Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.

Clinical outcomes of colistin methanesulfonate sodium in correlation with pharmacokinetic parameters in critically ill patients with multi-drug resistant bacteria-mediated infection: A systematic review and meta-analysis.

BACKGROUND: Colistin is a viable option for multidrug resistant gram-negative bacteria emerged from inappropriate antibiotic use. Nonetheless, suboptimal colistin concentrations and nephrotoxicity risks hinder its clinical use. Thus, the aim of this study is to investigate clinical outcomes in correlation with pharmacokinetic differences and infection types in critically ill patients on intravenous colistin methanesulfornate sodium (CMS). METHODS: A systematic literature search of Embase, Google Scholars, and PubMed was performed to identify clinical trials evaluating pharmacokinetic parameters along with clinical outcomes of CMS treatment from inception to July 2023. The pooled analyses of clinical impact of CMS on nephrotoxicity, mortality, clinical cure, and colistin concentration at steady state (Css,avg) were performed. This study was registered in the PROSPERO (CRD 42023456120). RESULTS: Total of 695 critically ill patients from 17 studies were included. The mortality was substantially lower in clinically cured patients (OR 0.05; 95% CI 0.02 - 0.14), whereas the mortality rate was statistically insignificant between nephrotoxic and non-nephrotoxic patients. Inter-patient variability of pharmacokinetic parameters of CMS and colistin was observed in critically ill patients. The standard mean differences of Css,avg were statistically insignificant between clinically cure and clinically failure groups (standard mean difference (SMD) -0.25; 95% CI -0.69 - 0.19) and between nephrotoxic and non-nephrotoxic groups (SMD 0.67; 95% CI -0.27-1.61). The clinical cure rate is substantially lower in pneumonia patients (OR 0.09; 95% CI 0.01 - 0.56), and pharmacokinetic parameters pertaining to microbiological cure were different among strains. CONCLUSION: The mortality rate was substantially lower in clinically cured patients with CMS. However, no significant differences in Css,avg of colistin were examined to determine the impact of pharmacokinetic differences on clinical outcomes including mortality rate and nephrotoxicity risk. Nevertheless, the clinical cure rate is substantially lower in patients with respiratory infection than patients with urinary tract infection.

Protective effects of naringin on colistin-induced damage in rat testicular tissue: Modulating the levels of Nrf-2/HO-1, AKT-2/FOXO1A, Bax/Bcl2/Caspase-3, and Beclin-1/LC3A/LC3B signaling pathways.

Antimicrobial agent resistance has become a growing health issue across the world. Colistin (COL) is one of the drugs used in the treatment of multidrug-resistant bacteria resulting in toxic effects. Naringin (NRG), a natural flavonoid, has come to the fore as its antioxidant, anti-inflammatory, and antiapoptotic activities. The aim of the present study was to determine whether NRG has protective effects on COL-induced toxicity in testicular tissue. Thirty-five male Spraque rats were randomly divided into five groups (n = 7 per group): Control, COL, NRG, COL + NRG 50, COL + NRG 100. COL (15 mg/kg b.w., i.p., once per/day), and NRG (50 or 100 mg/kg, oral, b.w./once per/day) were administered for 7 days. The parameters of oxidative stress, inflammation, apoptosis, and autophagic damage were evaluated by using biochemical, molecular, western blot, and histological methods in testicular issues. NRG treatment reversed the increased malondialdehyde level and reduced antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione) levels due to COL administration (p < 0.001), and oxidative stress damage was mitigated. Nuclear factor erythroid 2-related factor-2 pathway, one of the antioxidant defence systems, was stimulated by NRG (p < 0.001). NRG treatment reduced the levels of markers for the pathways of apoptotic (p < 0.001) and autophagic (p < 0.001) damages induced by COL. Sperm viability and the live/dead ratio were reduced by COL but enhanced by NRG treatment. Testicular tissue integrity was damaged by COL but showed a tendency to improve by NRG. In conclusion, COL exhibited toxic effect on testicular tissue by elevating the levels of oxidative stress, apoptosis, autophagy, inflammation, and tissue damage. NRG demonstrated a protective effect by alleviating toxic damage.

