Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.

Pharmacological agents for the prevention of colistin-induced nephrotoxicity.

BACKGROUND: Colistin is a polymyxin antibiotic which has been used for treatment of Gram-negative infections, but it was withdrawn due to its nephrotoxicity. However, colistin has gained its popularity in recent years due to the reemergence of multidrug resistant Gram-negative infections and drug-induced toxicity is considered as the main obstacle for using this valuable antibiotic. RESULTS: In total, 30 articles, including 29 animal studies and one clinical trial were included in this study. These compounds, including aged black garlic extract, albumin fragments, alpha lipoic acid, astaxanthin, baicalein, chrysin, cilastatin, colchicine, curcumin, cytochrome c, dexmedetomidine, gelofusine, grape seed proanthocyanidin extract, hesperidin, luteolin, lycopene, melatonin, methionine, N-acetylcysteine, silymarin, taurine, vitamin C, and vitamin E exhibited beneficial effects in most of the published works. CONCLUSIONS: In this review, the authors have attempted to review the available literature on the use of several compounds for prevention or attenuation of colistin-induced nephrotoxicity. Most of the studied compounds were potent antioxidants, and it seems that using antioxidants concomitantly can have a protective effect during the colistin exposure.

Efficacy and Safety of Ceftazidime-Avibactam for the Treatment of Carbapenem-Resistant Enterobacterales Bloodstream Infection: a Systematic Review and Meta-Analysis.

Several clinicians use ceftazidime-avibactam (CAZ-AVI) to treat bloodstream infections (BSIs) due to carbapenem-resistant Enterobacterales (CRE), although no conclusive data support this practice. We aimed to assess the efficacy and safety of CAZ-AVI in the treatment of CRE bacteremia. PubMed, Embase, and Cochrane Library were systematically searched until 5 November 2021. Studies comparing the clinical outcome of CAZ-AVI with other regimens in CRE BSI were included if they reported data on mortality. Results were expressed as risk ratios (RRs) or mean differences with accompanying 95% confidence intervals (95% CIs). Eleven articles with 1,205 patients were included. CAZ-AVI groups showed a significantly lower 30-day mortality than control groups of other regimens (RR = 0.55, 95% CI of 0.45 to 0.68, P < 0.00001). The result is robust when a colistin-based regimen serves as the control group (RR = 0.48, 95% CI 0.33 of 0.69, P < 0.0001). In subgroup meta-analyses, the 30-day mortality was significantly lower in patients infected with CRE producing Klebsiella pneumoniae carbapenemase (RR = 0.59, 95% CI of 0.46 to 0.75, P < 0.0001). Additionally, patients in CAZ-AVI groups had a significantly higher clinical cure rate (RR = 1.75, 95% CI of 1.57 to 2.18, P < 0.00001) and lower nephrotoxicity rate (RR = 0.41, 95% CI of 0.20 to 0.84, P = 0.02). No significant differences of relapse rates were demonstrated in 2 groups (RR = 0.69, 95% CI of 0.29 to 1.66, P = 0.41). Although the current study is based on observational studies with a small sample of participants, the findings suggest that CAZ-AVI treatment is effective and safe compared with other antibiotics, including colistin, in CRE BSI. IMPORTANCE Ceftazidime-avibactam (CAZ-AVI) has been used as a frontline agent in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections. However, the efficacy and safety of CAZ-AVI on carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) remain unclear. Patients with CRE BSIs were often enrolled in small-sized clinical studies, together with other sites of infections, which reported pooled results. In this meta-analysis, the efficacy and safety were compared between CAZ-AVI and any other regimens used against CRE infections. The findings suggest that patients in the CAZ-AVI group had a significantly lower 30-day mortality than any other regimens and than colistin-based regimens. This paper provides a rationale for the use of CAZ-AVI in one of the most urgent antimicrobial-resistant infections of CRE bloodstream infections.

Ceftolozane/tazobactam versus colistin in the treatment of ventilator-associated pneumonia due to extensively drug-resistant Pseudomonas aeruginosa.

