Colistin Loading Dose Research Articles

High-Loading-Dose Colistin with Nebulized Administration for Carbapenem-Resistant Acinetobacter baumannii Pneumonia in Critically Ill Patients: A Retrospective Cohort Study.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections pose a serious threat, with high morbidity and mortality rates. This retrospective cohort study, conducted at Nakornping Hospital between January 2015 and October 2022, aimed to evaluate the efficacy and safety of a high loading dose (LD) of colistin combined with nebulized colistin in critically ill patients with CRAB pneumonia. Of the 261 patients included, 95 received LD colistin, and 166 received LD colistin with nebulized colistin. Multivariate Cox regression analysis, adjusted for baseline covariates using inverse probability weighting, showed no significant difference in 30-day survival between patients who received LD colistin and those who received LD colistin with nebulized colistin (adjusted hazard ratio [aHR]: 1.17, 95% confidence interval [CI]: 0.80-1.72, p = 0.418). Likewise, there were no significant differences in clinical response (aHR: 0.93, 95% CI: 0.66-1.31, p = 0.688), microbiological response (aHR: 1.21, 95% CI: 0.85-1.73, p = 0.279), or nephrotoxicity (aHR: 1.14, 95% CI: 0.79-1.64, p = 0.492) between the two treatment groups. No significant adverse events related to nebulized colistin were reported. These findings suggest that the addition of nebulized colistin may not offer additional benefits in terms of 30-day survival, clinical or microbiological response, or nephrotoxicity in these patients.

The necessity of a loading dose when prescribing intravenous colistin in critically ill patients with CRGNB-associated pneumonia: a multi-center observational study

BackgroundThe importance or necessity of a loading dose when prescribing intravenous colistin has not been well established in clinical practice, and approximate one-third to half of patients with carbapenem-resistant gram-negative bacteria (CRGNB) infection did not receive the administration of a loading dose. The aim of this study is to investigate the efficacy and risk of acute kidney injury when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.MethodsThis was a multicenter, retrospective study that recruited ICU-admitted patients who had CRGNB-associated nosocomial pneumonia and were treated with intravenous colistin. Then, we classified the patients into colistin loading dose (N = 85) and nonloading dose groups (N = 127). After propensity-score matching for important covariates, we compared the mortality rate, clinical outcome and microbiological eradication rates between the groups (N = 67).ResultsThe loading group had higher percentages of patients with favorable clinical outcomes (55.2% and 35.8%, p = 0.037) and microbiological eradication rates (50% and 27.3%, p = 0.042) at day 14 than the nonloading group. The mortality rates at days 7, 14 and 28 and overall in-hospital mortality were not different between the two groups, but the Kaplan–Meier analysis showed that the loading group had a longer survival time than the nonloading group. Furthermore, the loading group had a shorter length of hospital stay than the nonloading group (52 and 60, p = 0.037). Regarding nephrotoxicity, there was no significant difference in the risk of developing acute kidney injury between the groups.ConclusionsThe administration of a loading dose is recommended when prescribing intravenous colistin for critically ill patients with nosocomial pneumonia caused by CRGNB.

Colistin Loading Dose in Septic Patients with Gram Negative Infections.

PurposeIntravenous (IV) colistin is commonly used to treat multidrug-resistant gram-negative infections. It is primarily eliminated renally and may induce acute kidney injury (AKI) at a rate of up to 53%. Consequently, septic patients who require colistin administration have an additional risk of developing AKI. The aim of this study is to investigate clinical failure and AKI predictors for septic patients treated with IV colistin.MethodsThis retrospective cohort study was conducted at a tertiary teaching hospital in Saudi Arabia. Adult septic patients with suspected or confirmed gram-negative infections who received colistin admitted to the hospital between May 2016 and December 2020 were screened after obtaining IRB approval. AKI was defined based on the AKI Network criteria. We investigated the incidence of clinical failure based on colistin dosing and AKI risk factors, such as the development of septic shock, severity of illness, and medication co-administration using a multiple logistic regression model.ResultsAfter screening 163 patients, 103 patients were included in the analysis. No difference was observed between the colistin dosing strategies for clinical failure. Of the included predictors, development of septic shock (OR: 3.75; 95% CI 1.18–13.15), carbapenem co-administration (OR, 3.96; 95% CI, 1.134–15.57) were associated with an increased risk of AKI. The other factors were not significant predictors.ConclusionClinical failure was not affected by colistin dosing strategies in our cohort of patients with sepsis. Moreover, the co-administration of carbapenems and the development of septic shock may increase the risk of inducing AKI in adult septic patients treated with IV colistin. Further studies are required to confirm these findings.

