In vivo bactericidal effect of colistin-linezolid combination in a murine model of MDR and XDR Acinetobacter baumannii pneumonia.

Recently, paradoxical combinations of colistin with anti-Gram-positive bacterial agents were introduced as a treatment alternative for multidrug-resistant Acinetobacter baumannii (MDRAB) infection. We assessed the therapeutic efficacy of the colistin-linezolid combination regimen in vitro and in a murine model of Acinetobacter baumannii pneumonia. A multidrug-resistant clinical strain (MDRAB31) and an extensively drug-resistant clinical strain (XDRAB78) were used in this study. The survival rates of mice and bacterial counts in lung tissue were used to assess the effects of colistin-linezolid combination. The survival rates of colistin-linezolid combination groups significantly increased compared with colistin groups for MDRAB31 (72% versus 32%, P = 0.03) and for XDRAB78 (92% versus 68%, P = 0.031). The colistin-linezolid combination groups significantly reduced the bacterial counts in lung tissue compared with colistin groups for MDRAB31 and for XDRAB78 (P < 0.05). The colistin-linezolid combination had a bactericidal and synergistic effect compared with colistin alone in time-kill assay and in murine model of pneumonia. Our data demonstrated the synergistic effect of colistin-linezolid combination regimen as a treatment alternative for the severe pulmonary infection caused by MDRAB and XDRAB.

The efficacy of colistin monotherapy versus combination therapy with other antimicrobials against carbapenem-resistant Acinetobacter baumannii ST2 isolates.

This study aimed to investigate the efficacy of colistin both alone and in combination with either meropenem or levofloxacin against CRAB clinical isolates. The OXA carbapenemase genes and multilocus sequence typing were detected after 35 CRAB isolates biochemical identification. Then, the minimum inhibitory concentrations, minimum bactericidal concentrations, antibiotic interactions of the test antibiotics, and synergistic effects were determined by the checkerboard method and time-kill assays. The chromosomal gene bla OXA-51-like was detected in all isolates, and bla OXA-23-like and bla OXA-24-like were present in 91.4% and 25.7% of the isolates, respectively. The combination of colistin and meropenem displayed the highest rate of synergy (51.4%) against the 35 isolates, while the colistin-levofloxacin combination showed a higher rate of indifference interaction (22.9%) than that of the colistin-meropenem (8.6%) combination. The synergistic effect of colistin against the CRAB isolates was confirmed. The combination of colistin with meropenem is recommended against CRAB isolates.

Efficacy and Therapeutic Drug Monitoring of Continuous Beta-Lactam Infusion for Osteoarticular Infections Caused by Fluoroquinolone-Resistant Pseudomonas aeruginosa: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Osteoarticular infections (OIs) caused by fluoroquinolone-resistant Pseudomonas aeruginosa, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, have poor outcomes. We evaluated the outcomes of an optimized strategy of continuous beta-lactam infusion (BL-CI) guided by therapeutic drug monitoring (TDM) for OIs caused by fluoroquinolone-resistant P. aeruginosa. METHODS: A prospective observational study of patients with P. aeruginosa OIs in a hospital-based BL-CI program (2016-2018) was carried out. TDM targeting free BL concentrations in plasma (fCss) of at least 3-4 × MIC was performed. We compared failure rates between patients with OIs caused by fluoroquinolone-resistant strains who were treated with BL-CI, with or without colistin, and patients with OIs caused by fluoroquinolone-susceptible strains who were treated with ciprofloxacin. RESULTS: Fifty-two patients were included in the study, 19 (36.5%) of whom had OIs caused by fluoroquinolone-resistant P. aeruginosa (13 (68.4%) MDR/XDR strains; 11 (57.9%) device-related infections). The median duration of BL-CI was 36 days; ten patients (52.6%) received BL-colistin combinations. Eighty-two samples were utilized in the TDM, and most patients were found to have a median fCss of 3-10 × MIC; 17 dose adjustments were performed and eight patients needed dose decreases, five of which were due to chronic kidney disease or acute kidney injury (AKI). BL-CI was well tolerated, with the most frequent adverse event being AKI. Failure occurred to 4 patients (21.1%), which was similar to the failure rate of patients with OIs caused by fluoroquinolone-susceptible P. aeruginosa treated with ciprofloxacin (5/30 [16.7%]) (p = 0.699). TDM was also used in the initial BL treatment of patients with OIs caused by susceptible strains before those patients were switched to treatment with ciprofloxacin alone (33 patients, 110 samples, 19 dose adjustments). CONCLUSIONS: BL-CI used with/without colistin and supported by TDM may be an alternative and effective treatment option for OIs caused by fluoroquinolone-resistant P. aeruginosa, where limited available therapeutic options exist, especially in the setting of multidrug resistance. Future research should elucidate whether this strategy can produce outcomes similar to those of patients treated for OIs caused by fluoroquinolone-susceptible strains.