Resistant strains of Pseudomonas aeruginosa are common pathogens in the intensive care unit (ICU), limiting available therapeutic options. We aimed to compare ceftolozane/tazobactam (C/T) with colistimethate sodium (CMS) in the treatment of ventilator-associated pneumonia (VAP) due to extensively drug-resistant (XDR) Pseudomonas aeruginosa. A retrospective, observational study was performed at a tertiary care ICU. Clinical and microbiological success rate, 28-day all-cause mortality, and adverse events were compared in patients who received C/T with those treated with systemic CMS. A total of 51 patients were included (18 in the C/T and 33 in the CMS group). Clinical success rates in the C/T and CMS groups were 13 (72.2%) and 10 (30.3%), respectively. On multivariate regression analysis, treatment with C/T was independently associated with clinical success (odds ratio 4.47, 95% CI 1.17-17.08). There was no difference in 28-day all-cause mortality (27.8% and 33.3% in the C/T and CMS group, p = 0.76). Acute kidney injury was more common in patients who received CMS (48.5% vs 11.1%, p = 0.01). In our study, ceftolozane/tazobactam was more efficacious in the treatment of XDR Pseudomonas aeruginosa VAP and showed a better safety profile compared to CMS.

Ceftolozane-tazobactam vs. colistin for the treatment of infections due to multidrug-resistant Pseudomonas aeruginosa: a multicentre cohort study.

OBJECTIVES: The aim of this study was to compare the safety and effectiveness of ceftolozane-tazobactam (C-T) to colistin-based regimen for treating infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa. METHODS: This was a retrospective, multicentre, observational cohort study of inpatients who received either C-T or intravenous colistin for treating infections caused by MDR P. aeruginosa. The study was conducted in five tertiary care hospitals in Saudi Arabia. The main study outcomes included clinical cure at end of treatment, in-hospital mortality, and acute kidney injury (AKI). Univariate analysis and multivariate logistic regression model were conducted to evaluate the independent effect of C-T on the clinical outcome. RESULTS: A total of 184 patients were included in the study: 82 patients received C-T, and 102 patients received colistin-based regimen. Clinical cure (77% vs. 57%; P = 0.005; OR, 2.52; 95% CI, 1.32-4.79) was significantly more common in patients who received C-T. After adjusting the difference between the two groups, treatment with C-T is independently associated with clinical cure (adjusted OR, 2.47; 95% CI, 1.16-5.27). In-hospital mortality (39% vs. 49%; P = 0.175; OR, 0.67; 95% CI, 0.37-1.20) was lower in patients who received C-T, but the difference was not significant. AKI (15% vs. 41%; P < 0.001; OR, 0.25; 95% CI, 0.12-0.51) was significantly less common in patients who received C-T. CONCLUSION: C-T is associated with a higher rate of clinical cure and lower rate of AKI compared to colistin. Our findings support the preferential use of C-T over colistin-based regimen for treating these infections.

Amikacin for the treatment of carbapenem-resistant Klebsiella pneumoniae infections: clinical efficacy and toxicity.

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) are an increasing global threat with limited therapeutic options. Our objective was to evaluate clinical and microbiological outcomes of patients treated with amikacin for CRKp infections. We did a retrospective cohort of patients > 18 years old, with CRKp infections treated with amikacin in two tertiary care hospitals in Porto Alegre, Brazil. The impact of clinical factors, antibiotic treatment, and amikacin minimum inhibitory concentration (MIC) on patients' 30-day mortality was assessed. Microbiological clearance and nephrotoxicity (assessed by RIFLE score) were evaluated as secondary outcomes. A Cox regression analysis was done for mortality. We included 84 patients for analysis. Twenty-nine (34.5%) patients died in 30 days. Amikacin MIC values ranged from 0.125 to 8 µg/mL and did not influence on mortality, regardless of the prescribed dose of this antibiotic (P = 0.24). Bacterial clearance occurred in 17 (58.6%) of 29 patients who collected subsequent cultures. Two (16.6%) of the 12 persistently positive cultures changed the amikacin susceptibility profile from susceptible to intermediate. Twenty-nine (37.2%) patients developed acute kidney injury (AKI): risk 13, injury 11, and failure 5. Risk factors for AKI were higher baseline eGFR (P < 0.01) and combination therapy with colistin (P = 0.02). Comparing patients who received combination with colistin vs polymyxin B, AKI occurred in 60.0% vs 20.6%, respectively, P < 0.01. Fifteen of the 16 (16.6%) patients who developed renal injury or failure were receiving colistin. In conclusion, amikacin was an effective treatment for CRKp infections. Within susceptible range, amikacin MIC values did not influence on clinical outcomes. Combination therapy of amikacin and colistin was highly nephrotoxic and should be used with caution.

