Efficacy and safety of different polymyxin-containing regimens for the treatment of pneumonia caused by multidrug-resistant gram-negative bacteria: a systematic review and network meta-analysis.

BACKGROUND: The optimal administration of polymyxins for treating multidrug-resistant gram-negative bacterial (MDR-GNB) pneumonia remains unclear. This study aimed to systematically assess the efficacy and safety of three polymyxin-containing regimens by conducting a comprehensive network meta-analysis. METHODS: We comprehensively searched nine databases. Overall mortality was the primary outcome, whereas the secondary outcomes encompassed microbial eradication rate, clinical success, acute kidney injury, and incidence of bronchospasm. Extracted study data were analyzed by pairwise and network meta-analyses. Version 2 of the Cochrane risk-of-bias tool and the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) assessment tool were used to assess the risk of bias in randomized trials and cohort studies, respectively. RESULTS: This study included 19 observational studies and 3 randomized controlled trials (RCTs), encompassing 3318 patients. Six studies with high risk of bias were excluded from the primary analysis. In the pairwise meta-analysis, compared to the intravenous (IV) polymyxin-containing regimen, the intravenous plus inhaled (IV + IH) polymyxin-containing regimen showed a significant decrease in overall mortality, while no statistically significant difference was found in the inhaled (IH) polymyxin-containing regimen. The network meta-analysis indicated that the IV + IH polymyxin-containing regimen had significantly lower overall mortality (OR 0.67; 95% confidence interval [CI] 0.50-0.88), higher clinical success rate (OR 1.90; 95% CI 1.20-3.00), better microbial eradication rate (OR 2.70; 95% CI 1.90-3.90) than the IV polymyxin-containing regimen, and significantly better microbial eradication rate when compared with the IH polymyxin-containing regimen (OR 2.30; 95% CI 1.30-4.20). Furthermore, compared with IV + IH and IV polymyxin-containing regimens, the IH polymyxin-containing regimen showed a significant reduction in acute kidney injury. CONCLUSIONS: Our study indicates that among the three administration regimens, the IV + IH polymyxin-containing regimen may be the most effective for treating MDR-GNB pneumonia, with a significantly lower overall mortality compared to the IV regimen and a considerably higher microbial eradication rate compared to the IH regimen. The IH regimen may be considered superior to the IV regimen due to its substantially lower incidence of acute kidney injury, even though the reduction in overall mortality was not significant.

Polymyxin Susceptibility Testing and Interpretive Breakpoints: Recommendations from the United States Committee on Antimicrobial Susceptibility Testing (USCAST).

The polymyxins are important agents for carbapenem-resistant Gram-negative bacilli. The United States Committee on Antimicrobial Susceptibility Testing breakpoint recommendations for colistin and polymyxin B are that isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae are considered susceptible at MIC values of ≤2 mg/liter. These recommendations are contingent upon dosing and testing strategies that are described in this commentary. Importantly, these recommendations are not applicable to lower respiratory tract infections, for which we recommend no breakpoints. Furthermore, there is no breakpoint recommendation for polymyxin B for lower urinary tract infections.

Acute and long-term effects of antibiotics commonly used in laboratory animal medicine on the fecal microbiota.

Biomedical research relies on the use of animal models, and the animals used in those models receive medical care, including antibiotics for brief periods of time to treat conditions such as dermatitis, fight wounds, and suspected bacterial pathogens of unknown etiology. As many mouse model phenotypes are sensitive to changes in the gut microbiota, our goal was to examine the effect of antibiotics commonly administered to mice. Therefore, four treatment groups (subcutaneous enrofloxacin for 7 days, oral enrofloxacin for 14 days, oral trimethoprim-sulfamethoxazole for 14 days, and topical triple antibiotic ointment for 14 days) alongside a fifth control group receiving no treatment (n = 12/group) were included in our study. Fecal samples were collected prior to treatment, immediately after two weeks of exposure, and four weeks after cessation of treatment, and subjected to 16S rRNA library sequencing. The entire experimental design was replicated in mice from two different suppliers. As expected, several treatments including enrofloxacin and triple antibiotic ointment substantially decreased the amount of DNA recovered from fecal material, as well as the microbial richness. Notably, many of these effects were long-lasting with diminished gut microbiota (GM) richness four weeks following exposure, in both substrains of mice. Trimethoprim-sulfamethoxazole induced minimal to no discernible changes in the taxonomic composition beyond that seen in control mice. Collectively, these data highlight the need to consider the impact on GM of brief and seemingly routine use of antibiotics in the clinical care of research animals.

