Burden of acute kidney injury in HIV patients under deoxycholate amphotericin B therapy for cryptococcal meningitis and cost-minimization analysis of amphotericin B lipid complex.

Deoxycholate amphotericin B (d-AMB) has a higher rate of acute kidney injury (AKI) in comparison of lipid formulations. However, lipid amphotericin B has high costs in developing countries. The aim of this study is to assemble a model of cost-minimization of amphotericin B lipid complex (ABLC) in patients with cryptococcal meningitis. This is a retrospective study done in a cohort of patients with cryptococcal meningitis to study the economic impact of its use in developing countries. Cost analysis were based on direct cost of different antifungal therapies, chronic dialysis after discharge, and survival of patients based on a retrospective cohort of 102 patients infected with human immunodeficiency virus with confirmed diagnosis of cryptococcal meningitis. From 102 patients treated with d-AMB, 60.78% developed any grade of AKI and 10.78% developed AKI demanding hemodialysis. The percentage of patients with meningeal cryptococcosis treated with d-AMB that requeired chronic HD was 2.39%. The same model was performed for patient that would be treated with ABLC, which resulted in 0.20% of patients demanding chronic HD due to its lower nephrotoxicity. When the model is applied in 100 patients, the total costs with d-AMB would be US$ 184,543 and with ABLC would be US$ 1,640,109 in 5 years. Treatment with ABLC would be cost saving in comparison to d-AMB treatment, if early switch of treatment occurred in patients presenting AKI. The change should be as soon as possible to avoid further complication, like dialysis, which is associated with a lower life expectancy.

Pharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review.

PURPOSE: Ceftazidime-avibactam is an antimicrobial association active against several Enterobacteriaceae species, including those resistant to carbapenem. Considering the importance of this drug in the current panorama of multidrug-resistant bacteria, we performed a systematic review about ceftazidime-avibactam with emphasis on clinical and pharmacological published data. METHODS: A systematic search of the medical literature was performed. The databases searched included MEDLINE, EMBASE and Web of Science (until September 2017). The search terms used were 'avibactam', 'NXL104' and 'AVE1330A'. Bibliographies from those studies were also reviewed. Ceftazidime was not included as a search term, once relevant studies about avibactam in association with other drugs could be excluded. Only articles in English were selected. No statistical analysis or quality validation was included in this review. RESULTS: A total of 151 manuscripts were included. Ceftazidime-avibactam has limited action against anaerobic bacteria. Avibactam is a potent inhibitor of class A, class C, and some class D enzymes, which includes KPC-2. The best pharmacodynamic profile of ceftazidime-avibactam is ƒT > MIC, validated in an animal model of soft tissue infection. Three clinical trials showed the efficacy of ceftazidime-avibactam in patients with intra-abdominal and urinary infections. Ceftazidime-avibactam has been evaluated versus meropenem/doripenem in hospitalized adults with nosocomial pneumonia, neutropenic patients and pediatric patients. CONCLUSION: Ceftazidime-avibactam has a favorable pharmacokinetic profile for severe infections and highly active against carbapenemases of KPC-2 type.

Polymyxin B and colistin-the economic burden of nephrotoxicity against multidrug resistant bacteria.

BACKGROUND: Polymyxin B and colistin are nephrotoxic drugs used in the treatment of carbapenem-resistant Enterobacteriaceae. The aim of this study is to evaluate the burden of costs due to polymyxin associated AKI and propose a simulated break-even price for new therapies. METHODS: The pharmacoeconomic model is based on two large cross-sectional studies of polymyxin nephrotoxicity. Total direct costs in patients with and without renal failure were compared. The direct cost of each hemodialysis section (USD82.94) and daily hospital charges (USD934.85) were based on the values used in a major public hospital in the city where the clinical study was performed. The break-even price of new drugs was simulated considering eventual new drugs as effective as polymyxins, but less nephrotoxic in different percentages. Outcomes of patients after hospital discharge were not evaluated. RESULTS: Total direct cost of the group of patients who survived without AKI was significantly lower than total direct cost of the groups either with AKI or the group who died without AKI. There was a tendency of even higher costs in those who died with AKI and dialysis. Direct cost of hemodialysis was not as important as the longer hospitalization after sepsis. Considering daily cost of polymyxin is USD60, drugs with 50% less AKI could be considered cost-beneficial if the daily cost is lower than USD160. CONCLUSIONS: AKI in patients with carbapenem-resistant Enterobacteriaceae treated with polymyxin increases both length of stay in hospital and total costs.

