Persistent Opioid Use After Combat Injury and Subsequent Long-term Risk of Abuse: A Retrospective Cohort Study.

OBJECTIVE: To determine whether persistent opioid use after injury is associated with subsequent long-term development of clinically recognized opioid abuse. SUMMARY BACKGROUND DATA: Opioid abuse is an epidemic in the United States and trauma can initiate persistent use; however, it remains unclear whether persistent opioid use contributes to the subsequent development of opioid abuse. The care of combat casualties by the Departments of Defense and Veterans Affairs uniquely allows investigation of this long-term outcome. METHODS: This retrospective cohort study randomly selected 10,000 battle-injured United States military personnel. We excluded patients who died during initial hospitalization or within 180 days of discharge, had a preinjury opioid abuse diagnosis, or had missing data in a preselected variable. We defined persistent opioid use as filling an opioid prescription 3 to 6 months after discharge and recorded clinically recognized opioid abuse using relevant diagnosis codes. RESULTS: After exclusion, 9284 subjects were analyzed, 2167 (23.3%) of whom developed persistent opioid use. During a median follow-up time of 8 years, 631 (6.8%) patients developed clinically recognized opioid abuse with a median time to diagnosis of 3 years. Injury severity and discharge opioid prescription amount were associated with persistent opioid use after trauma. After adjusting for patient and injury-specific factors, persistent opioid use was associated with the long-term development of clinically recognized opioid abuse (adjusted hazard ratio, 2.39; 95% confidence interval, 1.99-2.86). CONCLUSIONS: Nearly a quarter of patients filled an opioid prescription 3 to 6 months after discharge, and this persistent use was associated with long-term development of opioid abuse.

Incidence of Acute Kidney Injury among Patients Treated with Piperacillin-Tazobactam or Meropenem in Combination with Vancomycin.

Acute kidney injury (AKI) increases during empirical antimicrobial therapy with the combination of piperacillin-tazobactam (TZP) and vancomycin (VAN) compared to the number of incidences with monotherapy or the combination of cefepime and VAN. Limited data regarding the impact of meropenem (MEM) combined with VAN exist. This study examined the AKI incidence among patients treated with MEM plus VAN (MEM+VAN) or TZP+VAN. Data were collected from the University of Kentucky Center for Clinical and Translational Science Enterprise Data Trust from September 2007 through October 2015. Adults without previous renal disease who received MEM+VAN or TZP+VAN for at least 2 days were included. AKI was assessed using risk, injury, failure, loss, and end-stage (RIFLE) criteria. Inverse probability of treatment weighting was utilized to control for differences between groups. In total, 10,236 patients met inclusion criteria, with 9,898 receiving TZP+VAN and 338 receiving MEM+VAN. AKI occurred in 15.4% of MEM+VAN patients and in 27.4% of TZP+VAN patients (P < 0.001). TZP+VAN was associated with increased AKI compared to the level with MEM+VAN (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.82 to 3.52), after controlling for confounders. Use of MEM+VAN should be considered an appropriate alternative therapy to TZP+VAN if nephrotoxicity is a major concern. The results of this study demonstrate that judicial use of TZP+VAN for empirical coverage of infection is needed.

Nephrotoxicity in Patients with or without Cystic Fibrosis Treated with Polymyxin B Compared to Colistin.

Nephrotoxicity is the primary adverse effect of the polymyxins. The relative rates of toxicity of polymyxin B and colistin have not been fully elucidated, especially in patients with cystic fibrosis (CF). A retrospective cohort study of adults treated with polymyxin B or colistin for at least 48 h was conducted. The primary endpoint was the incidence of kidney injury assessed by RIFLE (i.e., risk, injury, failure, loss, end-stage renal disease) criteria. Risk factors for kidney injury were evaluated using multivariate Cox regression. A total of 414 patients were evaluated, 220 of whom had CF. In patients without CF, there was no difference in kidney injury with polymyxin B and colistin (42.9% versus 50.3%, P = 0.46). Loop diuretic exposure was a risk factor for kidney injury (adjusted hazard ratio [aHR], 1.82; 95% confidence interval [CI], 1.16 to 2.83) in this population. In patients with CF, polymyxin B and colistin were associated with similar rates of kidney injury (34.5% versus 29.8%, P = 0.77). Diabetes (aHR, 2.68; 95% CI, 1.01 to 7.11), loop diuretics (aHR, 3.02; 95% CI, 1.36 to 6.73), and progressive care unit admission (aHR, 8.21; 95% CI, 2.55 to 26.46) were risk factors for kidney injury, while higher baseline serum creatinine levels (per 1 mg/dl) were protective (aHR, 0.08; 95% CI, 0.01 to 0.48). Total unadjusted kidney injury in polymyxin-treated patients was less frequent in those who had CF (30.5% versus 48.5%, P < 0.001). Polymyxin B and colistin are associated with a high incidence of kidney injury; cystic fibrosis may be protective against polymyxin nephrotoxicity, but further investigation is needed to confirm this conjecture.

Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime.

Recent reports have demonstrated that vancomycin (VAN) may lead to an increase in the incidence of acute kidney injury (AKI) when it is combined with antipseudomonal beta-lactams. This study compared the incidence of AKI associated with VAN plus piperacillin-tazobactam (TZP) or cefepime (FEP). This was a retrospective, matched cohort study that was conducted at an academic medical center between September 2010 and September 2014 and that included adult patients without severe chronic or structural kidney disease, dialysis, pregnancy, cystic fibrosis, or a hospital transfer receiving TZP-VAN or FEP-VAN for at least 48 h. The primary outcome was the difference in the AKI incidence between the TZP-VAN and FEP-VAN groups, evaluated using the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria. Patients in the two groups were matched on the basis of age, sex, severity of illness, baseline creatinine clearance, hypotension, number of nephrotoxicity risk factors, and intravenous contrast exposure. In total, 4,193 patients met all inclusion criteria (3,605 received TZP-VAN and 588 received FEP-VAN). The unadjusted AKI incidence was 21.4% in patients receiving TZP-VAN, whereas it was 12.6% in patients receiving FEP-VAN (P < 0.001). After the patients were matched, 1,633 patients receiving TZP-VAN and 578 patients receiving FEP-VAN were evaluated. The AKI incidence remained higher in patients receiving TZP-VAN than in those receiving FEP-VAN (21.4% versus 12.5%, P < 0.0001). This trend remained true for all classifications of the RIFLE criteria. After controlling for remaining confounders, TZP-VAN therapy was associated with 2.18 times the odds of AKI than FEP-VAN therapy (95% confidence interval, 1.64 to 2.94 times) in logistic regression. AKI was significantly more common in patients receiving vancomycin in combination with piperacillin-tazobactam than in those receiving vancomycin in combination with cefepime. This finding reinforces the need for the judicious use of combination empirical antimicrobial therapy.

Influence of ß-Lactam Infusion Strategy on Acute Kidney Injury.

Limited literature is available assessing nephrotoxicity with prolonged ß-lactam infusions. This study compared the incidence of acute kidney injury (AKI) associated with a prolonged ß-lactam infusion or an intermittent infusion. This was a retrospective, matched-cohort study at an academic medical center from July 2006 to September 2015. Adult patients who received piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) for at least 48 h were evaluated. Patients were excluded for preexisting renal dysfunction or pregnancy. The primary outcome was difference in incidence of AKI evaluated using the RIFLE (risk, injury, failure, loss, and end-stage) criteria. Patients in the intermittent group were matched 3:1 to patients in the prolonged-infusion group based on the following: ß-lactam agent, age, gender, Charlson comorbidity index, baseline creatinine clearance, hypotension, receipt of vancomycin, and treatment in an intensive care unit. A total of 2,390 patients were included in the matched analysis, with 1,700 receiving intermittent infusions and 690 receiving prolonged infusion. The incidence of AKI was similar in the prolonged-infusion group to that in the intermittent-infusion group (21.6% versus 18.6%; P = 0.1). After multivariate regression, prolonged infusion was not associated with increased odds of AKI (odds ratio [OR], 1.07; 95% confidence interval [95% CI], 0.83 to 1.39). Independent predictors of AKI included TZP therapy, concomitant nephrotoxins, hypotension, and heart failure. Although AKIs were numerically more common in patients receiving prolonged ß-lactam infusions than those receiving intermittent infusions, prolonged infusion was not an independent risk factor for AKI.

Impact of total body weight on rate of acute kidney injury in patients treated with piperacillin-tazobactam and vancomycin.