Clinical Effects of Perioperative Selective Decontamination of the Digestive Tract (SDD) in Cardiac Surgery: A Propensity Score Matched Cohort Analysis.

OBJECTIVES: To determine the clinical effects of perioperative endotoxin reduction in the gut lumen in patients undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: Retrospective cohort analysis with propensity score matching according to treatment group. SETTING: Tertiary center for cardiopulmonary diseases and intensive care medicine. PARTICIPANTS: Included were patients who underwent cardiac surgery with cardiopulmonary bypass between 2008 and 2017. Excluded were readmitted patients. INTERVENTIONS: Endotoxin reduction in the gut lumen by ingestion of oral tobramycin 80 mg and polymyxin B 100 mg 4 times daily (TP) as part of selective digestive tract decontamination, which contains amphotericin B 500 mg as well. MEASUREMENTS AND MAIN RESULTS: A total of 6,394 patients were included, of whom 2,044 patients were in the intervention group. A total of 835 patients received both pre- and postoperative TP (Pre+/Post+), and 1,165 patients received TP only postoperatively (Pre-/Post+). The control group, not treated with TP at any moment, consisted of 4,350 patients (Pre-/Post-). After matching, 652 Pre+/Post+ patients were compared with an equal number of controls (Pre-/Post-). Pre+/Post+ group did not do better for any clinical outcome. A total of 682 Pre+/Post+ patients matched with an equal number of Pre-/Post+ patients. The latter group had a 0.3 points higher mean Sequential Organ Failure Assessment score and in the regression analysis a significantly higher intensive care unit mortality but not hospital mortality. A significant reduction in length of stay and length of mechanical ventilation for the Pre+/Post+ group was shown compared with Pre-/Post+, but these differences can be explained by unbalanced differences in the severity of illness. CONCLUSION: Cardiosurgical patients who receive tobramycin and polymyxin orally preoperatively to reduce the gut endotoxin level do not expose convincing and relevant beneficial effects on clinical outcomes in this retrospective propensity score matching cohort study.

Incidences of Pseudomonas aeruginosa-Associated Ventilator-Associated Pneumonia within Studies of Respiratory Tract Applications of Polymyxin: Testing the Stoutenbeek Concurrency Postulates.

Regimens containing topical polymyxin appear highly effective at preventing ventilator-associated pneumonia (VAP) overall and, more so, VAP caused by Gram-negative bacteria. However, Stoutenbeek's postulates that VAP incidences within studies of topical antibiotics depend on the context of whether the component (control and intervention) groups of each study were concurrent versus nonconcurrent remain untested. The literature was searched for concurrent control (CC) versus nonconcurrent control (NCC) designed studies of respiratory tract applications of topical polymyxin to mechanically ventilated (MV) patients that reported incidences of Pseudomonas-associated ventilator-associated pneumonia (PsVAP). Studies of various interventions other than topical polymyxin (nonpolymyxin studies) served to provide additional points of reference. The PsVAP incidences within the component groups of all studies were benchmarked against groups from observational studies. This was undertaken by meta-regression using generalized estimating equation methods. Dot plots, caterpillar plots, and funnel plots enable visual benchmarking. The PsVAP benchmark (and 95% confidence interval [CI]) derived from 102 observational groups is 4.6% (4.0 to 5.3%). In contrast, the mean PsVAP within NCC polymyxin intervention groups (1.6%; CI, 1.0 to 4.5%) is lower than that of all other component group categories. The mean PsVAP within CC polymyxin control groups (9.9%; CI, 7.6 to 12.8%) is higher than that of all other component group categories. The PsVAP incidences of control and intervention groups of studies of respiratory tract applications of polymyxin are dependent on whether the groups were within a concurrent versus nonconcurrent study. Stoutenbeek's concurrency postulates are validated.