Risk factors for mortality in patients with ventilator-associated pneumonia caused by carbapenem-resistant Enterobacteriaceae.

BACKGROUND: The ideal therapeutic option for ventilator associated pneumonia caused by carbapenem-resistant Enterobacteriaceae is not defined. The aim of this study was to assess mortality-associated risk factors in patients with VAP by CRE and determine the outcome of several treatment options. METHODS: This was a retrospective study performed in two tertiary hospitals involving patients with VAP caused by CRE between January 2010 and August 2014. The outcomes were mortality within 30 days of VAP diagnosis and overall mortality during hospital admission. Risk factors for mortality were assessed by comparing variables of survivors and non-survivors. RESULTS: One hundred and twelve patients with CRE-VAP were included, 73 (65%) male, median age 56 years. The 30-day mortality was 57.1% and the overall hospital mortality was 67%. In the binary logistic regression analysis, only age >50 years was independently associated to increased mortality. Polymyxin was the most used drug (47.5%), followed by tigecycline (29.2%) and aminoglycosides (2.4%). Combined therapy with two active drugs was used by 17 patients (20.8%). No therapeutic option was independently associated to survival. However, combined therapy with two active drugs was superior to the therapy with a single active drug when inappropriate therapy was the comparator (p=0.044). The addition of carbapenem was not associated with increased survival. CONCLUSION: The best therapeutic option for VAP by CRE is still not completely defined, but the therapy with at least two active drugs was superior in this study.

Combined therapy for multi-drug-resistant Acinetobacter baumannii infection--is there evidence outside the laboratory?

Acinetobacter are among the most common bacteria isolated in hospital infections, especially in developing countries. Multi-drug, extended-drug or pan-drug resistance makes treatment a real medical challenge. In the present review, the authors describe clinical and experimental data in order to present different current and potential future strategies to treat infections caused by multi-drug-resistant Acinetobacter. The therapeutic options for carbapenem-resistant Acinetobacter are scarce, and the current options have poor pharmacokinetic aspects and several side effects. Combined therapy has been an alternative for multi-drug-resistant Acinetobacter. However, this issue is always controversial. In some studies combined therapy has shown superiority for some strains of Acinetobacter in animal models and in vitro studies. However, studies with humans are scarce and too poor quality to suggest the best approach for the treatment of infections caused by multi-drug-resistant Acinetobacter baumannii.

KPC-producing Enterobacter aerogenes infection.

BACKGROUND: Enterobacter is a common nosocomial microorganism and its carbapenem's resistance has increased. The management of these cases is unclear. OBJECTIVE: We evaluated 16 patients with KPC-producing Enterobacter aerogenes infections, detailing the site of infection, therapy, clinical and epidemiological data. METHODS: A retrospective and descriptive study. Clinical data were revised and KPC-2 detection was by molecular methods. Risk factors associated with mortality were compared using appropriate tests according to variable type with a significance level of 0.05. RESULTS: The 30-day mortality rate was 37.5% with no association with inadequate treatment. Age (p=0.004) and Charlson score of comorbidities (p=0.048) were independent risk factors associated with death in the multivariate analysis. The odds ratio for age >43 years was 3.00 (95% CI: 1.02-9.32) and for Charlson score >3 was 2.00 (95% CI: 1.08-3.71). Five strains were pan-resistant based on automated susceptibility tests. All patients were treated with monotherapy. CONCLUSION: The clinician should be alert to carbapenem-resistant Enterobacteriaceae infection in older patients with comorbidities. The mortality is high and we believe that prompt and adequate therapy must be employed.

A simple mathematical model to determine the ideal empirical antibiotic therapy for bacteremic patients.

BACKGROUND: Local epidemiological data are always helpful when choosing the best antibiotic regimen, but it is more complex than it seems as it may require the analysis of multiple combinations. The aim of this study was to demonstrate a simplified mathematical calculation to determine the most appropriate antibiotic combination in a scenario where monotherapy is doomed to failure. METHODS: The susceptibility pattern of 11 antibiotics from 216 positive blood cultures from January 2012 to January 2013 was analyzed based on local policy. The length of hospitalization before bacteremia and the unit (ward or intensive care unit) were the analyzed variables. Bacteremia was classified as early, intermediate or late. The antibiotics were combined according to the combination model presented herein. RESULTS: A total of 55 possible mathematical associations were found combining 2 by 2, 165 associations with 3 by 3 and 330 combinations with 4 by 4. In the intensive care unit, monotherapy never reached 80% of susceptibility. In the ward, only carbapenems covered more than 90% of early bacteremia. Only three drugs combined reached a susceptibility rate higher than 90% anywhere in the hospital. Several regimens using four drugs combined reached 100% of susceptibility. CONCLUSIONS: Association of three drugs is necessary for adequate coverage of empirical treatment of bacteremia in both the intensive care unit and the ward.