Efficacy Assessment of High Dose Colistin against Carbapenem-Resistant Gram-Negative Bacteria (CR-GNB) in Critically Ill Patients: A Retrospective Non-Inferiority Trial

Background: Colistin is an effective treatment option, recommended for carbapenem resistant gram-negative bacilli (CR-GNB) in critically ill patients. Due to high nephrotoxicity, dose management of Colistin is a tough decision to make. At standard dosage the efficacy of Colistin is not well defined. Consequently, strategies involving higher dosages were suggested. Objective: To evaluate the high dose of Colistin as non-inferior to standard dose in the treatment of CR-GNB in critically ill patients. Study Design: Retrospective comparative study Place and Duration of Study: Intensive Care Unit, King Saud Medical City Riyadh, Saudi Arabia from 1st January 2015 to 31st December 2017. Methodology: One hundred and ninety two patients that met the inclusion criteria from all participants were further divided into two groups. Group H (High dose) given the high dose of Colistin (9 million units intravenously (IV) loading dose, and then 9 million units/day in 2 or three divided doses) whereas group S was administered with standard dose (no loading dose, 6 million units/day). The primary endpoint of the study was the assessment of nephrotoxicity after the start of Colistin and secondary endpoints were the mortality within 14 days of commencing Colistin along with clinical effects and microbial clearance upon completion of treatment. Results: The results of the study established the non-inferiority of high dose of Colistin for the renal safety and also showed significant improvement in microbial clearance and length of ICU stay as compared to the standard dose. The other secondary end points such as mortality (p = 0.99), length of hospital stay (p = 0.39), and global improvement (p value of 0.06) revealed no significant difference between the two groups. Conclusion: The high dose of Colistin for the treatment of carbapenem resistance gram negative bacilli (CRGNB) was as safe as the standard dose for renal safety. But we also found that it also accelerates microbial clearance and reduces the time spent in the intensive care unit. Key words: Colistin, Colestimethate sodium, Gram negative bacteraemia, Sepsis, Multi-drug resistant organisms, Acute kidney injury

No increased acute kidney injury rate through giving an intravenous colistin loading dose in pediatric patients

ObjectivesA colistin loading dose is required to achieve adequate drug exposure for the treatment of multidrug-resistant Gram-negative bacteria. However, data on acute kidney injury (AKI) rates associated with this approach in children have been unavailable. The aim of this study was to examine AKI rates in children who were prescribed a colistin loading dose. MethodsA retrospective study was conducted in patients aged 1 month to 18 years who had received intravenous colistin for ≥48 h. Loading dose (LD) was defined as colistin methanesulfonate at 4–5 mg of colistin base activity/kg/dose. AKI was defined according to KDIGO serum creatinine (SCr) criteria — SCr ≥ 1.5 times the baseline, measured 3–7 days after colistin initiation. Augmented renal clearance (ARC) was defined as an estimated glomerular filtration rate (eGFR) >150 mL/min/1.73 m2. The rates of AKI were compared between children receiving or not receiving an LD, and between different eGFR groups. ResultsIn total, 181 children were enrolled. The mean age was 4.3 years (95% confidence interval [CI], 3.6–4.9 years). Ninety-five of the subjects (52.5%) were male. There were 157 children with a baseline eGFR of ≥ 80 mL/min/1.73 m2. The overall AKI rate within the first week in this group was 20.4% (95% CI, 14.4–27.6%): LD, 16.1% vs no LD, 23.2% (p = 0.29). Subgroup analysis, excluding patients with ARC, showed a lower AKI rate of 12.8% (95% CI, 6.8–21.3%): LD, 9.7% vs no LD, 14.3% (p = 0.53). ConclusionsAKI rate was not different among children who received an intravenous colistin loading dose. This approach should be implemented to ensure the necessary drug exposure required for good treatment outcomes.