Polymyxin derivatives NAB739 and NAB815 are more effective than polymyxin B in murine Escherichia coli pyelonephritis.

Objectives: Extremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree. Here we have compared the efficacy of these NAB compounds and polymyxin B in the therapy of murine pyelonephritis caused by E. coli. Methods: The challenge organism was a uropathogenic E. coli clinical isolate. Mice were inoculated via urethral catheterization with 5 × 108 cfu. All treatment groups consisted of 12 animals. On day 1 and day 2 post-infection, the mice were treated subcutaneously with NAB739, NAB815, polymyxin B or vehicle twice a day and on day 3 post-infection the animals were sacrificed. cfu in the kidney and bladder tissues and in the urine were determined. Results: NAB739 reduced the bacterial burden in the kidney, urine and bladder at doses approximately 10-fold lower than those of polymyxin B. In the kidneys, the half-maximal effective dose (ED50) was 9-fold lower for NAB739 than for polymyxin B (0.24 mg/kg versus 2.1 mg/kg, respectively). NAB815 was as effective as NAB739. Conclusions: NAB739 and NAB815 were unequivocally more effective than polymyxin B in the murine pyelonephritis model.

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

BACKGROUND: The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. METHODS: The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. RESULTS: Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). CONCLUSIONS: Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Topical Polymyxin-Trimethoprim Prophylaxis May Decrease the Incidence of Driveline Infections in Patients With Continuous-Flow Left Ventricular Assist Devices.

This retrospective cohort study evaluated the effect of topical polymyxin-trimethoprim (poly) prophylaxis on the incidence of driveline infections (DLIs) in patients with continuous-flow left ventricular assist devices. All 84 cases implanted 2005-2014 with device support ≥30 days were reviewed; support ranged 1 m-5.2 yrs. Beginning 2008, poly was applied to the exit site with dressing changes. Sixty-five patients received poly (poly group) for duration of follow-up, 19 did not (no-poly); group baseline characteristics were similar. No patient developed side effects from poly. Nineteen DLIs (10 in no-poly) occurred; not using poly was a risk factor. 89% of poly group DLIs were superficial, 4 were culture-negative. DLI-related bacteremia occurred in 11% of no-poly group and 0% of poly group. Compared with no-poly, poly group demonstrated improved freedom from DLI by Kaplan-Meier analysis (P < 0.0001) and a 75% lower overall and 95% lower deep DLI incidence (P ≤ 0.001). Deep DLIs occurred in 31.6% of no-poly vs. 1.5% of poly patients (P = 0.0004), although mean support duration (1 yr) and % support >1 yr (38%) were similar. These findings, which should be confirmed with larger comparative studies, suggest that topical polymyxin-trimethoprim prophylaxis may be effective in preventing DLIs.

Imaging the distribution of polymyxins in the kidney.