PURPOSE: Results of a study to determine whether obesity is associated with acute kidney injury (AKI) among patients receiving combination therapy with piperacillin-tazobactam and vancomycin are reported. METHODS: A retrospective, single-center cohort study of patients who received combination therapy for at least 48 hours was conducted using data from the University of Kentucky Center for Clinical and Translational Science's Enterprise Data Trust. Patients with chronic kidney disease, baseline creatinine clearance of less than 30 mL/min, cystic fibrosis, or missing height or weight information were excluded. RESULTS: A total of 8,125 patients were included in the cohort. Among the variables evaluated, total body weight of 91 kg or more was the variable most predictive of AKI. Patients with a weight of 91 kg or higher were more likely than lower-weight patients to have diabetes (39% versus 21%, p < 0.00001), hypertension (64% versus 47%, p < 0.00001), and heart failure (15% versus 13%, p = 0.007). The median daily vancomcyin dose was lower in patients with a weight of less than 91 kg (2,000 mg versus 3,000 mg, p < 0.00001); however, weight-based doses were lower in patients weighing 91 kg or more (25.5 mg/kg/day versus 27.9 mg/kg/day, p < 0.00001). AKI was more common in patients weighing 91 kg or more (24% versus 18%, p < 0.00001; adjusted odds ratio, 1.46 [95% confidence interval, 1.28-1.66]). CONCLUSION: Increased total body weight increased the rate of AKI among patients concurrently treated with piperacillin-tazobactam and vancomycin independent of clinically important confounders, with an important breakpoint occurring at 91 kg.

Effect of increasing meropenem MIC on the killing activity of meropenem in combination with amikacin or polymyxin B against MBL- and KPC-producing Enterobacter cloacae.

Carbapenem resistant Enterobacteriaceae (CRE) are a growing threat worldwide. Infections caused by these organisms have exhibited high rates of mortality (50%) for which there is no standard of care and a dearth of clinical trials. Most in vitro data on CRE focus on Klebsiella pneumoniae, but it is known that effective therapy may depend on species or even strain. To address this, meropenem, amikacin, and polymyxin B alone and in combination were evaluated by time kill against four carbapenem-producing Enterobacter cloacae clinical isolates representing a range of meropenem nonsusceptibility (2-32 mg/L) and resistance mechanisms (KPC 2 and/or VIM 1). As meropenem minimum inhibitory concentration (MIC) increased, bactericidal activity and synergy were maintained for 48 hours in isolates exposed to meropenem and amikacin, but synergy and bactericidal activity were not maintained in all isolates exposed to meropenem and polymyxin B.

Acute Kidney Injury in Patients Treated with IV Beta-Lactam/Beta-Lactamase Inhibitor Combinations.

STUDY OBJECTIVE: Increased acute kidney injury (AKI) incidence has been reported in patients receiving piperacillin-tazobactam (PTZ) therapy compared with other ß-lactams. The authors sought to determine if the addition of ß-lactamase inhibitors impacts AKI incidence by comparing patients treated with PTZ or ampicillin-sulbactam (SAM). DESIGN: Retrospective cohort study. SETTING: Large academic tertiary care hospital. PATIENTS: Overall, 2448 patients received PTZ (n=1836) or SAM (n=612) for at least 48 hours between September 1, 2007, and September 30, 2015. Patients were excluded for pregnancy, cystic fibrosis, chronic kidney disease, and initial creatinine clearance < 30 ml/min. Patients were matched on Charlson Comorbidity Index, initial creatinine clearance, hypotension exposure, various nephrotoxic drug exposures, history of diabetes, heart failure, and hypertension. MEASUREMENTS AND MAIN RESULTS: AKI occurred in 265 patients at similar rates for both groups (PTZ 11.4% vs SAM 9.2%; p=0.14). After stratifying by vancomycin exposure and controlling for confounders, there was no difference in the risk of AKI for SAM or PTZ (adjusted odds ratio [aOR] 0.87, 95% confidence interval [CI] 0.59-1.25). The addition of vancomycin (VAN) to PTZ increased the likelihood of AKI compared with PTZ alone (aOR 1.77, 95% CI 1.26-2.46). Concomitant SAM and VAN therapy was not associated with a significant increase in AKI compared with SAM monotherapy (aOR 1.01, 95% CI 0.48-1.97). CONCLUSION: Rates of AKI were similar for PTZ and SAM in a matched cohort. The addition of a ß-lactamase inhibitor is not likely the mechanism in the observed increased rates of AKI in patients treated with vancomycin and PTZ.

Increasing Incidence of Multidrug Resistance Among Cystic Fibrosis Respiratory Bacterial Isolates.

