Alexandre Prehn Zavascki

Multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii: resistance mechanisms and implications for therapy

Pseudomonas aeruginosa and Acinetobacter baumannii are major nosocomial pathogens worldwide. Both are intrinsically resistant to many drugs and are able to become resistant to virtually any antimicrobial agent. An increasing prevalence of infections caused by multidrug-resistant (MDR) isolates has been reported in many countries. The resistance mechanisms of P. aeruginosa and A. baumannii include the production of β-lactamases, efflux pumps, and target-site or outer membrane modifications. Resistance to multiple drugs is usually the result of the combination of different mechanisms in a single isolate or the action of a single potent resistance mechanism. There are many challenges in the treatment of MDR P. aeruginosa and A. baumannii, especially considering the absence of new antimicrobials in the drug-development pipeline. In this review, we present the major resistance mechanisms of P. aeruginosa and A. baumannii, and discuss how they can affect antimicrobial therapy, considering recent clinical, microbiological, pharmacokinetic and pharmacodynamic findings of the main drugs used to treat MDR isolates.

Population Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients: Implications for Selection of Dosage Regimens

BACKGROUND Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients. METHODS Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted. RESULTS Twenty-four patients aged 21-87 years received intravenous polymyxin B (0.45-3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10-143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r(2) = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose. CONCLUSIONS Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.

Pharmacokinetics of Intravenous Polymyxin B in Critically Ill Patients

BACKGROUND Although not much pharmacokinetic knowledge is available, polymyxin B is increasingly used for treatment of infections caused by gram-negative bacteria that are resistant to all other antibiotics. METHODS This study involved 8 patients who received intensive care after intravenous administration of a 60-min infusion of polymyxin B at currently recommended doses. Blood and urine samples were collected, and plasma protein binding of polymyxin B was determined. Concentrations of polymyxin B in plasma and urine samples were measured by a specific high-performance liquid chromatographic method. RESULTS Polymyxin B was well tolerated. The peak plasma concentrations at the end of the infusion varied from 2.38 to 13.9 mg/L. For 4 patients from whom it was possible to collect urine samples over a dosing interval, only 0.04%-0.86% of the dose was recovered in the urine in unchanged form. Plasma protein binding of polymyxin B was higher in samples from patients (range, 78.5%-92.4%) than in plasma samples from healthy human subjects (mean +/- standard deviation, 55.9% +/- 4.7%). Unbound plasma concentrations of polymyxin B were in the vicinity of or lower than the minimum inhibitory concentration of the pathogen. CONCLUSION To our knowledge, this is the first study to report plasma concentrations over time and urinary recovery of polymyxin B in critically ill patients after intravenous administration. Polymyxin B is eliminated mainly by nonrenal pathways, and the total body clearance appears to be relatively insensitive to renal function. Additional investigations are required to assess the appropriateness of currently recommended doses of this drug for the treatment of severe infections in critically ill persons.

Reduction in incidence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection in an intensive care unit: role of treatment with mupirocin ointment and chlorhexidine baths for nasal carriers of MRSA.

After the introduction of routine treatment for every nasal carrier of methicillin-resistant Staphylococcus aureus, active follow-up surveillance for nosocomial methicillin-resistant S. aureus infection was conducted for 5 years in an intensive care unit of a tertiary-care teaching hospital. There was a significant decrease in the incidence of nosocomial methicillin-resistant S. aureus infection during the later years of follow-up. Decolonization of nasal carriers of methicillin-resistant S. aureus is probably associated with such findings.

Combination therapy for carbapenem-resistant Gram-negative bacteria

The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins; however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic/pharmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic/pharmacodynamic characteristics against CR GNB will be reviewed in this article.

Reappraisal of Pseudomonas aeruginosa hospital-acquired pneumonia mortality in the era of metallo-β-lactamase-mediated multidrug resistance: a prospective observational study