OBJECTIVES: Dose-limiting nephrotoxicity remains the Achilles' heel of polymyxin B and polymyxin E (also known as colistin), which are important last-line antibiotics used against infections caused by MDR Gram-negative 'superbugs'. An understanding of the mechanisms of nephrotoxicity, including renal tissue distribution, is crucial for the development of safer polymyxin lipopeptide antibiotics. This is the first study to visualize the kidney distribution of polymyxin B using a mouse nephrotoxicity model and in situ immunostaining of kidney sections. METHODS: Polymyxin B nephrotoxicity in mice was induced over the course of 3 days (accumulated intravenous dose 175 mg/kg) and kidneys were harvested and frozen sectioned. The sections were fixed in cold acetone, dried and treated with 1% hydrogen peroxide. Endogenous mouse immunoglobulins were blocked and the tissue sections were treated with anti-polymyxin B mouse IgM antibody. The sections were incubated with a biotinylated anti-mouse secondary antibody conjugate followed by an Alexa Fluor 647-streptavidin conjugate. Polymyxin B distribution in the kidney sections was then visualized using a fluorescence scanning microscope. Kidney sections were also subjected to haematoxylin and eosin staining to assess pathological damage from the polymyxin-induced nephrotoxicity. RESULTS: Immunostaining of kidney sections from a mouse with polymyxin B-induced nephrotoxicity revealed that polymyxin B distributed predominantly within the renal cortex. More specifically, polymyxin B accumulated within the proximal tubular cells. CONCLUSIONS: The observed accumulation of polymyxin B within proximal tubular cells is consistent with the extensive renal reabsorption of polymyxins and the likely cause of the associated nephrotoxicity.

In vitro assessment and multicenter cohort study of comparative nephrotoxicity rates associated with colistimethate versus polymyxin B therapy.

Despite concerns of nephrotoxicity, polymyxin antibiotics often remain the only susceptible agents for multidrug-resistant (MDR) Gram-negative bacteria. Colistin has been more commonly used clinically due to a perceived safety benefit. We compared the nephrotoxicity of colistin to polymyxin B. The in vitro cytotoxicity of colistin was compared to polymyxin B in two mammalian renal cell lines. To validate the clinical relevance of the findings, we evaluated adult patients with normal renal function who received a minimum of 72 h of polymyxin therapy in a multicenter study. The primary outcome was the prevalence of nephrotoxicity, as defined by the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. Colistin exhibited an in vitro cytotoxicity profile similar to polymyxin B. A total of 225 patients (121 receiving colistimethate, 104 receiving polymyxin B) were evaluated. Independent risk factors for colistimethate-associated nephrotoxicity included age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00 to 1.07; P = 0.03), duration of therapy (OR 1.08; 95% CI, 1.02 to 1.15; P = 0.02), and daily dose by ideal body weight (OR 1.40; 95% CI, 1.05 to 1.88; P = 0.02). In contrast, cystic fibrosis was found to be a protective factor in patients who received colistimethate (OR, 0.03; 95% CI, 0.001 to 0.79; P = 0.04). In a matched analysis based on the risk factors identified (n = 76), the prevalence of nephrotoxicity was higher with colistimethate than with polymyxin B (55.3% versus 21.1%; P = 0.004). Polymyxin B was not found to be more nephrotoxic than colistin and may be the preferred polymyxin for MDR infections. A prospective study comparing the two polymyxins directly is warranted.

Activities of tobramycin and polymyxin E against Pseudomonas aeruginosa biofilm-coated medical grade endotracheal tubes.

Indwelling medical devices have become a major source of nosocomial infections, especially Pseudomonas aeruginosa infections, which remain the most common cause of ventilator-associated pneumonia (VAP) in neonates and children. Using medical grade polyvinyl chloride endotracheal tubes (ETTs), the activity of tobramycin and polymyxin E was quantified in a simulated prevention and treatment static time-kill model using biofilm-forming P. aeruginosa. The model simulated three clinical conditions: (i) planktonic bacteria grown in the presence of antibiotics (tobramycin and polymyxin E) without ETTs, (ii) planktonic bacteria grown in the presence of P. aeruginosa, antibiotic, and ETTs (simulating prevention), and (iii) a 24-h-formed P. aeruginosa biofilm grown on ETTs prior to antibiotic exposure (simulating treatment). In the model simulating "prevention" (conditions 1 and 2 above), tobramycin alone or in combination with polymyxin E was more bactericidal than polymyxin E alone at 24 h using a concentration of greater than 2 times the MIC. However, after a 24-h-old biofilm was allowed to form on the ETTs, neither monotherapy nor combination therapy over 24 h exhibited bactericidal or bacteriostatic effects. Against the same pathogens, tobramycin and polymyxin E, alone or in combination, exhibited bactericidal activity prior to biofilm attachment to the ETTs; however, no activity was observed once biofilm formed on ETTs. These findings support surveillance culturing to identify pathogens for a rapid and targeted approach to therapy, especially when P. aeruginosa is a potential pathogen.