Risk factors and prognosis for the development of acute kidney injury in patients using colistin in the intensive care unit: A retrospective cohort study.

Colistin, an antibiotic of polymyxin group, has recently been increasingly used in the treatment of multidrug resistant gram-negative bacteria. However, it has serious adverse effects such as acute kidney injury (AKI). We aimed to determine the factors affecting the development of AKI due to colistin, which has serious adverse effects, such as nephrotoxicity and neurotoxicity. We retrospectively analyzed the data of patients who received colistin for multidrug resistant gram-negative sepsis in adult intensive care units between January 2020 and December 2022. Demographic data, blood test results, concomitant drug use, need for renal replacement therapy, and mortality were recorded. Kidney damage was assessed according to the Kidney Disease Improving Global Outcomes criterion. We obtained data from 103 patients, 45 (43.7%) of whom were women. The most common comorbidity was a neurological disorder. Renal damage developed in 59.2% of patients. Renal replacement was required in 50.8% of the patients. Among patients who received colistin, 64.1% died. The use of vasopressors, diuretics, nephrotoxic agents with colistin, advanced age, and hypoalbuminemia were more common in patients with renal injury. Multivariate regression analysis showed that vasopressor use, prior creatinine elevation, and diuretic use were independent risk factors for colistin-induced AKI. Vasoactive agent use, previous kidney injury, and furosemide use were independent risk factors for colistin-induced nephrotoxicity. Considering these factors may be instructive for better monitoring of patients when colistin is required in intensive care units.

Acute kidney injury associated with colistin sulfate vs. polymyxin B sulfate therapy: A real-world, retrospective cohort study.

OBJECTIVE: To compare the incidence of acute kidney injury (AKI) in patients treated with colistin sulfate (CS) and polymyxin B sulfate (PMB). METHODS: Sociodemographic and laboratory measures of adult patients who received intravenous CS or PMB for at least 72 h for the first time at the study hospital from October 2021 to November 2022 were collected retrospectively. The primary outcome was the incidence of AKI, defined by the Kidney Diseases Improving Global Outcomes criteria. The secondary outcome was 30-day mortality. RESULTS: In total, 109 patients were included in the CS cohort and 176 patients were included in the PMB cohort. The incidence of AKI was significantly higher in the PMB cohort compared with the CS cohort (50.6% vs. 18.3%; P<0.001). On multi-variate analysis, CS therapy [hazard ratio (HR) 0.275; P<0.001] was an independent protective factor for AKI, along with higher estimated glomerular filtration rate. Nevertheless, 30-day mortality was similar in the PMB and CS cohorts (21.6% vs. 13.8%; P=0.099). Multi-variate analyses revealed that CS therapy was not associated with 30-day mortality (HR 0.968; P=0.926), while intensive care unit admission, combination with meropenem, Charlson score and stage 3 AKI were independent risk factors for 30-day mortality. After balancing the baseline characteristics of patients using propensity score matching, the main results were unchanged. CONCLUSION: The incidence of AKI was significantly lower in the CS cohort compared with the PMB cohort. However, 30-day mortality was similar in the two cohorts.

Battle of polymyxin induced nephrotoxicity: Polymyxin B versus colistin.

OBJECTIVES: Nephrotoxicity is the most serious and common adverse effect that limits the use of polymyxins. This study compared polymyxin E (colistin) and polymyxin B regarding drug-related nephrotoxicity. METHODS: This study was conducted as a retrospective cohort study in a university hospital between January 2020 and July 2022. Patients older than 18 years and who received colistin or polymyxin B were identified using electronic hospital records. Kidney disease improving global outcome criteria were used for assessing nephrotoxicity. RESULTS: A total of 190 patients, 95 in both groups, were evaluated. The incidence of acute kidney injury during the treatment was higher in the colistin group [52.6% (n = 50) and 34.7% (n = 33), P = 0.013]. In patients who were exposed to high-dose, the rate of nephrotoxicity was higher in patients receiving colistin [25% (n = 3) vs. 76.9% (n = 10); P = 0.017]. Nephrotoxicity was reversible in 64.4% (n = 38) of patients and the reversibility rate was similar (70% and 52.6% for colistin and polymyxin; P = 0.248). In the multivariable analysis, colistin treatment [odds ratio (OR): 3.882, 95% confidence interval (95% CI) = (1.829-8.241)], concomitant vasopressor use (OR = 2.08, CI: 1.036-4.179), and age (OR=1.036, CI: 1.014-1.058) were found to be independent markers of nephrotoxicity. CONCLUSION: Nephrotoxicity was more common in patients receiving high-dose colistin than polymyxin B. Therefore, the use of appropriate doses of colistin is important in terms of preventing nephrotoxicity. In addition, advancing age and concomitant use of vasopressors contribute to polymyxin-related nephrotoxicity.