Is nosocomial Escherichia coli bacteremia a predictive risk factor for mortality?

The objective of this study was to determine risk factors associated with mortality in patients with nosocomial Escherichia coli bacteremia from January 2009 to January 2011. In a retrospective study the medical records of 88 patients over 18 years with nosocomial bacteremia caused by E. coli were analyzed. In univariate analysis several risk factors, including chronic renal failure, altered mental status, leukocytosis, and higher Charlson index of comorbidities were associated with mortality. In multivariate analysis only altered mental status remained independently associated with mortality. Mental confusion can be a risk factor for mortality in patients with E. coli bacteremia.

Risk factors for acute kidney injury in patients treated with polymyxin B or colistin methanesulfonate sodium.

Polymyxin B (PMB) and colistin, administered as the prodrug colistin methanesulfonate sodium (CMS), are increasingly used to treat carbapenem-resistant Gram-negative bacteria. Nephrotoxicity is the major dose-limiting adverse effect of both polymyxins. A retrospective cohort study of 132 patients was conducted to evaluate risk factors for acute kidney injury (AKI), classified according to Acute Kidney Injury Network criteria, in patients treated with ≥48h of intravenous PMB or CMS, with particular focus on potential differences between each polymyxin. The overall incidence of AKI was 25.8% (34/132) [20.8% (20/96) and 38.9% (14/36) in patients treated with PMB and CMS, respectively; P=0.06]. In the Cox regression model, doses ≥2million International Units (MIU) of PMB or >9MIU of CMS were the only variable independently associated with AKI [adjusted hazard ratio (aHR)=2.11, 95% confidence interval (CI) 1.01-4.41; P=0.04]. Vancomycin co-administration was strongly associated with AKI, although this was not statistically significant (aHR=2.22, 95% CI 0.98-5.04; P=0.058). There was no statistically significant difference in the incidence of AKI between patients treated with PMB or CMS in the multivariate model (aHR=1.74, 95% CI 0.82-3.69; P=0.15). High dose was the main risk factor for AKI regardless of the polymyxin administered. Vancomycin co-administration likely increases the risk of AKI. Although there was a higher overall incidence of AKI in patients treated with CMS compared with PMB, CMS was not significantly associated with this outcome after adjusting for the above variables.

Are there risk factors for acute renal failure in adult patients using deoxycholate amphotericin B?

BACKGROUND: Deoxycholate amphotericin B (DAB) is a nephrotoxic drug and the incidence of acute kidney injury (AKI) is high. AIMS: The aim of this study was to describe the incidence of AKI in patients under DAB therapy and determine risk factor to predict the AKI. METHODS: The data of this retrospective study included previously hospitalized patients treated with intravenous DAB for at least five days. Clinical and laboratorial data were evaluated and AKI was classified in stages using Acute Kidney Injury Network criteria. Univariated test followed by a multivariable analysis was performed to determine risk factor and Kaplan-Meier survival estimates were calculated to evaluate the role of AKI in the outcome. RESULTS: One hundred six patients were included in the final analysis. AKI occurred in 51.9% and dialysis was necessary in 4.7%. The occurrence of AKI was not associated with any risk factor. The mortality of the patients was neither associated with AKI nor with dialysis. Other nephrotoxic drugs were not risk factors for AKI. CONCLUSIONS: The incidence of AKI in patients using DAB is high and we cannot predict the chance of AKI using clinical or laboratorial data.

Seasonal humidity may influence Pseudomonas aeruginosa hospital-acquired infection rates.