Short-term decline in all-cause acquired infections with the routine use of a decontamination regimen combining topical polymyxin, tobramycin, and amphotericin B with mupirocin and chlorhexidine in the ICU: a single-center experience.

OBJECTIVES: In a multicenter, placebo-controlled, randomized, double-blind trial, we showed that acquired infections in intubated patients were reduced by the combination of topical polymyxin plus tobramycin and nasal mupirocin plus chlorhexidine body wash. Because intubated patients are particularly at risk for acquired infections, we reassessed the impact of this protocol as a routine procedure to control acquired infections in the ICU. DESIGN: Nonrandomized study comparing acquired infections in ICU patients during two 1-year periods: the last year before (group A, n = 925) and the first year after the implementation of the protocol (group B, n = 1,022). Acquired infections were prospectively recorded. SETTING: Polyvalent medical ICU at a university-affiliated hospital. PATIENTS: All patients admitted to the ICU. INTERVENTIONS: Administration of polymyxin/tobramycin/amphotericin B in the oropharynx and the gastric tube plus a mupirocin/chlorhexidine regimen in intubated patients and standard care in the other patients. MEASUREMENTS AND MAIN RESULTS: The comparison of acquired infection rates between groups was adjusted for differences at baseline. Infection rates were lower in group B compared with group A (5.3% vs 11.0%; p < 0.001), as were the incidence rates of total acquired infections (9.4 vs 23.6 per 1,000 patient-days; p < 0.001), intubation-related pneumonia (5.1 vs 17.1 per 1,000 ventilator-days; p < 0.001), and catheter-related bloodstream infections (1.0 vs 3.5 per 1,000 catheter-days; p = 0.03). There were fewer acquired infections caused by ceftazidime-resistant Enterobacteriaceae (0.8‰ vs 3.6‰; p < 0.001), ciprofloxacin-resistant Enterobacteriaceae (0.8‰ vs 2.5‰; p = 0.02), ciprofloxacin-resistant Pseudomonas aeruginosa (0.5‰ vs 1.6‰; p = 0.05), and colistin-resistant Gram-negative bacilli (0.7‰ vs 1.9‰; p = 0.04). Fewer patients got acquired infections due to multidrug-resistant aerobic Gram-negative bacilli (p = 0.008). CONCLUSIONS: In intubated patients, the use of topical polymyxin/tobramycin/amphotericin B plus mupirocin/chlorhexidine was associated with the reduction of all-cause ICU-acquired infections. Long-term emergence of multidrug-resistant organisms deserves further investigation.

Impact of carbapenem resistance and receipt of active antimicrobial therapy on clinical outcomes of Acinetobacter baumannii bloodstream infections.