Colistin co-administration with other nephrotoxins: experience of teaching hospital of Latvia.

Background Colistin is a potentially nephrotoxic antibiotic used for the management of multidrug-resistant bacterial infections in critically ill patients. Co-administration with other nephrotoxins was reported as a potentially modifiable risk factor of colistin acute kidney injury. Objective To establish the role of colistin dosing and co-medications in development of colistin kidney injury. Setting Community teaching hospital in Latvia. Method Adult patients from intensive care units with diagnosed Gram-negative bacterial infections, undergoing colistin treatment for longer than 72h, and not receiving renal replacement therapy were included in this retrospective study. Main outcome measure Colistin nephrotoxicity was defined as an increase in the serum creatinine level by at least 50% from the baseline after ≥ 48h. Results In 73 of 87 cases, Acinetobacter baumannii pneumonia was diagnosed. The nephrotoxicity rate was 27.6% with a median onset of 8days. In 79% of the cases, colistin was co-administrated with at least one potentially nephrotoxic agent. The most used nephrotoxins were loop diuretics (44 cases), non-steroidal anti-inflammatory drugs (19 cases) and vancomycin (11 cases). The use of nephrotoxins was similar in patients with colistin nephrotoxicity (group-1) and without it (group-2). Carbapenems were more common in group-2 (37% vs 62%, p = 0.004) and a colistin loading dose of 9 MU in group-1 (87% vs 62%, p = 0.027). However, in the multifactor regression analysis, the protective role of carbapenems was not confirmed. Conclusion Potentially nephrotoxic agents are commonly co-administrated with colistin. This study failed to prove their role in the development of acute kidney injury.

Intraventricular Tigecycline as a Last Resort Therapy in a Patient with Difficult-to-Treat Healthcare-Associated Acinetobacter baumannii Ventriculitis: a Case Report.

Healthcare-associated ventriculitis and meningitis is a common complication in patients who suffer from head trauma or have undergone a neurosurgery. Healthcare-associated ventriculitis and meningitis is associated with significant morbidity and mortality. Complications of healthcare-associated ventriculitis and meningitis include persistent vegetative state, moderate and severe disability, and death. Acinetobacter baumannii is the causative pathogen in 3.6–11.2% of cases of healthcare-associated ventriculitis and meningitis. Cases of difficult-to-treat healthcare-associated A. baumannii ventriculitis and meningitis are being reported more frequently. However, in most of these cases, a combination of intravenous (IV) and intraventricular (IVT)/intrathecal colistin achieves good therapeutic outcome. This report describes a clinical case of difficult-to-treat healthcare-associated A. baumannii ventriculitis. The A. baumannii strain was sensitive to colistin and trimethoprim-sulfamethoxazole, intermediate to tigecycline, and resistant to other antibiotics. While colistin was the drug of choice in our case, the patient developed anaphylactoid reaction during the IV administration of the loading dose of colistin, which mandated us to discontinue colistin and complicated the treatment of our patient. The patient did not respond to a combination of IV antibiotics that included meropenem, trimethoprim-sulfamethoxazole, and tigecycline. However, when IVT tigecycline was added as a last-resort therapeutic option, the patient’s ventriculitis dramatically improved, and the patient was discharged from the hospital. Physicians who treat patients with healthcare-associated A. baumannii ventriculitis might resort to IVT tigecycline when they run out of therapeutic options.

Efficacy and safety of colistin loading dose: a meta-analysis.