IntroductionHospital-acquired pneumonia (HAP) due to Pseudomonas aeruginosa is associated with high mortality rates. The metallo-β-lactamases (MBLs) are emerging enzymes that hydrolyze virtually all β-lactams. We aimed to assess P. aeruginosa HAP mortality in a setting of high-rate MBL productionMethodsA prospective cohort study was performed at two tertiary-care teaching hospitals. A logistic regression model was constructed to identify risk factors for 30-day mortality.ResultsOne-hundred and fifty patients with P. aeruginosa HAP were evaluated. The 30-day mortality was 37.3% (56 of 150): 57.1% (24 of 42) and 29.6% (32 of 108) for patients with HAP by MBL-producing P. aeruginosa and by non-MBL-producing P. aeruginosa, respectively (relative risk, 1.93; 95% confidence interval (CI), 1.30–2.85). The logistic regression model identified a higher Charlson comorbidity score (odds ratio, 1.21; 95% CI, 1.04–1.41), presentation with severe sepsis or septic shock (odds ratio, 3.17; 95% CI, 1.30–7.72), ventilator-associated pneumonia (odds ratio, 2.92; 95% CI, 1.18–7.21), and appropriate therapy (odds ratio, 0.24; 95% CI, 0.10–0.61) as independent factors for 30-day mortality. MBL production was not statistically significant in the final model.ConclusionMBL-producing P. aeruginosa HAP resulted in higher mortality rates, particularly in patients with ventilator-associated pneumonia, most probably related to the less frequent institution of appropriate antimicrobial therapy. Therapeutic approaches should be reviewed at institutions with a high prevalence of MBL.

The impact of polymyxin B dosage on in-hospital mortality of patients treated with this antibiotic

OBJECTIVE To assess the impact of dosage on in-hospital mortality of patients receiving intravenous polymyxin B. METHODS A retrospective cohort study was performed from January 2003 to December 2009. Patients ≥ 18 years receiving intravenous polymyxin B for ≥ 72 h were analysed. Clinical covariates were assessed and data were retrieved from medical records. Subgroup analyses were performed in patients with microbiologically confirmed infections and in patients with bacteraemia. Renal toxicity was also assessed. Logistic regression models (LRMs) were performed for the entire cohort and subgroups. RESULTS A total of 276 patients were included. The overall in-hospital mortality was 60.5% (167 of 276). The final LRM showed that severe sepsis or septic shock [adjusted odds ratio (aOR) 4.07; 95% confidence interval (CI) 2.22-7.46], presence of mechanical ventilation (aOR 3.14; 95% CI 1.73-5.71), Charlson co-morbidity score (aOR 1.25; 95% CI 1.09-1.44) and age (aOR 1.02; 95% CI 1.01-1.04) were independently associated with increased in-hospital mortality, while ≥ 200 mg/day polymyxin B was associated with lower risk for this outcome (aOR 0.43; 95% CI 0.23-0.79). The effect of ≥ 200 mg/day polymyxin B on in-hospital mortality was higher in both subgroups (microbiologically documented infections and bacteraemia). Patients receiving ≥ 200 mg/day of polymyxin B had significantly higher risk of severe renal impairment. CONCLUSION A dosage of ≥ 200 mg/day polymyxin B was associated with lower in-hospital mortality. The benefit of these higher doses outweighed the risk of severe renal dysfunction during therapy. Large prospective studies including pharmacokinetic/pharmacodynamic analysis are still required to define the best dosage regimens of polymyxin B.

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.

Polymyxin B versus other antimicrobials for the treatment of Pseudomonas aeruginosa bacteraemia

OBJECTIVES to compare the efficacy of intravenous polymyxin B with other antimicrobials in the treatment of nosocomial Pseudomonas aeruginosa bacteraemia, assessing many potential confounding factors, including optimal dosage regimens of drugs. METHODS a retrospective cohort study was performed. Patients ≥ 18 years of age and who received appropriate therapy for ≥ 48 h for P. aeruginosa bacteraemia were analysed. Clinical covariates were assessed and compared between patients treated with polymyxin B and other drugs (comparators). Data were retrieved from medical records. Renal toxicity was also assessed. A Cox regression model was performed including variables with a P  ≤  0.20 in the comparison between both groups. RESULTS a total of 133 patients were included: 45 (33.8%) treated with polymyxin B and 88 (66.2%) with comparators. Most comparators (83.0%) were β-lactams. The overall in-hospital mortality was 41.4% (55/133): 66.7% (30/45) and 28.4% (25/88) in polymyxin B and comparator groups, respectively (P  ≤  0.001). The final multivariate model showed that treatment with polymyxin B was independently associated with in-hospital mortality (adjusted hazard ratio 1.91, 95% confidence interval 1.05-3.45), after adjustment for Pitt bacteraemia score, and the presence of mechanical ventilation and primary bloodstream infection. Patients treated with polymyxin B presented a higher rate of ≥ 100% increase in creatinine level from baseline than comparators [11/45 (24.4%) versus 4/88 (4.5%); P = 0.002], although this was not subjected to multivariate analysis. CONCLUSIONS intravenous polymyxin B therapy was inferior to other drugs in the treatment of P. aeruginosa bacteraemia, as indicated by the higher rate of in-hospital mortality.

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.