Nosocomial Acinetobacter baumannii bloodstream infections occur with significant prevalence and mortality. The relationship between carbapenem resistance in A. baumannii and patient outcomes remains unclear. A retrospective cohort study was conducted on patients with A. baumannii bacteremia. Outcomes, controlling for confounders, were compared for carbapenem-nonresistant A. baumannii (CNRAB) and carbapenem-resistant A. baumannii (CRAB). The primary outcome studied was all-cause hospital mortality, and the secondary endpoints evaluated were time to mortality, time to negative cultures, and length of stay postinfection for survivors. A total of 79 patients, 37 infected with CRAB and 42 with CNRAB, were studied. Hospital mortality was greater in the CRAB group as determined based on bivariate analysis (P < 0.01); however, this effect was nullified when controlling for relevant confounders with logistic regression and a Cox proportional-hazards model (P = 0.71 and 0.75, respectively). Values for time to mortality and time to negative cultures did not differ between the groups. The median number of days of stay postinfection for survivors was greater for the CRAB group than the CNRAB group (14 versus 6.5; P < 0.01). Patients who received active antimicrobial therapy were less likely to die (93.5% versus 74.2%; P = 0.02), regardless of carbapenem susceptibility classifications, and this result was robust in the multivariate model (P = 0.02). Trends existed for improved outcomes in patients receiving an active beta-lactam, and patients fared worse if they had received a polymyxin as an active agent. Patients with CRAB bloodstream infections were more chronically ill and had more comorbidities. Inactive therapy was more important than carbapenem susceptibility with respect to outcomes, was a strong predictor of death, and is potentially modifiable.

The Low-Alkalinity Polymyxin Derivative, AL-6, Shows High Activity Against Multidrug-Resistant Acinetobacter baumannii Clinical Isolates In Vitro and A. baumannii ATCC 19606 In Vivo: Preliminary Analysis of the Antibacterial Mechanism.

Polymyxin B and colistin (polymyxin E) are increasingly used as the last line of therapy for infections caused by multidrug-resistant (MDR) gram-negative pathogens. However, nephrotoxicity is still a limiting factor for the use of polymyxin. Therefore, better tolerated and more effective polymyxin derivatives are urgently needed. In this study, we aimed to evaluate the activity of the low-alkalinity polymyxin derivative, AL-6, against MDR Acinetobacter baumannii (Ab) clinical isolates in vitro and A. baumannii ATCC 19606 in vivo. Additionally, we performed a preliminarily study of the antibacterial mechanism. AL-6 showed much higher activity (0.125-0.25 µg/mL) against MDR A. baumannii clinical isolates than polymyxin E2 (PE2, 0.5-1 µg/mL). AL-6 also showed much higher activity (0.5-256 µg/mL) against polymyxin-resistant strains than PE2 (16-1024 µg/mL). Additionally, AL-6 showed slow resistance against A. baumannii. AL-6 also increased the survival rates of mice by 10% at 48 h compared with PE2 (5 mg/kg). AL-6 could be used at a dose of up to 10 mg/kg, increasing the survival rate to 30% at 72 h after infection. A preliminary study of the antibacterial mechanism showed that AL-6 permeabilized the outer membrane and destroyed cell membrane integrity. Moreover, there was a substantial increase in zeta potential (i.e., less negative) upon AL-6 exposure for A. baumannii. Overall, AL-6 carrying only four positive charges showed high activity against A. baumannii in vitro by disrupting cell membrane integrity. Higher doses of AL-6 could increase survival rates of mice. Thus, AL-6 may have potential applications as a bactericidal agent.

Novel polymyxin derivatives are effective in treating experimental Escherichia coli peritoneal infection in mice.

OBJECTIVES: Novel synthetic polymyxin derivatives including NAB737 and NAB739 are as effective as polymyxin B in vitro against the common opportunistic pathogen Escherichia coli. Another derivative, NAB7061, lacks direct antibacterial action but sensitizes E. coli to several other antibacterial agents including macrolides. The renal handling of NAB739 and NAB7061 in rats differs from that of polymyxin B. Furthermore, the affinities of NAB739 and NAB7061 for isolated rat kidney brush border membrane are significantly lower than that of polymyxin B. Here we investigate the in vivo antibacterial effect of these compounds. METHODS: The polymyxin derivatives were evaluated in an experimental murine peritonitis model. Immunocompetent mice were infected intraperitoneally with E. coli IH3080 and were subcutaneously treated with NAB737, NAB739 or NAB7061. RESULTS: A >4.0 log(10) reduction in bacterial load compared with saline control was achieved 6 h after initiation of treatment with 1 mg/kg of NAB739 twice or 4 mg/kg of NAB737 twice. Combination therapy with NAB7061 (5 mg/kg) twice and erythromycin (10 mg/kg) resulted during the same time course in a >2.0 log(10) reduction in bacterial load compared with saline control. Neither NAB7061 nor erythromycin was effective as monotherapy. Together with the ability to reduce bacterial load, the NAB compounds also improved the clinical status of the mice. CONCLUSIONS: We found that the three novel synthetic polymyxin B derivatives had a potent in vivo bactericidal effect against E. coli.

