Murray A. Abramson

Antimicrobial Resistance among Gram-Negative Bacilli Causing Infections in Intensive Care Unit Patients in the United States between 1993 and 2004

ABSTRACT During the 12-year period from 1993 to 2004, antimicrobial susceptibility profiles of 74,394 gram-negative bacillus isolates recovered from intensive care unit (ICU) patients in United States hospitals were determined by participating hospitals and collected in a central location. MICs for 12 different agents were determined using a standardized broth microdilution method. The 11 organisms most frequently isolated were Pseudomonas aeruginosa (22.2%), Escherichia coli (18.8%), Klebsiella pneumoniae (14.2%), Enterobacter cloacae (9.1%), Acinetobacter spp. (6.2%), Serratia marcescens (5.5%), Enterobacter aerogenes (4.4%), Stenotrophomonas maltophilia (4.3%), Proteus mirabilis (4.0%), Klebsiella oxytoca (2.7%), and Citrobacter freundii (2.0%). Specimen sources included the lower respiratory tract (52.1%), urine (17.3%), and blood (14.2%). Rates of resistance to many of the antibiotics tested remained stable during the 12-year study period. Carbapenems were the most active drugs tested against most of the bacterial species. E. coli and P. mirabilis remained susceptible to most of the drugs tested. Mean rates of resistance to 9 of the 12 drugs tested increased with Acinetobacter spp. Rates of resistance to ciprofloxacin increased over the study period for most species. Ceftazidime was the only agent to which a number of species (Acinetobacter spp., C. freundii, E. aerogenes, K. pneumoniae, P. aeruginosa, and S. marcescens) became more susceptible. The prevalence of multidrug resistance, defined as resistance to at least one extended-spectrum cephalosporin, one aminoglycoside, and ciprofloxacin, increased substantially among ICU isolates of Acinetobacter spp., P. aeruginosa, K. pneumoniae, and E. cloacae.

Bacteriology of Moderate-to-Severe Diabetic Foot Infections and In Vitro Activity of Antimicrobial Agents

ABSTRACT As part of a United States-based multicenter clinical trial, conducted from 2001 to 2004, that compared ertapenem to piperacillin-tazobactam for the treatment of moderate-to-severe diabetic foot infections (DFIs), we obtained 454 pretreatment specimens from 433 patients. After debridement, the investigators collected wound specimens, mostly by curettage or biopsy, and sent them to the R. M. Alden Research Laboratory for aerobic and anaerobic culture. Among the 427 positive cultures, 83.8% were polymicrobial, 48% grew only aerobes, 43.7% had both aerobes and anaerobes, and 1.3% had only anaerobes. Cultures yielded a total of 1,145 aerobic strains and 462 anaerobic strains, with an average of 2.7 organisms per culture (range, 1 to 8) for aerobes and 2.3 organisms per culture (range, 1 to 9) for anaerobes. The predominant aerobic organisms were oxacillin-susceptible Staphylococcus aureus (14.3%), oxacillin-resistant Staphylococcus aureus (4.4%), coagulase-negative Staphylococcus species (15.3%), Streptococcus species (15.5%), Enterococcus species (13.5%), Corynebacterium species (10.1%), members of the family Enterobacteriaceae (12.8%), and Pseudomonas aeruginosa (3.5%). The predominant anaerobes were gram-positive cocci (45.2%), Prevotella species (13.6%), Porphyromonas species (11.3%), and the Bacteroides fragilis group (10.2%). Pure cultures were noted for 20% of oxacillin-resistant Staphylococcus aureus cultures, 9.2% of Staphylococcus epidermidis cultures, and 2.5% of P. aeruginosa cultures. Two or more species of Staphylococcus were present in 13.1% of the patients. Ertapenem and piperacillin-tazobactam were each active against >98% of the enteric gram-negative rods, methicillin-sensitive S. aureus, and anaerobes. Among the fluoroquinolones, 24% of anaerobes, especially the gram-positive cocci, were resistant to moxifloxacin; 27% of the gram-positive aerobes but only 6% of the members of the family Enterobacteriaceae were resistant to levofloxacin. Moderate-to-severe DFIs are typically polymicrobial, and almost half include anaerobes. Our antibiotic susceptibility results can help to inform therapeutic choices.

Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial.

