High-Dose Nebulized Colistin Methanesulfonate and the Role in Hospital-Acquired Pneumonia Caused by Gram-Negative Bacteria with Difficult-to-Treat Resistance: A Review.

Hospital-acquired pneumonia, including ventilator-associated pneumonia (VAP) due to difficult-to-treat-resistant (DTR) Gram-negative bacteria, contributes significantly to morbidity and mortality in ICUs. In the era of COVID-19, the incidences of secondary nosocomial pneumonia and the demand for invasive mechanical ventilation have increased dramatically with extremely high attributable mortality. Treatment options for DTR pathogens are limited. Therefore, an increased interest in high-dose nebulized colistin methanesulfonate (CMS), defined as a nebulized dose above 6 million IU (MIU), has come into sight. Herein, the authors present the available modern knowledge regarding high-dose nebulized CMS and current information on pharmacokinetics, clinical studies, and toxicity issues. A brief report on types of nebulizers is also analyzed. High-dose nebulized CMS was administrated as an adjunctive and substitutive strategy. High-dose nebulized CMS up to 15 MIU was attributed with a clinical outcome of 63%. High-dose nebulized CMS administration offers advantages in terms of efficacy against DTR Gram-negative bacteria, a favorable safety profile, and improved pharmacokinetics in the treatment of VAP. However, due to the heterogeneity of studies and small sample population, the apparent benefit in clinical outcomes must be proven in large-scale trials to lead to the optimal use of high-dose nebulized CMS.

Challenge for higher colistin dosage in critically ill patients receiving continuous venovenous haemodiafiltration.

Traditionally, reduced daily doses of colistin methanesulphonate (CMS) in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF) have resulted in suboptimal colistin concentrations. The necessity of a loading dose (LD) at treatment initiation has been proposed. A LD of 9 million IU (MU) [ca. 270 mg of colistin base activity (CBA)] was administrated with a maintenance dose of 4.5 MU (ca. 140 mg CBA) every 12 h (q12h) to eight critically ill patients receiving renal replacement therapy. Blood samples were collected immediately before and at different time intervals after the LD and the fourth dose, whilst pre-filter and post-filter blood samples were also collected. CMS and colistin concentrations were determined using an LC-MS/MS assay. Median maximum observed concentrations after the LD were 22.1 mg/L for CMS and 1.55 mg/L for colistin, whereas during maintenance dosing the corresponding values were 12.6 mg/L and 1.72 mg/L, respectively. CVVHDF clearance was determined as 2.98 L/h for colistin, equivalent to 62% of total apparent colistin clearance in CVVHDF patients. Both CMS and colistin were cleared by CVVHDF. Application of a LD of 9 MU CMS resulted in more rapid achievement of the target colistin concentration. Following implementation of a predicted pharmacokinetic model on plasma CMS/colistin concentrations, a LD of 12 MU CMS appears more appropriate, whilst a CMS maintenance dosage of at least 6.5-7.5 MU q12h is suggested in patients undergoing CVVHDF. However, further clinical studies are warranted to assess the safety of a LD of 12 MU CMS in patients receiving CVVHDF.

Pharmacokinetics of inhaled colistimethate sodium (CMS) in mechanically ventilated critically ill patients.

PURPOSE: The purpose of this study was to describe inhaled colistin pharmacokinetics in patients with ventilator-associated tracheobronchitis (VAT) due to polymyxin-only susceptible Gram-negative bacteria (GNB). METHODS: Inhaled colistimethate sodium (CMS) was administered at a dose of 80 mg every 8 h for 7 days. Mini bronchoalveolar lavage (BAL) was performed before and at 1, 4 and 8 h, while blood samples were collected before and at 0.16, 0.5, 1, 2, 4 and 8 h after the first dose. Colistin concentrations in BAL and serum were determined by high-performance liquid chromatography. RESULTS: Our study population included 20 patients. At the end of treatment, cure was achieved in 16 patients and favorable microbiological response in 12 patients. Median (25-75 % interquartile range) colistin concentrations in epithelial lining fluid (ELF) were 6.7 (4.8-10.1), 3.9 (2.5-6.0) and 2.0 (1.0-3.8) µg/ml at 1, 4 and 8 h, respectively, and fivefold higher than those achieved in serum. Median ELF concentrations at 1 and 4 h were above the minimum inhibitory concentrations of all isolated pathogens; however, the 4-h median was below the European Committee on Antimicrobial Susceptibility Guidelines (EUCAST) breakpoints for Pseudomonas aeruginosa and the 8-h median was low relative to EUCAST breakpoints for all GNB. Colistin pharmacokinetic/pharmacodynamic parameters in ELF were associated with favorable microbiological response at the end of treatment. CONCLUSION: Inhaled colistin may achieve high drug concentrations in the lung. However, a dose of 80 mg of inhaled CMS every 8 h may not be adequate for the treatment of lower respiratory tract infections due to multi-drug resistant GNB.