Colistin represents a polypeptide used for the treatment of MDR microorganisms, although the optimal dosing strategy is under investigation. The present meta-analysis aims to determine whether the administration of a colistin loading dose in patients receiving high-dose maintenance regimens changes the rates of treatment success and the risk of nephrotoxicity. Medline, Scopus, CENTRAL, Clinicaltrials.gov and Google Scholar were systematically searched from inception to 18 November 2019. Studies were considered eligible if they reported clinical outcomes among patients receiving high-dose colistin therapy with and without the administration of a loading dose. Meta-analysis was performed by fitting a random-effects model. Eight (three prospective and five retrospective cohort) studies were included, comprising 1115 patients. The administration of a colistin loading dose was associated with significantly higher microbiological [risk ratio (RR) = 1.23, 95% CI = 1.10-1.39] but not clinical (RR = 1.04, 95% CI = 0.87-1.24) success. No significant associations were calculated for nephrotoxicity (RR = 1.31, 95% CI = 0.90-1.91) and mortality (RR = 1.03, 95% CI = 0.82-1.29) risk. The results remained stable after adjustments for small sample size, credibility ceilings, publication bias and risk of bias. Observational evidence suggests that the administration of a colistin loading dose in patients receiving high maintenance dosage regimens is significantly associated with higher rates of microbiological response, but does not change clinical cure, mortality or nephrotoxicity risk. The dosing regimen that would provide the optimal balance between treatment efficacy and safety needs to be determined by future randomized controlled trials.

Greater optimisation of pharmacokinetic/pharmacodynamic parameters through a loading dose of intravenous colistin in paediatric patients

Use of colistin in children is rising in line with the increase of multidrug-resistant Gram-negative bacteria (MDR-GNB). In adults, a colistin loading dose is recommended to achieve therapeutic concentrations within 12-24 h. Here we aimed to describe the pharmacokinetic (PK) parameters of a loading dose versus a recommended initial dose of intravenous colistimethate sodium (CMS) in paediatric patients. A prospective, open-label, PK study was conducted in paediatric patients (age 2-18 years) with normal renal function. Patients (n=20) were randomly assigned to receive either a CMS loading dose (LD group) of 4 mg of colistin base activity (CBA)/kg/dose or a standard initial dose (NLD group) of 2.5 mg (12-h interval) or 1.7 mg (8-h interval) of CBA/kg/dose. Serial blood samples were collected. Plasma concentrations of formed colistin were measured by LC-MS/MS. PK parameters were reported. Acute kidney injury (AKI) was monitored by serum creatinine and urine NGAL. The median (interquartile range) age and body weight were 8.5 (3.5-11.3) years and 21.5 (13.5-20.0) kg. The mean (standard deviation) of first-dose PK parameters of the LD group versus the NLD group were: Cmax, 6.1 (2.4) vs. 4.1 (1.3) mg/L; AUC0-t, 26.5 (12.5) vs. 13.5 (3.6) mg/L·h; Vd, 0.7 (0.4) vs. 0.6 (0.3) L/kg; and t1/2, 2.9 (0.6) vs. 2.6 (0.4) h. No patient developed AKI by serum creatinine criteria. A CMS loading dose is beneficial for improvement of colistin exposure without increased AKI. A higher daily dose of CMS should be considered, especially for MDR-GNB treatment.

Differences in Colistin Administration and Bacterial and Treatment Outcomes in Critically Ill Patients

The desired target steady-state average colistin concentration (Css,avg) to balance between therapeutic effectiveness and nephrotoxicity is largely unclear. The objective of this study was to evaluate the effect of the desired target colistin Css,avg on the effectiveness and safety of IV colistin therapy in critically ill patients. Overall, 153 critically ill patients (71% males) receiving IV colistin were retrospectively analyzed. The desired target colistin Css,avg was estimated based on the daily colistin dose and creatinine clearance of each patient. No significant predictor for clinical cure was identified. However, microbiological outcome was significantly associated with pneumonia compared to bacteremia (odds ratio [OR] 0.092, 95% confidence interval [CI] [0.033–0.251], P < 0.001) and the use of IV colistin loading dose (OR 2.783, 95% CI [1.126–6.880], P = 0.027). Colistin-associated nephrotoxicity was significantly less likely to occur in patients who received inhaled colistin close to the time of IV colistin therapy (OR 0.331, CI [0.119–0.925], P = 0.035). The desired target Css,avg of colistin was not associated with treatment outcomes or the risk of nephrotoxicity. Loading dose and inhaled colistin use near the time of IV colistin therapy may be considered to maximize therapeutic effectiveness and minimize the risk of colistin-associated nephrotoxicity, respectively.