[Clinical Analysis of Colistin Sulfate in the Treatment of Hematonosis Infected by Multidrug-Resistant Gram-Negative Bacteria].

OBJECTIVE: To investigate the efficacy and safety of colistin sulfate in the treatment of hematonosis patients infected by multidrug-resistant (MDR) gram-negative bacteria (GNB), and discuss the possible factors that affect the efficacy of colistin sulfate. METHODS: The clinical data of 85 hematologic patients infected with MDR GNB in the Soochow Hopes Hematonosis Hospital from April 2022 to November 2022 were collected and divided into clinically effective group with 71 cases and ineffective group with 14 cases according to the therapeutic efficacy of colistin sulfate. The age, gender, type of hematologic disease, status of hematopoietic stem cell transplantation, infection sites, type of pathogen, timing of administration, daily dose and duration of colistin sulfate, and combination with other antibacterial agents of patients in two groups were compared. Logistic regression was used to analyze on the meaningful variables to study the influencing factors of colistin sulfate. The adverse reactions of colistin sulfate were also evaluated. RESULTS: There were no significant differences in age, gender, type of hematologic disease, hematopoietic stem cell transplantation status, infection sites and pathogen type between the effective group and the ineffective group (P>0.05). Compared with the medication time more than 7 days, meropenem used within 7 days in the clinical effective group, and timely replacement with colistin sulfate could obtain better efficacy, the difference was statistically significant (P=0.018). The duration of tigacycline before colistin sulfate did not affect the efficacy, and there was no significant difference in efficacy between the effective and ineffective groups. The therapeutic effect of colistin sulfate at daily dose of 500 000 U q8h was better than that of 500 000 U q12h, the difference was statistically significant (P=0.035). The time of colistin sulfate use in the clinically effective group was longer than that in the ineffective group, which had a statistical difference (P=0.003). Compared with the clinical ineffective group, the efficacy of combination regimens with colistin sulfate was better than that of colistin sulfate monotherapy, and the difference was statistically significant (P=0.013). Multivariate logistic regression analysis was performed on the indicators with statistical differences in the two groups of patients, which suggested that the use time of colistin sulfate (B: 2.358; OR: 10.573; CI: 1.567-71.361; P=0.015) and the combination of colistin sulfate (B: 1.720; OR: 5.586; CI: 1.210-25.787; P=0.028) were influential factors in the efficacy of colistin sulfate. During the treatment, the incidence of nephrotoxicity, hepatotoxicity and peripheral neurotoxicity were 5.9%, 1.2% and 1.2%, respectively. CONCLUSION: The use of colistin sulfate improves the clinical efficacy of MDR GNB infections in hematological patients, and the timing of colistin sulfate administration and the combination of drugs are independent factors affecting its clinical efficacy, and the safety during treatment is high.

Nephrotoxicity caused by colistin use in ICU: a single centre experience.