Outcome of antimicrobial therapy in documented biofilm-associated infections: a review of the available clinical evidence.

Numerous laboratory findings indicate that microbial biofilms may be encountered in several types of human infections, affecting the activity of antimicrobial agents. We evaluated the clinical evidence regarding the effectiveness of antimicrobial therapy for infections documented to be biofilm-associated, by performing a review of 15 relevant studies, excluding dental and eye infections. In a clinical trial, a significant difference was noted in the effectiveness of antibacterial agents used for catheter-related urinary tract infections in which substantial bacterial adherence on uroepithelial cells was observed. In case series and case reports, 28 patients with biofilm-associated infections documented by electron microscopy scanning were identified. Infection sites included ear, urinary tract, CNS, bloodstream and foreign body implantation site. Pseudomonas and Staphylococcus spp. were the predominant microorganisms among the bacterial or fungal causative pathogens. In 24 cases, infections related to the presence of foreign bodies. Treatment failure or recurrence was noted in all eight patients in whom targeted antimicrobial therapy was instituted before foreign body removal. Foreign body removal coupled with antimicrobial therapy was effective in all ten relevant cases. In four cases of native tissue urinary tract infections, the outcome of the initial antimicrobial therapy was poor. The limited available relevant clinical evidence indicates that conventional antimicrobial therapy alone is not adequately effective against documented biofilm-associated infections. Although some regimens might be more appropriate in this setting, further research on novel therapeutic strategies is needed to improve the outcome of patients with biofilm-associated infections.

Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials.

BACKGROUND: We investigated whether the use of respiratory fluoroquinolones was associated with better clinical outcomes compared with the use of macrolides and beta- lactams among adults with pneumonia. METHODS: We searched PubMed, Current Contents, Scopus, EMBASE, ClinicalTrials.gov and Cochrane with no language restrictions. Two reviewers independently extracted data from published trials that compared fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin) with macrolides or beta-lactams or both. A meta-analysis was performed with the clinical outcomes of mortality, treatment success and adverse outcomes. RESULTS: We included 23 trials in our meta-analysis. There was no difference in mortality among patients who received fluoroquinolones or the comparator antibiotics (OR 0.85, 95% CI 0.65-1.12). Pneumonia resolved in more patients who received fluoroquinolones compared with the comparator antibiotics for the included outcomes in the intention-to-treat population (OR 1.17, 95% CI 1.00-1.36), clinically evaluable population (OR 1.26, 95% CI 1.06-1.50) and the microbiologically assessed population (OR 1.67, 95% CI 1.28-2.20). Fluoroquinolones were more effective than a combination of beta-lactam and macrolide (OR 1.39, 95% CI 1.02-1.90). They were also more effective for patients with severe pneumonia (OR 1.84, 95% CI 1.02-3.29), those who required admission to hospital (OR = 1.30, 95% CI 1.04-1.61) and those who required intravenous therapy (OR = 1.44, 15% CI 1.13-1.85). Fluoroquinolones were more effective than beta-lactam and macrolide in open-label trials (OR = 1.35, 95% CI 1.08-1.69) but not in blinded randomized controlled trials (OR = 1.13, 95% CI 0.85-1.50). INTERPRETATION: Fluoroquinolones were associated with higher success of treatment for severe forms of pneumonia; however, a benefit in mortality was not evident. A randomized controlled trial that includes patients with severe pneumonia with or without bacteremia is needed.

Early switch to oral treatment in patients with moderate to severe community-acquired pneumonia: a meta-analysis.

BACKGROUND: Early switch to oral antibacterials is recommended for the treatment of hospitalized patients with community-acquired pneumonia (CAP). However, its efficacy and safety in patients with more severe forms of CAP have not been well established. OBJECTIVE: To evaluate early switch to oral treatment in hospitalized patients with moderate to severe CAP. METHODS: Two reviewers independently extracted data from relevant randomized controlled trials (RCTs) with the same total duration of antibacterial treatment in the compared groups (early switch from intravenous to oral and conventional intravenous treatment for the whole duration of therapy). RESULTS: Six RCTs including 1219 patients fulfilled the criteria for inclusion in the meta-analysis. Treatment success was not different between early switch to oral treatment and intravenous only treatment groups in both intention to treat (odds ratio [OR] 0.76; 95% CI 0.36, 1.59) and clinically evaluable patients (OR 0.92; 95% CI 0.61, 1.39). Mortality and recurrence of CAP were not different (OR 0.81; 95% CI 0.49, 1.33 and OR 1.81; 95% CI 0.70, 4.72, respectively), while duration of hospitalization was shorter (weight mean difference -3.34; 95% CI -4.42, -2.25) and drug-related adverse events were fewer in the early switch group (OR 0.65; 95% CI 0.48, 0.89). Findings were similar in patients with severe CAP. CONCLUSIONS: Early conversion to oral antibacterials seems to be as effective as continuous intravenous treatment in patients with moderate to severe CAP and results in substantial reduction in duration of hospitalization.