OBJECTIVE: The objective of this study was to determine the association of seasonal climatic conditions with the incidence of Pseudomonas aeruginosa infections. METHODS: A retrospective study was carried out to evaluate all infections caused by P. aeruginosa in a 660-bed tertiary-care hospital in Brazil over a period of 5 years. To assess seasonal patterns, monthly temperature, relative humidity, and precipitation averages were obtained. Correlations of seasonal variations with infection rates (IR) were determined by Pearson correlation coefficient. Linear regression was used to determine trends, and multivariable linear regression was performed using a Poisson distribution. RESULTS: A total of 844 cases of P. aeruginosa infection were identified for 1 058 501 patient-days during 1826 days (overall IR 7.97/10 000 patient-days). The mean temperature was 18.2±2.8°C, relative humidity was 80.3±3.6%, and precipitation was 104.7±64.38mm. The Pearson correlation was significant between urinary tract infection and temperature (R=0.29; p=0.021) and precipitation (R=0.27; p=0.036). A correlation was also significant between hospital-associated pneumonia and precipitation (R=0.29; p=0.022) and relative humidity (R=0.31; p=0.013). Relative humidity was associated with a higher IR of other infections caused by P. aeruginosa, but it was not possible to build a predictive model when multiple linear regression and Poisson regression were tested. CONCLUSION: Climatic conditions are another factor that may interfere with the IR of Pseudomonas aeruginosa.

Risk factors for pan-resistant Pseudomonas aeruginosa bacteremia and the adequacy of antibiotic therapy.

INTRODUCTION: The aim of this study was to determine risk factors for acquiring carbapenem-resistant Pseudomonas aeruginosa bacteremia (CR-PA) and factors associated with in-hospital mortality. METHODS: Seventy-seven cases of bacteremia caused by P. aeruginosa were evaluated in a hospital with high incidence of CR-PA. Clinical and laboratorial factors, and previous use of antibiotics were also evaluated. In one analysis, CR-PA and carbapenem-susceptible P. aeruginosa (CS-PA) bacteremia were compared. A second analysis compared patients who died with survivors. RESULTS: Among 77 P. aeruginosa bacteremia, 29 were caused by CR-PA. Admission to the intensive care unit, higher number of total leukocytes, and previous use of carbapenem were statistically associated with CR-PA. In the multivariate analysis, only previous use of carbapenem (including ertapenem) turned out to be a risk factor for CR-PA (p=0.014). The 30-day mortality of patients with P. aeruginosa bloodstream infection was 44.8% for CS-PA and 54.2% for patients with CR-PA (p=0.288). Chronic renal failure, admission to the intensive care unit, mechanical ventilation, and central venous catheter were risk factors for mortality. Incorrect treatment increased mortality of patients with bacteremia caused by CS-PA, but not for CR-SA. The odd ratio of mortality associated with incorrect therapy in patients with CS-PA was 3.30 (1.01-10.82; p=0.043). The mortality of patients with bacteremia caused by CR-PA was unexpectedly similar regardless of antimicrobial treatment adequacy. CONCLUSION: Appropriate treatment for CS-PA bacteremia initiated within the first 24 hours was associated with lower mortality, but this cannot be extrapolated for CR-PA.

Sex, drugs, bugs, and age: rational selection of empirical therapy for outpatient urinary tract infection in an era of extensive antimicrobial resistance.

BACKGROUND: Optimal empirical therapy of urinary tract infection requires accurate knowledge of local susceptibility patterns, which may vary with organism and patient characteristics. METHODS: Among 9,798 consecutive, non-duplicate, community-source urine isolates from ambulatory patients > 13 years old, from clinical laboratory and an academic medical center in Curitiba, Brazil (May 1st to December 1st, 2009), susceptibility data for ampicillin, nitrofurantoin, trimethoprim-sulfamethoxazole, gentamicin, fluoroquinolones, and ceftriaxone/cefotaxime were compared with organism and patient gender and age. RESULTS: The female-to-male ratio decreased with age, from 28.1 (among 20-29 year-olds) to 3.3 (among > 80 year-olds). Overall, susceptibility prevalence varied widely by drug class, from unacceptably low levels (53.5% and 61.1%: ampicillin and trimethoprimsulfamethoxazole) to acceptable but suboptimal levels (81.2% to 91.7%: fluoroquinolones, ceftriaxone, nitrofurantoin, and gentamicin). E. coli isolates exhibited higher susceptibility rates than other isolates, from 3-4% higher (fluoroquinolones, gentamicin) to > 30% (nitrofurantoin, ceftriaxone). Males exhibited lower susceptibility rates than females. Within each gender, susceptibility declined with increasing age. For females, only nitrofurantoin and gentamicin were suitable for empirical therapy (> 80% susceptibility) across all age cohorts; fluoroquinolones were suitable only through age 60, and ceftriaxone only through age 80. For males, only gentamicin yielded > 80% susceptibility in any age cohort. CONCLUSION: Few suitable empirical treatment options for community-source urinary tract infection were identified for women aged over 60 years or males of any age. Empirical therapy recommendations must consider the patient's demographic characteristics. Site-specific, age and gender-stratified susceptibility surveillance involving all uropathogens is needed.