BACKGROUND: We aimed to determine the risk factors that may be associated with colistin-induced acute kidney injury (AKI) to promote the safer use of colistin in the treatment of nosocomial infections caused by multidrug-resistant Gram-negative bacteria in intensive care units. MATERIALS AND METHODS: This retrospective observational study was conducted among adult patients who received a minimum of 48 h of intravenous colistin from January 2020 to December 2020 at the intensive care unit of a tertiary care hospital. AKI diagnosis and staging were made based on the Kidney Disease Improving Global Outcome Criteria. RESULTS: Of 148 patients who received intravenous colistin at a daily dose of 9 million IU, 54 (36%) developed AKI. In the univariate analysis, age, Charlson comorbidity index, APACHE II score, duration of colistin treatment, basal creatinine level, use of vasopressors, and vancomycin were significantly associated with AKI (p < 0.05). The multivariate analysis revealed that the independent predictor of AKI was the use of vasopressors (OR: 3.14; 95% confidence interval: 1.39-97.07; p = 0.06). CONCLUSION: The use of vasopressors in critically ill patients was independently associated with AKI developing during colistin treatment.

Colistin versus polymyxin B: A pragmatic assessment of renal and neurological adverse effects and effectiveness in multidrug-resistant Gram-negative bacterial infections.

OBJECTIVES: Our study aimed to evaluate the real-world data on renal and neurological adverse effects and effectiveness of colistimethate sodium (CMS) and polymyxin B (PMB). MATERIALS AND METHODS: An observational prospective study was performed on inpatients receiving CMS and PMB for multidrug-resistant Gram-negative bacterial infections. CMS dose was titrated to renal function, and serum creatinine was assessed daily. The incidence of nephrotoxicity, the primary outcome, was evaluated based on an increase in serum creatinine from baseline as well as by the Risk, Injury, Failure, Loss of kidney function, and End-stage renal disease criteria. Neurological adverse effects were assessed based on clinical signs and symptoms, and the causality and severity were assessed by the Naranjo scale and modified Hartwig-Siegel scale, respectively. The effectiveness of polymyxin therapy was ascertained by a composite of microbiological eradication of causative bacteria and achievement of clinical cure. Thirty-day all-cause mortality was also determined. RESULTS: Between CMS and PMB, the incidence of nephrotoxicity (59.3% vs. 55.6%, P = 0.653) or neurotoxicity (8.3% vs. 5.6%, P = 0.525) did not significantly differ. However, reversal of nephrotoxicity was significantly more with patients receiving CMS than PMB (48.4% vs. 23.3%, P = 0.021). Favorable clinical outcomes (67.6% vs. 37%, P < 0.001) and microbiological eradication of causative bacteria (73.1% vs. 46.3%, P = 0.001) were significantly more with CMS than PMB. Patients treated with CMS had lower all-cause mortality than those with PMB treatment (19.4% vs. 42.6%, P = 0.002). CONCLUSION: There is no significant difference in the incidence of renal and neurotoxic adverse effects between CMS and PMB when CMS is administered following renal dose modification. CMS shows better effectiveness and lower mortality compared to PMB.

Tigecycline-Containing Regimens and Multi Drug-Resistant Acinetobacter baumannii: A Systematic Review and Meta-Analysis.

Introduction: The use of tigecycline (TG) for the treatment of Acinetobacter baumannii is controversial. In this systematic review and meta-analysis, we aimed to better explore the safety and efficacy of TG for the treatment of multi drug-resistant (MDR) Acinetobacter. Methods: We searched PubMed/MEDLINE, Scopus, Cochrane Central, and Web of Science to identify studies reporting the clinical and microbiological efficacy and safety of regimens containing TG in patients with drug susceptibility testing (DST)-confirmed MDR A. baumannii, published until December 30, 2022. Observational studies were included if they reported clinical and microbiological efficacy of TG-based regimens. The Newcastle-Ottawa Scale (NOS) and Joana Briggs Institute (JBI) critical appraisal tool were used to assess the quality of included studies. Results: There were 30 observational studies, of which 19 studies were cohort and 11 studies were single group studies. Pooled clinical response and failure rates in the TG-containing regimens group were 58.1 (95% confidence interval [CI] 49.2-66.6) and 40.2 (95% CI 31.1-50.0), respectively. The pooled microbiological response rate was 32.1 (95% CI 19.8-47.5), and the pooled all-cause mortality rate was 41.1 (95% CI 34.1-48.4). Pooled clinical response and failure rates in the colistin-based regimens group were 52.7 (42.7-62.5) and 43.1 (33.1-53.8), respectively. The pooled microbiological response rate was 42.9 (16.2-74.5), and the pooled all-cause mortality rate was 34.3 (26.1-43.5). Conclusions: According to our results, the efficacy of the TG-based regimen is the same as other antibiotics. However, our study showed a high mortality rate and a lower rate of microbiological eradication for TG compared with colistin-based regimen. Therefore, our study does not recommend it for the treatment of MDR A. baumannii. However, this was a prevalence meta-analysis of observational studies, and for better conclusion experimental studies are required.