Short- versus long-course antibacterial therapy for community-acquired pneumonia : a meta-analysis.

BACKGROUND: The evidence for traditionally recommended 7- to 14-day duration of antibacterial therapy for community-acquired pneumonia (CAP) is not well established. OBJECTIVES: We endeavoured to assess the effectiveness and safety of shorter than traditionally recommended antibacterial therapy for CAP. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) comparing short- (< or = 7 days) versus long- (> or = 2 days difference) course therapy for CAP with the same antibacterial regimens, in the same daily dosages. RESULTS: Five RCTs involving adults (including outpatients and inpatients who did not require intensive care) and two RCTs involving children (aged 2-59 months, residing in developing countries) were included. All RCTs were double-blind and assessed patients with CAP of mild to moderate severity. No differences were found between short- (adults 3-7 days; children 3 days) and long- (adults 7-10 days; children 5 days) course regimens (adults - amoxicillin, cefuroxime, ceftriaxone, telithromycin and gemifloxacin; children - amoxicillin) regarding clinical success at end-of-therapy (six RCTs; 5107 patients [1095 adults, 4012 children]; fixed-effect model [FEM]; odds ratio [OR] = 0.89; 95% CI 0.74, 1.07), clinical success at late follow-up, microbiological success, relapses, mortality (seven RCTs; 5438 patients; FEM; OR = 0.57; 95% CI 0.23, 1.43), adverse events (five RCTs; 3214 patients; FEM; OR = 0. 90; 95% CI 0.72, 1.13) or withdrawals as a result of adverse events. No differences were found in subset analyses of adults or children, and of patients treated with no more than 5-day short-course regimens versus at least 7-day long-course regimens. CONCLUSION: No difference was found in the effectiveness and safety of short- versus long-course antimicrobial treatment of adult and paediatric patients with CAP of mild to moderate severity.

Administration of antibiotics via the respiratory tract as monotherapy for pneumonia.

There is increasing interest in applying alternatives to the systemic modes of administration of antimicrobial agents for the treatment of patients with pneumonia. We endeavored to accumulate and evaluate the published evidence on the role of aerosolized antimicrobials administered as monotherapy for patients with pneumonia through searches of PubMed, Scopus and relevant bibliographies. Seven relevant studies (one randomized controlled trial, four case series and two case reports), including 63 patients, were identified; 37% (23 out of 63) and 63% (40 out of 63) of these patients suffered from community-acquired and nosocomial (including ventilator-associated) pneumonia, respectively. Acinetobacter baumannii (41%), Gram-positive cocci (37%) and Pseudomonas aeruginosa (16%) were the pathogens most frequently isolated from sputum, tracheal aspirates, bronchoalveolar lavage and bronchial brush specimens. Colistin (49%), penicillin (37%) and aminoglycosides (17%) were the antimicrobials administered via the respiratory tract. Concurrent systemic antimicrobials (without activity against the isolated pathogens) were given to 33% (21 out of 63) of patients. Clinical cure and bacteriological eradication from the aforementioned specimens were observed in 86% (54 out of 63) and 85% (33 out of 39) of patients, respectively. For the 31 patients for whom data were available, all-cause mortality and attributable mortality were 36% (11 out of 31) and 10% (three out of 31), respectively. The very limited published data preclude any strong conclusions; however, the available data seem to suggest that aerosolized antimicrobial monotherapy for pneumonia should not be a priori excluded when systemic access is unavailable, denied by the patient or when concerns exist regarding bioavailability in the lungs or systemic toxicity. Clinicians are encouraged to publish any relevant experience in order for a considerable body of literature to be accumulated.

Frequency and predictors of ventilator-associated pneumonia recurrence: a meta-analysis.

Large clinical series focusing on the risk factors associated with recurrence after the onset of an initial episode of ventilator-associated pneumonia (VAP) produced inconsistent results. A meta-analysis would be helpful to shed light on the issue. Our objective was to estimate the frequency of VAP recurrence and to identify risk factors associated with it. PubMed, Scopus, Current Contents, and references of retrieved articles were searched without language restrictions. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using both the Mantel-Haenszel fixed-effect and the DerSimonian-Laird random effects models. The overall frequency of VAP recurrence in 969 patients of the seven eligible reports was 26.8%. Among the 20 evaluated risk factors, only acute lung injury/acute respiratory distress syndrome (OR, 1.76; 95% CI, 1.12-2.75) and shock (OR, 1.55; 95% CI, 1.01-2.41) at the day of diagnosis of the first VAP episode were found to be associated with VAP recurrence. There was also evidence, albeit inconsistent, that severity of illness at intensive care unit admission was associated with VAP recurrence. Recurrence involves almost one in four cases of VAP and is associated with acute lung injury/acute respiratory distress syndrome and shock, but not with first-episode causative pathogens. Recognition of these predictors may permit the timely implementation of measures to prevent recurrence of VAP.