Polymyxin-direct hemoperfusion for sepsis-induced multiple organ failure.

We report a case of multiple organ failure caused by the Bacillus cereus infection during acute lymphoblastic leukemia therapy, who was treated successfully. A 15-year-old male developed (B. cereus) sepsis on the 19th day after chemotherapy initiation. Polymyxin-direct hemoperfusion for septic shock was started, followed by continuous hemodiafiltration. His condition improved after starting the hemoperfusion. At the onset of sepsis, elevated levels of serum inflammatory cytokines, anti-inflammatory cytokines, and plasminogen-activator inhibitor complex-1 were observed. Serum levels of these cytokines and bioactive substances decreased after blood purification therapy, which correlated with the improvement of clinical symptoms.

Treatment of infections caused by Gram-negative pathogens: current status on the pharmacokinetics/pharmacodynamics of parenteral and inhaled polymyxins in patients.

Polymyxins are increasingly used as a last resort for the treatment of infections caused by multidrug-resistant Gram-negative bacteria in patients. Over the last decade, significant progress has been made in understanding the pharmacokinetics/pharmacodynamics/toxicodynamics (PK/PD/TD) of parenteral and inhaled polymyxins. This mini-review provides an overview of polymyxin chemistry, different dose definitions, and the latest research on their clinical use, toxicities, and PK/PD after intravenous and inhalation administration. Optimising the PK/PD/TD of polymyxins in patients is critical to maximise their efficacy while minimising toxicities and the emergence of resistance.

Pharmacokinetics of novel antimicrobial cationic peptides NAB 7061 and NAB 739 in rats following intravenous administration.

OBJECTIVES: To determine the disposition of novel antimicrobial cationic peptides NAB 7061 and NAB 739 following intravenous administration in rats. METHODS: Sprague-Dawley rats received a single intravenous bolus of 1.0 mg/kg NAB 7061 or NAB 739. Plasma concentrations of NAB 7061 or NAB 739 were determined by HPLC or liquid chromatography-mass spectrometry. The pharmacokinetic parameters of NAB 7061 and NAB 739 were calculated using non-compartmental analysis. RESULTS: Corresponding total body clearance, volume of distribution at steady state and terminal half-life of NAB 7061 and NAB 739 averaged 3.84 and 2.63 mL/min/kg, 339 and 222 mL/kg, and 66.2 and 69.0 min, respectively. Approximately 7.16% and 19.4% of the dose was eliminated in an unchanged form via the urine in 24 h for NAB 7061 and NAB 739, respectively. CONCLUSIONS: While both compounds had generally similar pharmacokinetics to colistin, even minor alterations in the chemical structures appear to have an impact on their pharmacokinetics, especially on their clearance by the kidney. There are also substantial differences in relation to the relative contributions of renal and non-renal clearance to overall elimination from the body.

Multiple drug-resistant Alcaligenes xylosoxidans keratitis in a sanitation worker.