Comparative study of polymyxin B and colistin sulfate in the treatment of severe comorbid patients infected with CR-GNB.

BACKGROUND: With the difficulties in choosing colistin sulfate and polymyxin B sulfate (PBS) for carbapenem-resistant gram-negative bacteria (CR-GNB), we compared the efficacy and safety of these two old polymyxins in treatment of critically ill patients infected with CR-GNB infection. METHODS: One hundred four patients infected with CR-GNB in ICU were retrospectively grouped by PBS (68 patients) or colistin sulfate (36 patients). Clinical efficacy including symptoms, inflammatory parameters, defervescence, prognosis and microbial efficacy were analyzed. Hepatotoxicity, nephrotoxicity, and hematotoxicity were evaluated by TBiL, ALT, AST, creatinine, and thrombocytes. RESULTS: Demographic characteristics between colistin sulfate and PBS were not significantly different. Most of the CR-GNB were cultured in respiratory tract (91.7% vs 86.8%), and almost all were polymyxin-sensitive (98.2% vs 100%, MIC ≤ 2 µg/ml). The microbial efficacy in colistin sulfate (57.1%) was significantly higher than PBS (30.8%) (p = 0.022), however, no significant difference in clinical success was seen in both groups (33.8% vs 41.7%), as well as mortality, defervescence, imaging remission, days in the hospital, microbial reinfections, and prognosis, and almost all patients defervesce within 7 days (95.6% vs 89.5%). CONCLUSIONS: Both polymyxins can be administrated in critically ill patients infected with CR-GNB and colistin sulfate is superior to PBS in microbial clearance. These results highlight the necessity of identifying CR-GNB patients who may benefit from polymyxin and who are at higher risk of mortality.

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.

Pathogen-Targeted Clinical Development to Address Unmet Medical Need: Design, Safety, and Efficacy of the ATTACK Trial.

There is a crucial need for novel antibiotics to stem the tide of antimicrobial resistance, particularly against difficult to treat gram-negative pathogens like Acinetobacter baumannii-calcoaceticus complex (ABC). An innovative approach to addressing antimicrobial resistance may be pathogen-targeted development programs. Sulbactam-durlobactam (SUL-DUR) is a ß-lactam/ß-lactamase inhibitor combination antibiotic that is being developed to specifically target drug-resistant ABC. The development of SUL-DUR culminated with the Acinetobacter Treatment Trial Against Colistin (ATTACK) trial, a global, randomized, active-controlled phase 3 clinical trial that compared SUL-DUR with colistin for treating serious infections due to carbapenem-resistant ABC. SUL-DUR met the primary noninferiority endpoint of 28-day all-cause mortality. Furthermore, SUL-DUR had a favorable safety profile with a statistically significant lower incidence of nephrotoxicity compared with colistin. If approved, SUL-DUR could be an important treatment option for infections caused by ABC, including carbapenem-resistant and multidrug-resistant strains. The development program and the ATTACK trial highlight the potential for pathogen-targeted development programs to address the challenge of antimicrobial resistance.