BACKGROUND Diabetic foot infections are a common and serious problem, yet few randomised trials of adequate quality have compared the efficacy of the various antibiotic regimens available for their treatment. Our aim was to assess the efficacy and safety of ertapenem versus piperacillin/tazobactam for foot infections. METHODS We did a randomised, double-blinded, multicentre trial in adults (n=586) with diabetes and a foot infection classified as moderate-to-severe and requiring intravenous antibiotics. We assigned patients intravenous ertapenem (1 g daily; n=295) or piperacillin/tazobactam (3.375 g every 6 h; n=291) given for a minimum of 5 days, after which oral amoxicillin/clavulanic acid (875/125 mg every 12 h) could be given for up to 23 days. Investigators retained the option to administer vancomycin to patients in either group to ensure adequate coverage for potentially antibiotic resistant Enterococcus spp and meticillin-resistant Staphylococcus aureus (MRSA). Our primary outcome was the proportion of patients with a favourable clinical response (cure or improvement) on the day that intravenous antibiotic was discontinued. Analyses were by an evaluable-patient only approach. This study is registered with , number NCT00229112. FINDINGS Of the 576 patients treated, 445 were available for assessment at the end of intravenous therapy. Both baseline characteristics and favourable clinical response rates were similar for the 226 who received ertapenem and the 219 who received piperacillin/tazobactam (94%vs 92%, respectively; between treatment difference 1.9%, 95% CI -2.9 to 6.9). Rates of favourable microbiological responses (eradication rates and clinical outcomes, by pathogen) and adverse events did not differ between groups. INTERPRETATION Clinical and microbiological outcomes for patients treated with ertapenem were equivalent to those for patients treated with piperacillin/tazobactam, suggesting that this once-daily antibiotic should be considered for parenteral therapy of diabetic foot infections, when deemed appropriate.

Definitive Risk Factors for Anastomotic Leaks in Elective Open Colorectal Resection

HYPOTHESIS Anastomotic leaks following elective colorectal resections increase morbidity, mortality, and the need for additional interventions. An accurate understanding of risk factors would potentially reduce anastomotic leaks and/or allow appropriate selection of patients for diverting stomas. DESIGN Prospective review of patient and operative characteristics that contribute to anastomotic leaks. SETTING Fifty-one sites within the United States (May 2002-March 2005). PATIENTS Six hundred seventy-two patients who participated in a trial comparing preoperative antimicrobials in elective open colorectal surgery. MAIN OUTCOME MEASURES Anastomotic leaks were diagnosed using clinical findings and were confirmed with imaging. We examined 20 variables possibly affecting anastomotic healing in univariate and multivariate analyses. RESULTS There were 24 anastomotic leaks in 672 patients (3.6%) undergoing elective colorectal resection. There were 10 deaths (1.5%). A baseline albumin level of less than 3.5 g/dL (to convert to grams per liter, multiply by 10) (P = .04) and male sex (P = .03) were associated with anastomotic leaks in both univariate and multivariate analyses (adjusted odds ratios, 2.56 and 3.12, respectively). Increased duration of surgery (SD, 60 minutes; odds ratio, 1.53; 95% confidence interval, 1.06-2.22; P = .03) and steroid use at the time of surgery (odds ratio, 3.85; 95% confidence interval, 1.24-11.93; P = .02) were significant in univariate analysis. Surgical procedure with rectal resection; prophylaxis with ertapenem (vs cefotetan); or history of obesity, tobacco use, or diabetes was not associated with anastomotic leaks. CONCLUSIONS Significant risk factors for anastomotic leaks include low preoperative serum albumin level, steroid use, male sex, and increased duration of surgery. Appreciation of risk factors provides a rational basis for temporary diversion.

In vitro susceptibilities of aerobic and facultatively anaerobic gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: 2005 results from Study for Monitoring Antimicrobial Resistance Trends (SMART).

BACKGROUND The Study for Monitoring Antimicrobial Resistance Trends (SMART) is examining aerobic and facultatively anaerobic gram-negative bacilli (GNB) isolated from intra-abdominal infections. This report summarizes the 2005 annual data. METHODS During 2005, 76 medical centers in 31 countries in five regions collected intra-abdominal GNB for antimicrobial susceptibility testing using broth microdilution according to the Clinical and Laboratory Standards Institute guidelines. RESULTS A total of 5,476 unique aerobic and facultatively anaerobic GNB were isolated. Enterobacteriaceae accounted for 86% (4,711) of the total isolates. Among the 12 antimicrobial agents tested, the carbapenems and amikacin were the most reliably active against the Enterobacteriaceae, whereas ampicillin/sulbactam most often was the least active. Escherichia coli was the species most commonly isolated, at 48% (2,654). Extended-spectrum beta-lactamases (ESBLs) were detected phenotypically in 12% (325/2,329) of E. coli and 18% (151/856) of Klebsiella spp. In general, ESBL producers demonstrated lower susceptibility to the majority of the antibiotics than the non-producers; however, ESBL producers usually were susceptible to the carbapenems tested. CONCLUSIONS In 2005, antibiotic resistance continued to be a problem among GNB isolated from intra-abdominal infections, with the highest resistance rates observed in the Asia/Pacific region. Imipenem-cilastatin, ertapenem, and amikacin were the agents most consistently active in vitro against the Enterobacteriaceae isolated.