Colistin plus meropenem for carbapenem-resistant Gram-negative infections: in vitro synergism is not associated with better clinical outcomes.

OBJECTIVES: In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. METHODS: This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin-meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin-meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. RESULTS: The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31-1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22-2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26-1.04) or 14-day mortality (aOR1.09, 95% CI 0.60-1.96). DISCUSSION: In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.

Colistin for pneumonia involving multidrug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex.

OBJECTIVES: To investigate clinical and microbiological response, and 30-day mortality of pneumonia involving multidrug-resistant (MDR) Acinetobacter calcoaceticus-Acinetobacter baumannii (Acb) complex treated with colistin, and identify associated factors of these outcomes. METHODS: A retrospective study of 183 adult patients with colistin treatment for at least 7 days between January 2014 and October 2017. RESULTS: The mean age was 76.8 years, and mean Acute Physiology and Chronic Health Evaluation II score was 17.7. Eighteen (9.8%) and 128 (69.9%) patients had intravenous (IV) colistin alone and inhaled (IH) colistin alone, respectively. Thirty-seven patients had both IV and IH colistin, including 5 (2.7%) with concurrent, and 32 (17.5%) with non-concurrent use of IV and IH colistin. The 30-day mortality rate was 19.1% and 131 (71.6%) patients had clinical response. In the 175 patients with available data, 126 (72%) had microbiological eradication. The multivariate analyses revealed that IH colistin alone was an independent predictor for 30-day survival, clinical response, and microbiological eradication, and IV colistin alone was an independent predictor for clinical failure. Patients with IV colistin alone had a significantly higher nephrotoxicity rate than IH colistin alone (37.5% vs 6.1%, P = 0.001). Sub-group analysis of 52 patients with IV colistin for ≧ 4 days revealed that 14 (26.9%) patients had inappropriate dose, and inappropriate dose was an independent predictor for 30-day mortality. CONCLUSIONS: IH colistin provided good outcomes with few side effects, and appropriate dosing of IV colistin was important to avoid excess mortality.

Comparison of two therapeutic approaches for the management of ventilator-associated pneumonia due to multidrug-resistant Acinetobacter: a randomized clinical trial study.

Management of ventilator-associated pneumonia (VAP) is a puzzling issue for infectious disease specialist. The present clinical trial study was aimed to comparing the effects of injectable colistin plus nebulized colistin and injectable colistin plus nebulized tobramycin on management of patients with VAP due to multidrug-resistant Acinetobacter. VAP patients were randomly divided into two groups (n = 30/each): Group 1 - patients that received intravenous (IV) meropenem, injectable colistin plus nebulized colistin, as a routine treatment, and Group 2 - patients that received IV meropenem, injectable colistin plus nebulized tobramycin. A total of 14 days of therapeutic intervention are required for every case. Follow-up for subjects was performed at five time-points: days 1, 3, 5, 7, and 14 after intervention. Also, a mean of creatinine levels of patients was determined in five times. In the present study, the clinical pulmonary infection score (CPIS) was determined on the basis of points assigned for various clinically manifestations of VAP. Based on our statistical analysis, there was no significant difference between CPIS and creatinine level in both Groups 1 and 2 (p > .05). CPIS and other clinical investigation appeared effectiveness of the treatment with injected colistin plus nebulized tobramycin; on the other hand, the results of present clinical trial showed that aforementioned therapeutic approach can be used as an alternative treatment for the management of infection in VAP patients.

Colistin-containing cement spacer for treatment of experimental carbapenemase-producing Klebsiella pneumoniae prosthetic joint infection.

Carbapenemase-producing Enterobacteriaceae (CPE) are emerging multidrug-resistant bacteria responsible for invasive infections, including prosthetic joint infections (PJIs). Local administration of colistin may provide bactericidal concentrations in situ. This study evaluated the efficacy of a colistin-impregnated cement spacer, alone and in combination with systemic antibiotics, in a rabbit model of CPE-PJI. Elution of 3 MIU of colistimethate sodium (CMS) in 40 g of poly(methyl methacrylate) cement was studied in vitro. In vivo, 5 × 108 CFU of KPC-producing Klebsiella pneumoniae (colistin and meropenem MICs of 1 mg/L and 4 mg/L, respectively) were injected close to a prosthetic knee. Surgical debridement and prosthesis removal were performed 7 days later, and rabbits were assigned to six treatment groups (11-13 rabbits each): drug-free spacer; colistin-loaded spacer; colistin intramuscular (i.m.); colistin i.m. + colistin spacer; colistin i.m. + meropenem subcutaneous (s.c.); and colistin i.m. + meropenem s.c. + colistin spacer. Systemic treatment was administered at doses targeting pharmacokinetics in humans, and rabbits were euthanised 7 days later to evaluate bacterial counts in infected bones. In vitro, CMS elution was low (<0.1% at 24 h) but reached a local concentration of ≥20 mg/L (>20 × MIC). In vivo, combinations of local and systemic colistin, with or without meropenem, were the only regimens superior to the control group (P ≤ 0.05) in terms of viable bacterial counts and the proportion of rabbits with sterile bone, with no emergence of colistin-resistant strains. Colistin-loaded cement spacer in combination with systemic antibiotics were the most effective regimens in this CPE-PJI model.

Colistin for the treatment of urinary tract infections caused by extremely drug-resistant Pseudomonas aeruginosa: Dose is critical.

OBJECTIVES: Optimal dosage regimens of colistin for the treatment of urinary tract infections (UTI) are unknown. Colistimethate sodium (CMS), the inactive prodrug of colistin, is mainly excreted in urine and converts to colistin after filtration by glomeruli, suggesting that concentrations of colistin in urine could be much higher than in plasma. Therefore, there is a need to optimize dosage regimens of intravenous CMS for UTI. The aim of this study was to examine the relationship between AUC/MIC of formed colistin and clinical outcomes in patients with UTI caused by extremely drug resistant (XDR) Pseudomonas aeruginosa. METHODS: This prospective, observational cohort study involved patients with UTI caused by XDR P. aeruginosa. Clinical cure, bacteriological clearance and acute kidney injury (AKI) were analyzed. Steady-state colistin plasma concentrations (Css) were measured using HPLC. Based on the PK/PD of colistin in neutropenic mouse thigh infection models with P. aeruginosa, the optimal AUC/MIC should be ≥60 mg·h/L. According to the pharmacokinetics (PK) in critically-ill patients, the Css target of formed colistin in plasma was 2.5 mg/L. RESULTS: Thirty-three patients were included (24 lower UTI and 9 pyelonephritis). The MIC50 and MIC90 values for colistin were 0.5 and 2 mg/L respectively. Nineteen patients (57.6%) received colistin monotherapy (84.2% lower UTI and 15.8% pyelonephritis). Of these, clinical cure was achieved in 89.5% of cases. Among patients with clinical cure and monotherapy, only 5 (29.4%) attained an optimal plasma AUC/MIC and only 1 (5.9%) the therapeutic level of formed colistin (2.5 mg/L). However, 10 (58.8%) patients showed colistin plasma concentrations above the MIC of the isolated P. aeruginosa. Microbiological eradication was achieved in 76.9% of patients. AKI at the end of treatment was present in 29.4% of patients. CONCLUSIONS: The currently recommended dosage regimens of CMS showed high efficacy for the treatment of lower complicated UTI caused by XDR P. aeruginosa in non-critically ill patients and in the case of low MIC values, but also a considerable nephrotoxicity rate. Our data suggest that the use of lower CMS doses for lower UTI should be investigated in future studies to minimize the unnecessary nephrotoxicity.

Variation in treatment strategies for the eradication of Pseudomonas aeruginosa in primary ciliary dyskinesia across European centers.

Primary ciliary dyskinesia (PCD) is a rare disease causing motile cilia dysfunction, recurrent airway infection, and bronchiectasis. Airway infection management strategies are borrowed from cystic fibrosis. The aim of this study is to describe the management of airway infection with Pseudomonas aeruginosa ( PA) in children and adults with PCD across European centers. An online survey questionnaire was sent electronically using SurveyMonkey® to 55 PCD centers in 36 European countries. Fifty-two responded from 43 centers in 26 countries, a response rate of 70%. Most (89%) countries did not have written guidelines for PCD management. Airway sampling for infection detection at each clinic visit was more likely when follow-up was frequent. Eighty-seven percent of centers chose to treat the first PA isolate, most prescribing combined oral ciprofloxacin and inhaled colistimethate sodium (43%, n = 18). The preferred treatment for chronic infection with PA was nebulized colistimethate in 51% ( n = 22). In summary, considerable variation exists across European centers in the frequency of patient follow-up and airway sampling for infection, treatment goals, and the management of PA infection. Few centers had written guidelines for PCD management. Clinical trials to determine optimal treatment of PA in PCD patients are urgently needed.

Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model.

Objectives: The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes. Methods: To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose-response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs). Results: Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs. Conclusions: The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

Colistin monotherapy versus colistin/rifampicin combination therapy in pneumonia caused by colistin-resistant Acinetobacter baumannii: A randomised controlled trial.

OBJECTIVES: The aim of this study was to confirm the synergistic effect of colistin/rifampicin combination therapy compared with colistin monotherapy in pneumonia caused by colistin-resistant Acinetobacter baumannii (CoRAB). The utility of the Etest was also assessed. METHODS: Nine subjects with pneumonia caused by CoRAB were enrolled from 20 July 2016 to 21 June 2018. Subjects were randomised to colistin/rifampicin combination therapy or colistin monotherapy. After exclusion of one patient who dropped out, the microbiological response (MR) and clinical response (CR) on Day 14 and mortality on Day 30 were assessed. Etest was conducted using CoRAB isolated at study enrolment. RESULTS: The MR rate in the colistin/rifampicin combination group (100.0%) was better than that in the colistin group (40.0%), however the difference was not statistically significant (P=0.196). The CR rate was not significantly different between the two groups. The MR (100.0%) and CR (100.0%) rates in subjects with 'partial synergy' as shown by Etest were higher than those (25.0% and 50.0%, respectively) in subjects with 'indifferent' results (i.e. no synergistic effect), however the difference was not statistically significant (P=0.143 and 0.429, respectively). Mortality occurred in two subjects with 'indifferent' results by Etest. CONCLUSIONS: Colistin/rifampicin combination therapy may have potential to achieve MR in pneumonia caused by CoRAB; however, achieving CR with this treatment is doubtful. 'Partial synergy' of colistin and rifampicin, as shown by Etest, may be a good prognostic factor [ClinicalTrial.gov ID: NCT03622918].

Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin.

This study aimed to investigate the effect of chrysin on colistin-induced reproductive toxicity. Twenty-eight adult male Sprague-Dawley rats were divided into four groups of seven rats each. Group I received physiological saline for 7 days. Group II received 50 mg/kg/day chrysin for 7 days. Group III received a total dose of 73 mg/kg colistin for 7 days. Group IV received 50 mg/kg/day chrysin by an oral gavage after the colistin treatment. Colistin causes an increase in oxidative stress (OS) in the testis. Chrysin treatment significantly decreased the OS in the chrysin + colistin group compared with the colistin group. The highest caspase-3 and LC3B expression levels were found in the colistin group and these levels were statistically lower in the chrysin + colistin group. Colistin treatment caused a decrease in sperm motility and an increase in sperm abnormality. Chrysin treatment mitigated these side effects significantly. In conclusion, chrysin treatment can be beneficial against colistin-induced reproductive toxicity.

Using the Chinese herb Scutellaria barbata against extensively drug-resistant Acinetobacter baumannii infections: in vitro and in vivo studies.

BACKGROUND: No animal model studies have been conducted in which the efficacy of herbal compounds has been tested against multidrug-resistant Acinetobacter baumannii infections. Very few antibiotics are available for the treatment of pulmonary infections caused by extensively drug-resistant Acinetobacter baumannii (XDRAB). To find alternative treatments, traditional Chinese herbs were screened for their antimicrobial potential. METHODS: The present study screened 30 herbs that are traditionally used in Taiwan and that are commonly prescribed for heat clearing and detoxification. The herbs with antibacterial activities were analysed by disc diffusion assays, time-kill assays and a murine lung infection model. RESULTS: Of the 30 herbs tested, only Scutellaria barbata demonstrated 100% in vitro activity against XDRAB. Furthermore, we compared the antibacterial effect of the S. barbata extract with that of colistin, and the S. barbata extract showed better antibacterial effect. In the XDRAB pneumonia murine model, we compared the antimicrobial effects of the orally administered S. barbata extract (200 mg/kg, every 24 h), the intratracheally administered colistin (75,000 U/kg, every 12 h), and the control group. The bacterial load in the lungs of the treatment group that received the oral S. barbata extract showed a significant decrease in comparison to that in the lungs of the control group. In addition, histopathological examinations also revealed better resolution of perivascular, peribronchial, and alveolar inflammation in the oral S. barbata extract-treated group. CONCLUSIONS: Our in vitro and in vivo data from the animal model support the use of S. barbata as an alternate drug to treat XDRAB pulmonary infections. However, detailed animal studies and clinical trials are necessary to establish the clinical utility of S. barbata in treating XDRAB pulmonary infections.

Evaluation of growth performance and gastro-intestinal parameters on the response of weaned piglets to dietary organic acids

ABSTRACT Two experiments (E) were carried out to evaluate the effects of fumaric acid and an acidifier blend [composed by calcium formate, calcium lactate and medium-chain fatty acids (capric and caprylic)] in piglet diets containing colistin (40 ppm) or halquinol (120 ppm) on performance, diarrhea incidence (E1), organs relative weight, pH values, intestinal morphometry and microbiota (E2). In E1, 192 and E2, 24 piglets weaned at 21-day-old were randomly assigned to blocks with 2x2 factorial arrangement of treatments [absence or presence of fumaric acid x absence or presence of acidifier blend], six replicates of eight (E1) and one piglet per pen (E2). For E1, the treatments were control (CD): no acidifier product + 40 ppm of colistin, FA: fumaric acid in absence of acidifier blend, AB: acidifier blend in absence of fumaric acid and, AF+AB: presence of fumaric acid and acidifier blend. For E2, the pre-starter I diet were used and the same treatments as E1 evaluated. No treatment effects (P>0.05) were observed on performance, diarrhea incidence (E1), gut pH values and duodenum morphometry of piglets (E2). However, the addition of AB increased (P<0.05) large intestine relative weight and, FA addition decreased (P<0.05) pancreas relative weight, jejunum villi height and, total coliform and E. coli counts in cecum. The inclusion of FA and AB in diets containing colistin or halquinol did not improve performance, although FA exerted an inhibitory effect on cecum microbiota.

Evaluation of growth performance and gastro-intestinal parameters on the response of weaned piglets to dietary organic acids.

Two experiments (E) were carried out to evaluate the effects of fumaric acid and an acidifier blend [composed by calcium formate, calcium lactate and medium-chain fatty acids (capric and caprylic)] in piglet diets containing colistin (40 ppm) or halquinol (120 ppm) on performance, diarrhea incidence (E1), organs relative weight, pH values, intestinal morphometry and microbiota (E2). In E1, 192 and E2, 24 piglets weaned at 21-day-old were randomly assigned to blocks with 2x2 factorial arrangement of treatments [absence or presence of fumaric acid x absence or presence of acidifier blend], six replicates of eight (E1) and one piglet per pen (E2). For E1, the treatments were control (CD): no acidifier product + 40 ppm of colistin, FA: fumaric acid in absence of acidifier blend, AB: acidifier blend in absence of fumaric acid and, AF+AB: presence of fumaric acid and acidifier blend. For E2, the pre-starter I diet were used and the same treatments as E1 evaluated. No treatment effects (P>0.05) were observed on performance, diarrhea incidence (E1), gut pH values and duodenum morphometry of piglets (E2). However, the addition of AB increased (P<0.05) large intestine relative weight and, FA addition decreased (P<0.05) pancreas relative weight, jejunum villi height and, total coliform and E. coli counts in cecum. The inclusion of FA and AB in diets containing colistin or halquinol did not improve performance, although FA exerted an inhibitory effect on cecum microbiota.

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.

Zinc oxide nanoparticles as a substitute for zinc oxide or colistin sulfate: Effects on growth, serum enzymes, zinc deposition, intestinal morphology and epithelial barrier in weaned piglets.

The objective of this study was to evaluate effects of zinc oxide nanoparticles (nano-ZnOs) as a substitute for colistin sulfate (CS) and/or zinc oxide (ZnO) on growth performance, serum enzymes, zinc deposition, intestinal morphology and epithelial barrier in weaned piglets. A total of 216 crossbred Duroc×(Landrace×Yorkshire) piglets weaned at 23 days were randomly assigned into 3 groups, which were fed with basal diets supplemented with 20 mg/kg CS (CS group), 20mg/kg CS+3000 mg/kg ZnO (CS+ZnO group), and 1200 mg/kg nano-ZnOs (nano-ZnO group) for 14 days. Results indicated that compared to CS group, supplementation of 1200 mg/kg nano-ZnOs (about 30 nm) significantly increased final body weight and average daily gain, and 3000 mg/kg ZnO plus colistin sulfate significantly increased average daily gain and decreased diarrhea rate in weaned piglets. There was no significant difference in growth performance and diarrhea rate between nano-ZnO and CS+ZnO groups. Supplementation of nano-ZnOs did not affect serum enzymes (glutamic oxalacetic transaminase, glutamic-pyruvic transaminase, and lactate dehydrogenase), but significantly increased plasma and tissue zinc concentrations (liver, tibia), improved intestinal morphology (increased duodenal and ileal villus length, crypt depth, and villus surface), enhanced mRNA expression of ZO-1 in ileal mucosa, and significantly decreased diamine oxidase activity in plasma, total aerobic bacterial population in MLN as compared to CS group. Effects of nano-ZnOs on serum enzymes, intestinal morphology, and mRNA expressions of tight junction were similar to those of high dietary ZnO plus colistin sulfate, while nano-ZnOs significantly reduced zinc concentrations of liver, tibia, and feces, and decreased total aerobic bacterial population in MLN as compared to CS+ZnO group. These results suggested that nano-ZnOs (1200 mg/kg) might be used as a substitute for colistin sulfate and high dietary ZnO in weaned piglets.

Visual compatibility of colistin injection with other antibiotics during simulated Y-site administration.

PURPOSE: The compatibility of colistin with other antibiotics at concentrations commonly used in intensive care units was studied. METHODS: A vial of colistin was dissolved in sterile water for injection. The reconstituted solution (colistin base 75 mg/mL) was then diluted in 0.9% sodium chloride injection in polyvinyl chloride (PVC) infusion bag to give a total volume of 100 mL (colistin 1.5 mg/mL). Secondary drugs, including cefoperazone-sulbactam, ceftazidime, ertapenem, fosfomycin, imipenem-cilastatin, linezolid, meropenem, piperacillin-tazobactam, and vancomycin, were reconstituted if necessary and then diluted in 0.9% sodium chloride injection in PVC infusion bags to give final study concentrations of one-hundredth of their initial concentrations. The admixtures were collected in beakers at the end of the i.v. line and stored at 26 °C under constant fluorescent light throughout the study. Compatibility was assessed visually during delivery of each drug pair at time 0 and at 1 hour after starting the infusion. Compatibility was defined as the absence of visually detected particulate formation, haze, precipitation, color change, or gas evolution. Each combination was tested in triplicate. RESULTS: No particulate formation or other evidence of incompatibility was found in any of the studied drug combinations when observed immediately after mixing or at 1 hour. No particulate matter was observed with the unaided eyes, during microscopic evaluation, or against black and white backgrounds. CONCLUSION: Colistin 1.5 mg/mL was visually compatible with single concentrations of 9 other antimicrobial products during simulated Y-site injection at 26 °C without light protection for at least 1 hour.

Determination of the spatiotemporal dependence of Pseudomonas aeruginosa biofilm viability after treatment with NLC-colistin.

The emergence of colistin-resistant Pseudomonas aeruginosa in cystic fibrosis (CF) patients, particularly after long-term inhalation treatments, has been recently reported. Nanoen-capsulation may enable preparations to overcome the limitations of conventional pharmaceutical forms. We have determined the time-dependent viability of P. aeruginosa biofilms treated with both free and nanoencapsulated colistin. We also examined the relationship between the optimal anti-biofilm activity of nanostructured lipid carrier (NLC)-colistin and the structural organization of the biofilm itself. The results showed the more rapid killing of P. aeruginosa bacterial biofilms by NLC-colistin than by free colistin. However, the two formulations did not differ in terms of the final percentages of living and dead cells, which were higher in the inner than in the outer layers of the treated biofilms. The effective anti-biofilm activity of NLC-colistin and its faster killing effect recommend further studies of its use over free colistin in the treatment of P. aeruginosa infections in CF patients.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

BACKGROUND: Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.This is an update of a Cochrane review first published in 2003, and previously updated in 2006, 2009 and 2014. OBJECTIVES: To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 10 October 2016. SELECTION CRITERIA: We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data. MAIN RESULTS: The search identified 60 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval (CI) 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% CI 0.02 to 0.79).One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence .A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28). Using GRADE, the quality of evidence for outcomes was downgraded to moderate to very low. Downgrading decisions for Pseudomonas aeruginosa eradication and lung function were based on applicability (participants mostly children) and limitations in study design, with imprecision an additional limitation for lung function, growth parameters and adverse effects. AUTHORS' CONCLUSIONS: We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.