Eficacia y seguridad de ceftazidima-avibactam en pacientes pediátricos de 3 meses a más con sepsis causada por bacterias Gram-negativas productoras de carbapenemasas y resistentes a colistina / Efficacy and safety of ceftazidime-avibactam in pediatric patients aged 3 months and older with sepsis caused by Gram-negative carbapenemase-producing bacteria resistant to colistin

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el cual expone la evaluación de la eficacia y seguridad de ceftazidima-avibactam en pacientes pediátricos de 3 meses a más con sepsis causada por bacterias Gram-negativas productoras de carbapenemasas y resistentes a colistina. Así, el Dr. Michael Algio Quispe Huarcaya y la Dra. Mabel Rubi Carhuana Salazar, médicos especialistas en gastroenterología pediátrica del Hospital Nacional Edgardo Rebagliati Martins (HNERM), siguiendo la Directiva N° 003-IETSIESSALUD-2016, enviaron al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI las solicitudes de autorización de uso del producto farmacéutico ceftazidima-avibactam no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: La sepsis se define como una disfunción orgánica potencialmente mortal causada por una respuesta desregulada del huésped a la infección (Pomerantz y Weiss 2022). Se caracteriza por un síndrome de respuesta inflamatoria sistémica (SRIS) en respuesta a una infección, que en pacientes pediátricos consiste en: i) temperatura anormal' y/o recuento anormal de leucocitos, más ii) el ritmo cardiaco anormal2y/o frecuencia respiratoria anormalmente alta' (DynaMed 2022). La sepsis no tratada tempranamente, puede ocasionar daño irreversible a los tejidos, shock séptico, insuficiencia orgánica múltiple y poner en riesgo la vida (OPS 2022). Se estima que la mortalidad hospitalaria en pacientes pediátricos con sepsis es 2 % al 10 %, mientras que en pacientes pediátricos cuya sepsis se complica a sepsis grave (sepsis con disfunción de órganos diana) o shock séptico (sepsis con disfunción cardiovascular), la mortalidad es de 14 % al 50 % (DynaMed 2022; Weiss et al. 2020). METODOLOGÍA Se realizó una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad de C-A, en comparación con la mejor terapia de soporte, en pacientes pediátricos de 3 meses a más con sepsis causada por bacterias Gram-negativas productoras de carbapenemasas y resistentes a colistina (población objetivo). La búsqueda bibliográfica se llevó a cabo en las bases de datos: PubMed, The Cochrane Library, Web of Science y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) incluyendo el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), el Scottish Intercollegiate Guidelines Network (SIGN), el Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), la International Database of GRADE Guideline, el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Guidelines International Network (GIN), el National Health and Medical Research Council (NHMRC), la Cancer Guidelines Database, el New Zealand Guidelines Group (NZGG), el Instituto de Evaluación Tecnológica en Salud (IETS), el Instituto de Efectividad Clínica y Sanitaria (IECS), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la Organización Mundial de la Salud y el Ministerio de Salud del Perú (MINSA). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en infectología, tales como: la European Society of Clinical Microbiology and Infectious Diseases (ESCMID), la European Society of Intensive Care Medicine (ESICM), la Pediatric Infectious Diseases Society (PIDS) y la Infectious Diseases Society of America (IDSA). Finalmente, se realizó una búsqueda en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o que no hayan sido publicados aún. RESULTADOS: Luego de la búsqueda bibliográfica hasta noviembre de 2022, se identificaron dos GPC elaboradas por la IDSA (Tamma et al. 2022) y la ESCMID (Paul et al. 2022), una ETS elaborada por NICE (NICE 2022) y un estudio observacional publicado por Wang et al. (Wang et al. 2022). Cabe mencionar que se excluyeron un ECA (Bradley et al. 2019) y dos GPC (Weiss et al. 2020; NICE 2017). Este ECA fue excluido porque evaluó pacientes pediátricos con infección urinaria complicada donde no se describe si los pacientes presentaron o no sepsis. Además, no se especifica si dichas infecciones fueron o no por bacterias productoras de carbapenemasas o al menos si fueron o no resistentes a carbapenémicos; por lo tanto, no brinda información que permita responder a la pregunta PICO del presente dictamen. Respecto a las GPC, estas dos guías (Weiss et al. 2020; NICE 2017) fueron excluidas porque sus recomendaciones no están dirigidas a la población objetivo del presente dictamen (pacientes con sepsis por bacterias gram-negativas productoras de carbapenemasas). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de ceftazidima-avibactam para pacientes pediátricos de 3 meses a más con sepsis causada por bacterias Gram-negativas productoras de carbapenemasas y resistentes a colistina, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Impact of clinical pharmacist's interventions on clinical outcomes in appropriate use of colistin: a prospective pre-post intervention study.