Long-term cost-effectiveness of lipid formulations of amphotericin B in the empirical therapy of invasive mycosis in a developing country / Rentabilidad a largo plazo de las formulaciones lipídicas de anfotericina B en la terapia empírica de micosis invasivas en un país en desarrollo

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Risk factors for mortality in patients with ventilator-associated pneumonia caused by carbapenem-resistant Enterobacteriaceae

Abstract Background: The ideal therapeutic option for ventilator associated pneumonia caused by carbapenem-resistant Enterobacteriaceae is not defined. The aim of this study was to assess mortality-associated risk factors in patients with VAP by CRE and determine the outcome of several treatment options. Methods: This was a retrospective study performed in two tertiary hospitals involving patients with VAP caused by CRE between January 2010 and August 2014. The outcomes were mortality within 30 days of VAP diagnosis and overall mortality during hospital admission. Risk factors for mortality were assessed by comparing variables of survivors and non-survivors. Results: One hundred and twelve patients with CRE-VAP were included, 73 (65%) male, median age 56 years. The 30-day mortality was 57.1% and the overall hospital mortality was 67%. In the binary logistic regression analysis, only age >50 years was independently associated to increased mortality. Polymyxin was the most used drug (47.5%), followed by tigecycline (29.2%) and aminoglycosides (2.4%). Combined therapy with two active drugs was used by 17 patients (20.8%). No therapeutic option was independently associated to survival. However, combined therapy with two active drugs was superior to the therapy with a single active drug when inappropriate therapy was the comparator (p = 0.044). The addition of carbapenem was not associated with increased survival. Conclusion: The best therapeutic option for VAP by CRE is still not completely defined, but the therapy with at least two active drugs was superior in this study.

Risk factors for KPC-producing Klebsiella pneumoniae bacteremia.

The molecular epidemiology of carbapenemase-producing Klebsiella pneumoniae (KPC) has been largely investigated, but limited clinical information is available. A case-control study was performed to evaluate the risk factors for KPC bacteremia in hospitalized patients. Cases were patients with KPC bacteremia and controls were patients with non-KPC bacteremia. A total of 85 patients were included, 18 (21.2%) were KPC, and 67 (78.8%) were non-KPC (40 [59.7%] of them were extended-spectrum beta-lactamase producers). All KPC isolates were type 2 producers. These isolates belong to five distinct clones. Multivariate analysis showed that age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02 - 1.11; p = 0.004), presence of mechanical ventilation (OR, 11.1; 95% CI, 1.92 - 63.3; p = 0.007) and fluoroquinolone exposure during hospitalization (OR, 28.9; 95% CI, 1.85 - 454.6; p = 0.02) were independent risk factors for KPC in patients with K. pneumoniae bacteremia. Factors associated with severity of illness, such as age and mechanical ventilation, seem to be the main risks factors for KPC. Fluoroquinolones use might be a risk factor for KPC bacteremia. Further investigations on risk factors for KPC are warranted.

A simple mathematical model to determine the ideal empirical antibiotic therapy for bacteremic patients

BACKGROUND: Local epidemiological data are always helpful when choosing the best antibiotic regimen, but it is more complex than it seems as it may require the analysis of multiple combinations. The aim of this study was to demonstrate a simplified mathematical calculation to determine the most appropriate antibiotic combination in a scenario where monotherapy is doomed to failure. METHODS: The susceptibility pattern of 11 antibiotics from 216 positive blood cultures from January 2012 to January 2013 was analyzed based on local policy. The length of hospitalization before bacteremia and the unit (ward or intensive care unit) were the analyzed variables. Bacteremia was classified as early, intermediate or late. The antibiotics were combined according to the combination model presented herein. RESULTS: A total of 55 possible mathematical associations were found combining 2 by 2, 165 associations with 3 by 3 and 330 combinations with 4 by 4. In the intensive care unit, monotherapy never reached 80% of susceptibility. In the ward, only carbapenems covered more than 90% of early bacteremia. Only three drugs combined reached a susceptibility rate higher than 90% anywhere in the hospital. Several regimens using four drugs combined reached 100% of susceptibility. CONCLUSIONS: Association of three drugs is necessary for adequate coverage of empirical treatment of bacteremia in both the intensive care unit and the ward. .