A Randomized Clinical Trial Evaluating the Efficacy of Colistin Loading Dose in Critically Ill Children.

Objective:Pharmacokinetic and clinical studies recommend applying loading dose of colistin for the treatment of severe infections in the critically ill adults. Pharmacokinetic studies of colistin in children also highlight the need for a loading dose. However, there are no clinical studies evaluating the effectiveness of colistin loading dose in children.Methods:In a randomized trial, children with ventilator-associated pneumonia or central line-associated bloodstream infection (CLABSI) for whom colistin was initiated, were enrolled. Patients were randomized into two groups; loading dose and conventional dose treatment arms. In the conventional treatment arm, colistimethate sodium was initiated with maintenance dose. In the loading dose group, colistimethate sodium was commenced with a loading dose of 150,000 international unit/kg, then on the maintenance dose. Both treatment arms also received meropenem as combination therapy. Primary outcomes were overall efficacy, clinical improvement and microbiological cure. Secondary outcomes were colistin-induced nephrotoxicity and development of resistance.Findings:Thirty children completed this study. There was a significantly higher overall efficacy in the group received loading dose (42.9 vs. 6.3%, P = 0.031). There weren’t any significant differences in the clinical and microbiological endpoints. In the subgroup of children with CLABSI, results illustrated a trend toward (though statistically nonsignificant) better clinical cure for patients receiving loading dose.Conclusion:This preliminary study suggests that colistin loading dose might have some benefits in critically ill children, specifically in children with CLABSI. Further trials are required to elucidate colistin best dosing strategy in critically ill children with severe infections.

Inhalation with intravenous loading dose of colistin in critically ill patients with pneumonia caused by carbapenem-resistant gram-negative bacteria.

Background:Despite the increasing use of colistin in clinical practice, the optimal dosing, and administration route have not been established. This study aimed to evaluate the clinical outcome and safety of intravenous (IV) colistin with a loading dose (LD) and adjunctive aerosolized (AS) colistin administration in critically ill patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by carbapenem-resistant gram-negative bacteria (CRGNB).Methods:We retrospectively reviewed 191 critically ill patients who received colistin for the treatment of HAP or VAP caused by CRGNB. Patients were divided into three groups: non-LD IV (patients received only IV colistin without LD), LD IV (patients received only IV colistin with LD), and AS–LD (patients received IV colistin with LD and adjunctive AS colistin).Results:There was no difference in clinical response between the three groups. However, the rate of microbiological eradication was significantly higher in the AS–LD group (60%) than in the non-LD IV (31%), and LD IV (33%) groups (p = 0.010). Patients treated with adjunctive AS colistin in combination with LD IV had significantly lower 30-day mortality rates than patients treated with IV colistin alone (p = 0.027). After adjusting for potential confounding factors, adjunctive AS colistin was still significantly associated with lower mortality (adjusted OR 0.338, CI 95% 0.132–0.864, p = 0.024). However, nephrotoxicity did not change according to the use of LD regimen and AS colistin administration (p = 0.100).Conclusions:Adjunctive AS colistin in combination with IV colistin with LD was related to an improved 30-day mortality and microbiological outcome without an increase in nephrotoxicity in critically ill patients with HAP and VAP caused by CRGNB. The reviews of this paper are available via the supplemental material section.

Interim Study: Comparison Of Safety And Efficacy of Levofloxacin Plus Colistin Regimen With Levofloxacin Plus High Dose Ampicillin/Sulbactam Infusion In Treatment of Ventilator-Associated Pneumonia Due To Multi Drug Resistant Acinetobacter.