This study aims to evaluate the clinical pharmacist's contribution impact on the appropriate use of colistin. Our study was conducted prospectively in patients in the Internal Diseases Intensive Care Unit of Gazi University Medical Faculty Hospital for eight months. The first four months of the study were with the observation group, while the next four months were with the intervention group. The study determined how the active participation of clinical pharmacists had affected the appropriateness of colistin use. The results showed that the appropriate use of colistin was higher in the intervention group than in the observational group; furthermore, incidence of nephrotoxicity was lower. The difference between both groups was statistically significant (p < 0.001, p < 0.05), respectively. This study showed that the clinical pharmacist's active intervention by following the patients increased the frequency and percentage of the appropriate use of colistin. This decreased the incidence of nephrotoxicity, colistin's most important side effect.

Nebulized colistin as the adjunctive treatment for ventilator-associated pneumonia: A systematic review and meta-analysis.

PURPOSE: Nebulized colistin (NC) is a potential therapy for ventilator-associated pneumonia (VAP); however, the clinical efficacy and safety of NC remain unclear. This study investigated whether NC is an effective therapy for patients with VAP. MATERIALS AND METHODS: We performed a search in Web of Science, PubMed, Embase, and the Cochrane Library to retrieve randomized controlled trials (RCTs) and observational studies published at any time until February 6, 2023. The primary outcome was clinical response. Secondary outcomes included microbiological eradication, overall mortality, length of mechanical ventilation (MV), length of intensive care unit stay (ICU-LOS), nephrotoxicity, neurotoxicity, and bronchospasm. RESULTS: Seven observational studies and three RCTs were included. Despite exhibiting a higher microbiological eradication rate (OR,2.21; 95%CI, 1.25-3.92) and the same nephrotoxicity risk (OR,0.86; 95%CI, 0.60-1.23), NC was not significantly different in clinical response (OR,1.39; 95%CI, 0.87-2.20), overall mortality (OR,0.74; 95%CI, 0.50-1.12), MV length (mean difference (MD),-2.5; 95%CI, -5.20-0.19), and the ICU-LOS (MD,-1.91; 95%CI, -6.66-2.84) than by the intravenous antibiotic. Besides, the risk of bronchospasm raised significantly (OR, 5.19; 95%CI, 1.05-25.52) among NC. CONCLUSION: NC was associated with better microbiological outcomes but did not result in any remarkable changes in the prognosis of patients with VAP.

Dexmedetomidine may reduce the risk of acute kidney injury development in critically ill patients during colistin therapy.

INTRODUCTION: Colistin is considered as a last resort therapy for multidrug-resistant gram-negative organisms. It is widely used despite the significant risk of nephrotoxicity. Experimental studies showed the nephroprotective effect of dexmedetomidine, a sedative agent, against colistin toxicity. This study was performed to show the possible nephroprotective effect of dexmedetomidine among critically ill patients who received colistin. METHODS: Adult (>17 years) patients who were admitted to our surgical and medical intensive care unit (ICU) from March 2018 through March 2021, and who received colistin were included. Patients who receive Colistin therapy or intensive care unit follow-up of <72 h (discharge or death) and Acute kidney injury (AKI) or need hemodialysis prior to colistin therapy at the same hospitalization were excluded. AKI risk factors were examined by grouping patients with and without AKI. Patients, receiving colistin concomitantly with dexmedetomidine were also evaluated. RESULTS: Of the 139 patients included, 27 (17.8%) patients received dexmedetomidine. Sixty-five patients (47%) had AKI, at a median 5 (4-7) days after the initiation of colistin. Older age, lower baseline estimated glomerular filtration rate, and vasopressor use were associated with a higher risk of AKI, while dexmedetomidine use was associated with a lower risk. In the multivariate regression model, dexmedetomidine use was independently associated with a lower risk of AKI development (OR 0.20 95% CI 0.07-0.59, p = 0.003). CONCLUSION: In respect to these findings, dexmedetomidine may provide protection against AKI during colistin therapy in critically ill patients.