Pseudomonas aeruginosa and Staphylococcus aureus are common pathogens in cystic fibrosis (CF) patients with increasing multidrug resistance (MDR). This study characterized antimicrobial susceptibility trends among organisms isolated from the respiratory tract of CF patients. Microbiological culture and sensitivity results for all CF patients were collected from January 2010 through December 2014. Minimum inhibitory concentrations were obtained using Phoenix® and Etest® methods. Clinical and Laboratory Standards Institute guidelines were used to remove duplicate isolates and develop antimicrobial susceptibility reports. MDR was defined as resistance to one agent in three or more antibiotic classes or oxacillin resistance in S. aureus. Overall, 542 bacterial isolates from 376 cultures were analyzed for trends. P. aeruginosa (41%), S. aureus (40%), and Stenotrophomonas maltophilia (8%) were the most commonly isolated organisms. Multidrug-resistant organism isolation increased from 39% to 49% (r = 0.76, p = 0.13), while representing 47.6% of all isolates. Multidrug-resistant P. aeruginosa incidence increased each year from 26% to 43% (r = 0.89, p = 0.046), while P. aeruginosa isolation decreased from 47% to 38% over the study period (r = -0.93, p = 0.02). MRSA accounted for 62.6% of all S. aureus isolated, while overall multidrug-resistant S. aureus incidence was 73.1% in all cultures. MDR among common pathogens in CF continues to increase. Empiric therapy for CF exacerbations should be targeted to previous antimicrobial susceptibility, and P. aeruginosa and S. aureus should be empirically covered.

Acute kidney injury in patients treated with vancomycin and piperacillin-tazobactam: A retrospective cohort analysis.

BACKGROUND: Empiric antimicrobial therapy often consists of the combination of gram-positive coverage with vancomycin (VAN) and gram-negative coverage, specifically an antipseudomonal beta-lactam such as piperacillin-tazobactam (PTZ). Nephrotoxicity is commonly associated with VAN therapy; however, recent reports show higher nephrotoxicity rates among patients treated with the combination of VAN and PTZ. OBJECTIVE: This study evaluated the effect of the VAN/PTZ combination on acute kidney injury (AKI) compared to VAN and PTZ monotherapies. DESIGN, SETTING, AND PATIENTS: This is a retrospective cohort analysis of adult patients without renal disease receiving VAN, PTZ, or the combination from September 1, 2010 through August 31, 2014 at an academic medical center. MEASUREMENTS: The primary outcome was AKI incidence as defined by the Risk, Injury, Failure, Loss, End-stage (RIFLE) criteria. METHODS: Continuous and categorical variables were assessed with appropriate tests. Univariate and multivariate logistic regressions were performed to assess for associations between variables and AKI incidence. Subanalyses based on severity of illness were performed. RESULTS: Overall, 11,650 patients were analyzed, with 1647 (14.1%) developing AKI. AKI was significantly more frequent in the VAN/PTZ group (21%) compared to either monotherapy group (VAN 8.3%, PTZ 7.8%, P ⟨ 0.001 for both). Combination therapy was independently associated with higher AKI odds compared to monotherapy with either agent (adjusted odds ratio [aOR], 2.03; 95% confidence interval [CI], 1.74-2.39; aOR, 2.31; 95% CI, 1.97-2.71, for VAN and PTZ, respectively). Receipt of concomitant nephrotoxic drugs was independently associated with increased AKI rates, as were increased duration of therapy, hospital length of stay, increasing severity of illness, and increasing baseline renal function. CONCLUSIONS: In this study of more than 10,000 patients, VAN combined with PTZ was associated with twice the odds of AKI development compared to either agent as monotherapy. This demonstrates the need for judicious use of combination empiric therapy. Journal of Hospital Medicine 2017;12:77-82.

Optimizing beta-lactam pharmacodynamics against Pseudomonas aeruginosa in adult cystic fibrosis patients.

BACKGROUND: Patients with cystic fibrosis (CF) exhibit increased clearance of beta-lactams. The purpose of this study was to predict the probability of beta-lactam target attainment (PTA) against Pseudomonas aeruginosa in adult CF patients based on local microbiological data. METHODS: CF-specific pharmacokinetic parameters were obtained from published data for aztreonam, cefepime, ceftazidime, meropenem and piperacillin-tazobactam. Pharmacodynamic modeling was used to determine the PTA for bolus, prolonged infusion, and continuous infusion regimens. RESULTS: Prolonged infusion of meropenem 2g every 8h performed the best among all regimens tested, with a PTA of 83%. The PTA was increased with both prolonged and continuous infusion; however, no regimen reached the target PTA of >90% against P. aeruginosa in CF patients at our institution. CONCLUSIONS: Prolonged and continuous infusion provided higher PTA than bolus for all regimens. Further investigation of novel regimens in CF patients is needed.