PURPOSE: To report a case of daily wear soft contact lens-associated keratitis caused by Alcaligenes xylosoxidans in a portable toilet sanitation worker. METHODS: A previously healthy 30-year-old man presented with bilateral decreased vision, redness, and irritation, beginning 1 week earlier. The patient had been treated with moxifloxocin for 1 week before presentation without improvement. Bacterial staining cultures were performed from corneal scrapings, contact lenses, contact lens case, and solution. Preliminary culture results and antibiotic sensitivities were generated using an automated identification system. Positive results from the contact lens, case, and solution were confirmed using polymerase chain reaction (PCR). RESULTS: The contact lenses, contact lens case, and solution cultures revealed heavy growth of A. xylosoxidans. These findings were confirmed by PCR. The organism was found to be resistant to aminoglycosides, fluoroquinolones, and cephalosporins. The patient was started on polymyxin B or trimethoprim. After 21 days of treatment, the infection completely resolved with a final spectacle-corrected visual acuity of 20/25. CONCLUSIONS: To our knowledge, this is the first case report of a corneal infection caused by A. xylosoxidans, which was isolated and identified from a contact lens, case, and solution using culture and PCR technique as well the first description of ocular surface disease resolution after the treatment with topical polymyxin B or trimethoprim. A. xylosoxidans should be considered as uncommon but potential pathogen capable of infectious spread through contaminated contact lens solution.

Neomycin-polymyxin or gentamicin bladder instillations decrease symptomatic urinary tract infections in neurogenic bladder patients on clean intermittent catheterization.

INTRODUCTION: Recurrent urinary tract infections (UTIs) are common in patients with neurogenic bladder (NGB) performing clean intermittent catheterization (CIC) treated with or without oral antibiotic prophylaxis. OBJECTIVE: The authors aim to determine if daily neomycin-polymyxin or gentamicin bladder instillations reduce the rate of symptomatic UTIs, the need for oral antibiotic prophylaxis, emergency department (ED) visits for UTI, and inpatient hospitalizations for UTI in patients with NGB on CIC. The authors also aim to investigate resistance patterns in urine microorganisms in patients treated with antibiotic bladder instillations. STUDY DESIGN: The authors retrospectively reviewed the records of all-age patients cared for in the pediatric urology clinic with NGB on CIC having symptomatic UTIs and on daily intravesical instillations of neomycin-polymyxin or gentamicin between 2013 and 2017. Symptomatic UTIs were defined as a positive urine culture with greater than 10,000 colony forming units/mL associated with one or more of the following patient complaints: cloudy/foul-smelling urine, fevers, chills, increase in bladder spasms, pain, urinary leakage, or physician decision for antibiotic treatment. Multidrug-resistant organisms were resistant to two or more classes of antibiotics. RESULTS: Fifty-two patients with a median age of 14.5 years and 192 distinct urine cultures were identified. 90.4% and 9.6% of patients received neomycin-polymyxin and gentamicin instillations, respectively. After initiation of intravesical antibiotics, the rate of symptomatic UTIs was reduced by 58% (incidence rate ratio [IRR]: 0.42, 95% confidence interval [CI]: 0.31-0.56; P < 0.001), the rate of ED visits was reduced by 54% (IRR: 0.46, 95% CI: 0.30-0.71; P < 0.001), and the rate of inpatient hospitalizations for UTI was reduced by 39% (IRR: 0.61, 95% CI: 0.37-0.98; P = 0.043). Fewer patients received oral antibiotic prophylaxis after initiation of antibiotic instillations (odds ratio: 0.12, 95% CI: 0.02-0.067; P = 0.016). There was a trend toward a decrease in multidrug resistance and no change in gentamicin resistance in urine microorganisms. DISCUSSION: This study describes a feasible alternative treatment for patients with NGB on CIC who have persistent UTIs despite oral antibiotic prophylaxis, and for some patients, it may suggest a possibility of discontinuing oral prophylaxis. Limitations include a retrospective design with a small cohort of patients and varying dosages of neomycin-polymyxin. CONCLUSIONS: Antibiotic bladder instillations appear to decrease frequency of symptomatic UTIs, ED visits for UTI, inpatient hospitalizations for UTI, and the need for oral antibiotic prophylaxis in patients with NGB on CIC. There was no increase in multidrug resistance or gentamicin resistance in UTI organisms with use of intravesical antibiotic instillation.