Due to the emerging antibiotic resistance of Acinetobacter, which is the leading cause of ventilator-associated pneumonia (VAP) in critically ill patients, there is an urgent need for studies comparing various antibiotic regimens for its treatment. In this single blinded randomized clinical trial, adult patients with VAP due to multi drug resistant Acinetobacter (MDRA), were randomly assigned to receive 9×109 unit loading dose of colistin followed by 4.5×109 unit intravenously twice daily plus 750 mg intravenous levofloxacin daily or continuous infusion of ampicillin/sulbactam, 24g daily plus 750mg IV levofloxacin daily. Dose and dosing interval were adjusted according to serum creatinine levels during the study. Clinical and microbiological cure, inflammatory biomarkers, and possible adverse effects were recorded in participants. Twenty-nine patients were recruited (14 in colistin and 15 in ampicillin/sulbactam groups). Three patients were excluded in each group. Clinical response occurred in 3 (27%) and 10 (83%) in colistin and ampicillin-sulbactam arms, respectively (P = 0.007). Nephrotoxicity happened in 6 (54%) and 1 (8%) of cases in colistin and ampicillin-sulbactam groups, (P = 0.016). 14-day and 28-day survival rate were significantly higher in ampicillin-sulbactam group compared to colistin arm with P values of 0.002 and 0.049, respectively. This study revealed that levofloxacin plus high dose ampicillin/sulbactam as continuous infusion is more effective than levofloxacin plus colistin in patients with MDR Acinetobacter VAP with significantly lower risk of nephrotoxicity.

Clinical outcomes and nephrotoxicity of colistin loading dose for treatment of extensively drug-resistant Acinetobacter baumannii in cancer patients.

BackgroundColistin is a last-line defense therapy against extensively drug-resistant Acinetobacter baumannii (XDR-AB). Despite a loading dose of colistin being applied in many clinical practices, studies evaluating the effect of the loading dose of colistin in cancer patients remain limited.Patients and methodsA retrospective cohort study of cancer patients who received either a loading or non-loading dose of colistin for treatment of XDR-AB was conducted. For each group, the clinical response, bacteriological eradication and serum creatinine were recorded. Logistic regression was applied to evaluate the effects of therapy on each of the three aforementioned outcomes.ResultsOne hundred and two patients diagnosed with XDR-AB infections between January 2012 and December 2015 were recruited. Only 75 patients were given a loading dose of colistin. There was no significant clinical and microbiological response in patients in the loading dose group or patients in the non-loading dose group. However, 38 (50.67%) patients in the loading dose group and 6 (22.22%) patients in the non-loading dose group developed nephrotoxicity according to the RIFLE criteria (p = 0.013). Multivariate logistic regression analysis showed that independent predictors of clinical response were Charlson score ≥4 and duration of colistin treatment ≥10 days. Septic shock correlated with both poor clinical and microbiological response. Independent predictors for nephrotoxicity were loading dose colistin and patient’s age ≥60 years.ConclusionAdministration of colistin loading dose did not significantly increase clinical response, microbiological response or mortality rate compared to non-loading dose in cancer patients with XDR-AB-related infections. However, nephrotoxicity was significantly higher when patients received loading dose colistin.

Evaluating Adherence of Health-Care Team to Standard Guideline of Colistin Use at Intensive Care Units of a Referral Hospital in Shiraz, Southwest of Iran.

Purpose: To evaluate colistin use according to global standard drug consumption in intensive care units of a referral hospital in Shiraz, IranMethods: A prospective, interventional study was performed during an 11 month period on 100 patients admitted to ICUs of a teaching hospital being treated with colistin for at least 3 subsequent doses. Required demographic, clinical, and paraclinical data were gathered by a pharmacist. Fifteen indexes were considered to evaluate colistin use. A clinical pharmacist reviewed indication and dose of colistin at the time of prescribing this agent.Results: In our study population, pneumonia (69%) was the main indication of colistin. In 87% of patients, colistin administration was based on microbiological laboratory evidence. Continuation of therapy was inappropriate in 5% of cases. By the intervention of the clinical pharmacist, colistin was discontinued in all patients in whom empirical therapy was continued incorrectly. None of the patients received loading dose of colistin. The maintenance dose, dose interval, and duration of treatment of colistin were appropriate in 76%, 71%, and 100% of patients, respectively. For none of the patients, the pharmacokinetic dosing method was used. In all patients, serum creatinine and WBC count were evaluated on daily basis. The sum indexes of colistin use were relevant to standard guidelines in 67.33% of the cases.Conclusion: The results of this study highlight the necessity of the pharmaceutical care team participation in all stages of treatment with antibiotics. After pharmacist interventions, some criteria of colistin utilization were corrected and brought closer to standard values.