Molecular characteristics of carbapenem-resistant Acinetobacter spp. from clinical infection samples and fecal survey samples in Southern China.

BACKGROUND: Carbapenem resistance among Acinetobacter species has become a life-threatening problem. As a last resort in the treatment of gram-negative bacteria infection, resistance to colistin is also a serious problem. The aim of study was to analyze the mechanism of resistance and perform genotyping of carbapenem-resistant Acinetobacter from clinical infection and fecal survey samples in Southern China. METHODS: One hundred seventy and 74 carbapenem-resistant Acinetobacter were isolated from clinical infection samples and fecal survey samples, respectively. We detected the related genes, including carbapenemase genes (blaKPC, blaIMP, blaSPM, blaVIM, blaNDM, blaOXA-23-like, blaOXA-24/40-like, blaOXA-51-like, and blaOXA-58-like), colistin resistance-related genes (mcr-1, mcr-2, mcr-3, mcr-4, and mcr-5), a porin gene (carO), efflux pump genes (adeA, adeB, adeC, adeI, adeJ, and adeK), mobile genetic element genes (intI1, intI2, intI3, tnpU, tnp513, IS26, ISAba1, and ISAba125), and the integron variable region. Genotyping was analyzed by enterobacterial repetitive intergenic consensus (ERIC)-PCR and dendrogram cluster analysis. RESULTS: Among the 244 carbapenem-resistant Acinetobacter, the common carbapenemase-positive genes included the following: blaOXA-51-like, 183 (75.00%); blaOXA-23-like, 174 (71.30%); blaNDM-1, 57 (23.40%); and blaOXA-58-like, 30 (12.30%). The coexistence of mcr-1 and blaNDM-1 in five strains of A. junii was found for the first time. Eleven distinct carO gene variants were detected in 164 (67.20%) strains, and ten novel variants, which shared 92-99% identity with sequences in the Genbank database, were first reported. Efflux system genes were present in approximately 70% of the isolates; adeABC and adeIJK were observed in 76.23 and 72.13%, respectively. Class 1 integrons were detected in 180 (73.80%) strains and revealed that four gene cassette arrays contained 11 distinct genes. The genotyping by ERIC-PCR demonstrated a high genetic diversity of non-baumannii Acinetobacter, and greater than 90% similarity to A. baumannii. CONCLUSIONS: The blaNDM-1 gene was identified in up to 77% of the carbapenem-resistant Acinetobacter isolated from fecal survey samples, indicating that the gut might be a reservoir of resistant opportunistic bacteria. Intestinal bacteria can be transmitted through the fecal-hand, which is a clinical threat, thus, the monitoring of carbapenem-resistant bacteria from inpatients' feces should be improved, especially for patients who have been using antibiotics for a long time.

Relative potency of different generic brands of meropenem, colistin and fosfomycin: Implications for antimicrobial therapy and antimicrobial formulary.

There is a need of a relatively simple and inexpensive method for the determination of relative potency of various generic brands of antibiotics in comparison to original products. The current study describes an agar diffusion method which can be performed in any microbiology laboratory, is cheap (costs $2 per test) and its results can be available after overnight incubation. The results show that neither all generics are reliable nor are all generic antibiotics of poor quality.

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.

Retrospective analysis of colistin-resistant bacteria in a tertiary care centre in India.

The incidence of carbapenem-resistant Enterobacteriaceae has been steadily rising. The morbidity, mortality and financial implications of such patients are significant. We did a retrospective analysis of the case records of 11 patients who had culture report positive for pan drug-resistant (PDR) organisms. There were total 15 isolates of PDR organisms in 11 patients. These were associated with catheter-associated urinary tract infections (7), tracheitis (4), bacteraemia (2), meningitis (1) and soft-tissue infection (1). Average APACHE II score was 23.72 (range 7-36) indicating patients with multiple co-morbidities and organ dysfunction. The average length of hospital stay was 60.72 (25-123) days. The overall mortality rate was 81.81 per cent, while PDR infection-related mortality was 18.18 per cent. Strict implementation of antibiotic stewardship programme is essential to limit use and prevent abuse of colistin.

The aqueous extract of aged black garlic ameliorates colistin-induced acute kidney injury in rats.

The use of colistin in the treatment of multidrug-resistant Gram-negative bacterial infections is restricted due to nephrotoxicity. We investigated the effects of aged black garlic extract (ABGE) on colistin-induced kidney injury in rats. Rats were assigned to four groups. Normal saline was intraperitoneally and intragastrically injected for control group. ABGE was intragastrically injected for garlic group. Ten mg/kg of colistin was intraperitoneally injected for 6 consecutive days for colistin group. One percent of ABGE was done 30 min prior to colistin injection for treatment group. Rats were sacrificed on the next day after last colistin injection. Colistin injection increased the serum levels of blood urea nitrogen and creatinine; however, ABGE prevented deterioration of these serum levels. ABGE also alleviated tubular damage, including vacuolation and necrosis. TUNEL-positive cells were observed less frequently for the ABGE-treated groups. CD68 positive cells were significantly decreased by pretreatment with ABGE. Levels of oxidative stress biomarkers such as 8-hydroxydeoxyguanosine and malondialdehyde were lower in the ABGE-treated groups. Levels of NF-κB, inducible NO synthase, COX-2, and TGF-ß1 were lower in rats that had been treated with ABGE injection. Renal levels of IL-1ß and TNF-α were increased by colistin administration whereas renal SOD, catalase, and GSH levels were restored by ABGE administration. These results suggest that ABGE, which has antioxidant and anti-inflammatory properties, might be a potential therapeutic agent to prevent renal toxicity of colistin.

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.

Collateral damage of using colistin in hospitalized patients on emergence of colistin-resistant Escherichia coli and Klebsiella pneumoniae colonization and infection.

Background: Colistin has been used for therapy of carbapenem-resistant Gram-negative infections in Thailand, especially carbapenem-resistant A. baumannii and P. aeruginosa, for more than 10 years. However, the prevalence of colistin-resistant A. baumannii or P. aeruginosa is still less than 5%. Colistin-resistant Enterobacteriaceae has been increasingly reported globally over the past few years and the use of colistin in food animals might be associated with an emergence of colistin resistance in Enterobacteriaceae. This study aimed to determine the effect of colistin exposure in hospitalized patients who received colistin on development of colistin-resistant (CoR) Escherichia coli (EC) or Klebsiella pneumoniae (KP) colonization and infection. Methods: A prospective observational study was performed in adult hospitalized patients at Siriraj Hospital who received colistin for treatment of infections during December 2016 and November 2017. The surveillance culture samples were collected from the stool and the site of infection of each patient who received colistin at the study enrollment, days 3 and 7 after the study enrollment, and once a week thereafter for determination of CoR EC and CoR KP. CoR EC and CoR KP were also tested for a presence of mcr-1 gene. Results: One hundred thirty-nine patients were included. Overall prevalence of CoR EC or CoR KP colonization was 47.5% among 139 subjects. Prevalence of CoR EC or CoR KP colonization was 17.3% of subjects at study enrollment, and 30.2% after study enrollment. Use of fluoroquinolones, aminoglycosides, and colistin was found to be significantly associated with CoR EC or CoR KP colonization. The mcr-1 gene was detected in 13.0% of CoR EC or CoR KP isolates, and in 27.3% of subjects with CoR EC or CoR KP colonization. CoR EC or CoR KP colonization persisted in 65.2% of the subjects at the end of the study. Five patients with CoR KP infections received combination antibiotics and they were alive at hospital discharge. Conclusions: Prevalence of CoR EC or CoR KP colonization in hospitalized patients receiving colistin was high and it was associated with the use of colistin. Therefore, patients who receive colistin are at risk of developing CoR EC or CoR KP colonization and infection.