Clinical predictors of treatment failure for diabetic foot infections: Data from a prospective trial

To aid clinicians in selecting the appropriate approach for treating patients with diabetic foot infections, we investigated whether any baseline clinical findings predicted an unfavourable clinical outcome. Using data from a large, prospective treatment trial of diabetic foot infections (SIDESTEP), we assessed the association between clinical treatment failure and baseline history, physical and laboratory findings, by univariate and multivariate logistic regression analyses. Among 402 patients clinically evaluable 10 days after completing antibiotic therapy, baseline factors significantly (P < 0·05) associated by univariate analysis with treatment failure were ‘severe’ (versus ‘moderate’) University of Texas (UT) wound grade; elevated white blood cell count, C‐reactive protein or erythrocyte sedimentation rate; high wound severity score; inpatient treatment; low serum albumin; male sex; and skin temperature of affected foot >10°C above that of unaffected foot. By multivariate logistic regression only severe UT wound grade (odds ratio 2·1) and elevated white blood cell count [odds ratio 1·7 for a 1 standard deviation (2971 cells/mm3) increase] remained statistically significant. Clinical failure rates were 46% for patients with both risk factors compared with 10% for patients with no risk factors and 16–17% for patients with one risk factor. Increased white blood cell count and severe UT wound grade at baseline, but not other features, were significant independent and additive risk factors for clinical failure in patients treated for a diabetic foot infection.

Acquisition of Resistant Bowel Flora during a Double-Blind Randomized Clinical Trial of Ertapenem versus Piperacillin-Tazobactam Therapy for Intraabdominal Infections

ABSTRACT Bowel colonization with resistant bacteria can develop in patients receiving broad-spectrum antimicrobial therapy. We compared the impact of two antimicrobial regimens often used to treat intraabdominal infections on susceptibility patterns of bowel flora at the end of therapy. In a double-blind clinical trial, adults with complicated intraabdominal infection requiring surgery were randomized to receive piperacillin-tazobactam (3.375 g every 6 h) or ertapenem (1 g once a day) for 4 to 14 days. Rectal swabs were obtained at baseline and at the end of study therapy to determine the acquisition rates of Enterobacteriaceae resistant to the study drug, extended-spectrum β-lactamase (ESBL)-producing Escherichia coli or Klebsiella species, Pseudomonas aeruginosa resistant to imipenem or piperacillin-tazobactam, and vancomycin-resistant Enterococcus faecalis or Enterococcus faecium. Treated patients were assessable for the acquisition of resistant bacteria if appropriate specimens were obtained at both time points. Enterobacteriaceae resistant to the treatment received were acquired during study therapy by 8/122 assessable piperacillin-tazobactam recipients (6.6%) compared to 0/122 assessable ertapenem recipients (P = 0.007). Neither ESBL-producing E. coli or Klebsiella species nor P. aeruginosa resistant to piperacillin-tazobactam was isolated from patients in either treatment group. Imipenem-resistant P. aeruginosa was acquired by two of the ertapenem recipients (1.6%) versus zero of the piperacillin-tazobactam recipients (P = 0.50). Vancomycin-resistant enterococci were acquired during therapy by 8/125 assessable ertapenem recipients (6.4%) versus 2/123 assessable piperacillin-tazobactam recipients (1.6%; P = 0.10). In this study, the acquisition of resistant Enterobacteriaceae occurred significantly more often in patients treated with piperacillin-tazobactam than in those treated with ertapenem.

Effect of body mass index and ertapenem versus cefotetan prophylaxis on surgical site infection in elective colorectal surgery.