Efficacy and Safety of High Loading Dose of Colistin in Multidrug-Resistant Acinetobacter baumannii: A Prospective Cohort Study.

We aimed to assess the efficacy and safety of a high loading dose of colistin and no loading dose of colistin to treat multidrug-resistant (MDR) Acinetobacter baumannii infections. We conducted a prospective cohort study of patients with MDR A baumannii infections at a university-affiliated hospital from December 2014 to January 2016. In the high loading dose group, the patients received a high loading dose of 300 mg colistin base activity (CBA) followed by a maintenance dose of 150 mg CBA twice daily, and patients in the no loading dose group received only the maintenance dose. The primary outcome was clinical response. The secondary outcomes were 28-day mortality and microbiological response. A total of 255 cases were identified. The high loading dose of colistin strategy provided no significant difference in good clinical response when compared to the no loading dose group (65.5% vs 70.4%; P = .442), without a significant difference in the development of renal dysfunction (52.3% vs 49.4%; P = .664). However, microbiological eradication was significantly higher among patients who received the high loading dose of colistin when compared to those who received the no loading dose (87.9% vs 70.4%; P = .0006). The high loading dose of colistin strategy was effective and safe for treating patients with MDR A baumannii.

Optimizing colistin dosing: Is a loading dose necessary?

Published literature on the pharmacokinetics and effectiveness of colistin loading doses is reviewed. Colistin is increasingly used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria (GNB). A literature search identified seven reports on studies of colistin loading doses. All reviewed studies involved small samples of critically ill patients, with considerable variation in the colistin products and loading doses used. Pharmacokinetic studies indicated that because of the slow rate of conversion of the prodrug colistimethate sodium to the active drug colistin and the long half-life of colistin, it can take two to three days to attain adequate colistin concentrations without a loading dose. The clinical effectiveness of colistin loading doses was evaluated in two studies, neither involving the use of a comparator group. In one of those studies, clinical cure and bacteriological clearance were reported in 82.1% and 73.9% of cases, respectively; in the other, clinical resolution was reported in 77% of patients. Two studies were conducted to compare clinical outcomes of colistin loading-dose regimens and standard regimens with no loading dose; while use of a loading dose was associated with a higher cure rate (63.0% versus 41.3%, p = 0.04) in one study, no improvement in clinical outcomes was reported in the other study. Published data on the effectiveness of colistin loading doses are limited. The available evidence suggests that it may be necessary to administer a colistin loading dose in severe and life-threatening infections due to MDR GNB.

Colistin loading dose enhanced antimicrobial activity for invivo mouse thigh infection model with Pseudomonas aeruginosa with highly antimicrobial resistant.

This is the first report to test the loading dosage of colistin against Pseudomonas aeruginosa, including MDRP. Using invivo murine thigh infection model, in the loading dosage regimen (Day 1:50mg/kg q12h, Day 2-3: 25mg/kg q12h) group, 5 to 6 log10CFU/ml reduction compared with control were observed for both strains of P.aeruginosa with colistin MIC 0.5 and 1μg/mL at 72h. But, similar reduction was observed for the strains with colistin MIC 0.5μg/mL only in normal dosage regimen (Day 1-3: 25mg/kg q12h) group. For P.aeruginosa with colistin MIC 1μg/mL, colistin loading dosage regimens showed greater antimicrobial activity than that of without loading dosage group (p<0.05). These data suggest that the colistin loading regimen would be one of the useful options for P.aeruginosa with antimicrobial resistance infection treatment.

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia.

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model.

Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa. In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem. A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h. The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance.