humphries RM, Lewinski MA. Revised cefazolin breakpoints: potential impact on therapeutic guidance of urinary tract infections. In: Program and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston, MA: American Society for Microbiology, d CID 2011:52 (1 April) d MEDICAL MICROBIOLOGY