BACKGROUND The effectiveness of prophylactic antibiotics in the prevention of surgical site infection (SSI) after elective colorectal surgery is dependent on many factors, including the body mass index (BMI) of the patient. In this study, the association of BMI and type of antibiotic prophylaxis with SSI was evaluated in patients undergoing elective colorectal surgery. METHOD A post-hoc analysis was performed using data obtained from a multicenter randomized, double-blind study of 1,002 patients undergoing elective colorectal surgery who received prophylactic administration of ertapenem (1 g) or cefotetan (2 g). Among 650 evaluable patients, the effect of BMI and type of antibiotic prophylaxis on SSI rates was assessed four weeks after surgery. Mechanical bowel preparation was standardized, and no patient received oral antibiotics; intravenous antibiotics were not repeated during or after surgery. RESULTS The majority of patients had a BMI between 18.5 and 39.9 kg/m2. Regardless of the type of prophylaxis, SSI rates were significantly higher in patients with a BMI > or = 30 kg/m2 than in those with a BMI < 30 kg/m2. However, failure, defined as SSI, was significantly less common after ertapenem than after cefotetan prophylaxis at both BMI < 30 kg/m2 (12.7% vs. 26.4%, respectively; difference -13.7; 95% confidence interval [CI] -21.0, -6.5) and BMI > or = 30 kg/m2 (26.7% vs. 41.9%, respectively; difference -15.3; 95% CI -28.2, -2.0). The most prevalent type of SSI was superficial incisional infection, which was more common with both treatments in patients with a BMI > or = 30 kg/m2; however, the incidence of superficial SSI was lower after ertapenem than cefotetan prophylaxis. CONCLUSION In patients undergoing elective colorectal surgery, the incidence of SSI, specifically superficial incisional SSI, was higher in patients with a BMI > or = 30 kg/m2, regardless of the prophylactic antibiotic given. Ertapenem prophylaxis was more effective than cefotetan in the prevention of SSI at any BMI.

Infection after Elective Colorectal Surgery: Bacteriological Analysis of Failures in a Randomized Trial of Cefotetan vs. Ertapenem Prophylaxis

BACKGROUND A randomized study comparing single-dose cefotetan and ertapenem prophylaxis for elective colorectal surgery in 1,002 patients found ertapenem to be significantly more effective (p < 0.001). Failures of prophylaxis were thought to involve organisms resistant to both antimicrobial agents, isolated most often from deep or superficial incision sites. METHODS Further testing and analysis of the microbial data was performed. Susceptibility results were correlated with the clinical outcomes reported previously. RESULTS Of the 216 aerobes tested, 62.6% were resistant to cefotetan and 44% to ertapenem. Enterococci and methicillin-resistant Staphylococcus epidermidis were the aerobes recovered most frequently, and Bacteroides thetaiotaomicron, Clostridium innocuum, and Eubacterium lentum were the most frequent anaerobes. Enterococcus faecalis usually was associated in mixed culture with Bacteroides fragilis group species. Approximately one-half of the 158 anaerobes (50.7%), including all the species above, were resistant to cefotetan; most of these (61.4%) came from superficial incision sites. Only one anaerobe (Desulfovibrio fairfieldensis), found in a superficial incisional infection, was resistant to ertapenem, and no ertapenem-resistant enteric bacteria were recovered. In vitro resistance was associated with therapeutic failure. CONCLUSIONS The in vitro activity of ertapenem was superior to that of cefotetan against all anaerobic and many aerobic bacteria isolated from postoperative cultures of patients who failed prophylaxis with these agents. Our findings help to elucidate the results of the clinical trial.

Does dermal thermometry predict clinical outcome in diabetic foot infection? Analysis of data from the SIDESTEP trial*

The purpose of the study was to assess in patients with a diabetic foot infection (DFI), whether differences in skin temperature of the affected foot as compared to the corresponding site on the contralateral foot using dermal thermometry (DT) correlates with infection severity and clinical outcome. As part of the SIDESTEP DFI study, investigators took DT measurements at baseline and the discontinuation of intravenous therapy (DCIV) and performed a systematic evaluation of the infected limb to calculate a wound score. We compared the skin temperature differential between the limbs at the two assessments and determined the correlation between this value and surrogate markers of inflammation and the clinical response to treatment. Among patients enrolled in SIDESTEP, 332 were fully evaluable. The mean temperature differential between the limbs was 2·81 ± 5·75°F at baseline and 2·43 ± 4·84°F at DCIV (mean change: −0·37; 95% confidence interval (CI): −0·98, 0·23; P= 0·225). Skin temperature differential at baseline did not correlate with white blood cell count, level of C‐reactive protein or erythrocyte sedimentation rate or the infection severity score (r= 0·058, 0·148, −0·002, 0·067, respectively). We observed no overall trend between surface temperature differential at baseline and clinical outcome at DCIV, but patients with a skin temperature differential of ≥10°F at baseline had a significantly lower clinical response than those whose differential was <10°F (81·4% versus 94·3%; difference 12·9%; 95% CI: 3·5, 27·3%, P= 0·007). While there was no overall relationship between skin temperature and poor clinical outcome, there may be a threshold effect in DT (<10°F versus >10°F) between the limbs at baseline that predicts outcome of therapy.