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.

Comparative efficacy and safety of treatment options for MDR and XDR Acinetobacter baumannii infections: a systematic review and network meta-analysis.

OBJECTIVES: To comprehensively compare and rank the efficacy and safety of available treatment options for patients with MDR and XDR Acinetobacter baumannii (AB) infection. METHODS: We searched PubMed, Embase and the Cochrane register of trials systematically for studies that examined treatment options for patients with MDR- and XDR-AB infections until April 2016. Network meta-analysis (NMA) was performed to estimate the risk ratio (RR) and 95% CI from both direct and indirect evidence. Primary outcomes were clinical cure and microbiological cure. Secondary outcomes were all-cause mortality and nephrotoxic and non-nephrotoxic adverse events. RESULTS: A total of 29 studies with 2529 patients (median age 60 years; 65% male; median APACHE II score 19.0) were included. Although there were no statistically significant differences between treatment options, triple therapy with colistin, sulbactam and tigecycline had the highest clinical cure rate. Colistin in combination with sulbactam was associated with a significantly higher microbiological cure rate compared with colistin in combination with tigecycline (RR 1.23; 95% CI 1.03-1.47) and colistin monotherapy (RR 1.21; 95% CI 1.06-1.38). No significant differences in all-cause mortality were noted between treatment options. Tigecycline-based therapy also appeared less effective for achieving a microbiological cure and is not appropriate for treating bloodstream MDR- and XDR-AB infections. CONCLUSIONS: Combination therapy of colistin with sulbactam demonstrates superiority in terms of microbiological cure with a safety profile similar to that of colistin monotherapy. Thus, our findings support the use of this combination as a treatment for MDR- and XDR-AB infections.

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.

Clinical translation of polymyxin-based combination therapy: Facts, challenges and future opportunities.

The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy.

Colistin-associated Acute Kidney Injury in Severely Ill Patients: A Step Toward a Better Renal Care? A Prospective Cohort Study.

BACKGROUND: Critically ill patients with severe sepsis or septic shock may need relatively high colistin daily doses for efficacy against multidrug-resistant and extensively drug-resistant gram-negative rods. However, acute kidney injury (AKI) may represent a major dose-limiting adverse effect of colistin. We sought to determine AKI occurrence and to identify factors influencing AKI risk in severely ill patients receiving colistin according to a recently proposed dosing strategy. METHODS: A prospective, observational, cohort study involving patients with severe sepsis or septic shock who received colistin was performed. AKI was defined according to Acute Kidney Injury Network criteria. Colistin administration was driven by a modified pharmacokinetics-pharmacodynamics (PK/PD)-based dosing approach. RESULTS: Of 70 patients who received colistin at a median daily dose of 9 million IU (MIU; interquartile range, 5.87-11.1 MIU), 31 (44%) developed AKI. In univariate analysis, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA), score and baseline renal impairment were significantly associated with AKI. Moreover, patients with AKI were less frequently treated with adjuvant ascorbic acid (P = .003). In multivariate analysis, independent predictors of AKI were baseline renal impairment (adjusted hazard ratio, 4.15; 95% confidence interval, 1.9-9.2; P < .001) and age (1.03; 1.0-1.05; P = .028), whereas a strong independent renal-protective role emerged for ascorbic acid (0.27; .12-.57; P < .001). CONCLUSIONS: In severely ill patients receiving colistin according to a PK/PD-driven dosing approach, baseline renal impairment and older age strongly predict AKI occurrence, but concomitant administration of ascorbic acid markedly reduces AKI risk, allowing safer use of colistin.