Outcome and safety of colistin usage in pediatric cancer patients with carbapenem-resistant enterobacteriaceae bacteremia at children cancer hospital Egypt.

Background: Carbapenem resistant Enterobacteriacae (CRE) bloodstream infection (BSI) causes complicated infections, especially in immunocompromised patients. This study aimed to assess the renal toxicity and the efficacy of therapy with colistin in a cohort of pediatric cancer patients with BSIs due to CRE and sensitivity to colistin. Patients and Methods: This was an observational, prospective cohort study from May 2017 to October 2017 in Children's Cancer Hospital Egypt 57,357. All patients who had blood stream infections due to CRE receiving intravenous colistin were prospectively enrolled. We used a standardized case form to record patient characteristics, including age, sex, weight, underlying comorbidities, type of infection, causative organism, and antibiotic susceptibility testing. Daily doses, duration of colistin therapy, and co-administered antibiotics (aminoglycosides, vancomycin) were collected. Furthermore, clinical and microbiological responses to treatment were reported. The dosing schedule was based on a loading dose of 5 MU and a 5-MU twice-daily divided maintenance dose, titrated on renal function. Clinical cure, bacteriological clearance, and daily serum creatinine were recorded. Results: One hundred and forty-one Blood Stream infectious episodes mainly due to Klebsiella Species (pneumoniae and Oxytoca) (27%) and Escherichia coli (68%) were analyzed. All strains were susceptible to colistin with Minimum inhibitory concentration (MICs) of 0.19-1.5 mg/L. Patients were predominantly females (69%), with a mean age of 7 years. It was used as a combination therapy with carbapenems (69.2%) or aminoglycosides (80%). The median duration of treatment was 9 days (Range 1-50 days). Clinical and microbiological cure was observed in 110 cases (80%). Acute kidney injury developed during five treatment courses (4%) in which colistin was used in combination with amikacin. No renal replacement therapy was required and subsided within 7 days from colistin discontinuation. Conclusions: Our study showed that colistin had a high efficacy without significant renal toxicity in severe infections due to CRE Gram-negative bacteria.

Résumé Carbapenem-resistant Gram-negative (CRE) bloodstream infection (BSI) causes complicated infections, especially in immunocompromised patients .This study aimed to assess the renal toxicity and the efficacy of therapy with colistin in a cohort of pediatric cancer patients with BSIs due to CRE and sensitivity to colistin. colistin proved to be effective and safe in managing CRE in children with cancer Mots-clés: Colistin, cancer, children, and Carbapenem-Resistant Enterobacteriaceae.

Amikacin-induced acute kidney injury in mechanically ventilated critically ill patients with sepsis.

In this retrospective cohort study, we aimed to evaluate the incidence, risk factors and outcomes of amikacin-induced acute kidney injury (AKI) in critically ill patients with sepsis. A total of 311 patients were included in the study. Of them, 83 (26.7%) had amikacin-induced AKI. In model 1, the multivariable analysis demonstrated concurrent use of colistin (OR 25.51, 95%CI 6.99-93.05, p< 0.001), presence of septic shock during amikacin treatment (OR 4.22, 95%CI 1.76-10.11, p=0.001), and Charlson Comorbidity Index (OR 1.14, 95%CI 1.02-1.28, p=0.025) as factors independently associated with an increased risk of amikacin-induced AKI. In model 2, the multivariable analysis demonstrated concurrent use of at least one nephrotoxic agent (OR 1.95, 95%CI 1.10-3.45; p=0.022), presence of septic shock during amikacin treatment (OR 3.48, 95%CI 1.61-7.53; p=0.002), and Charlson Comorbidity Index (OR 1.12, 95%CI 1.01-1.26; p=0.037) as factors independently associated with an increased risk of amikacin-induced AKI. In conclusion, before amikacin administration, the risk of AKI should be considered, especially in patients with multiple complicated comorbid diseases, septic shock, and those receiving colistin therapy.

Colistin (Polymyxin E) Use in Abdominal Solid Organ Transplant Recipients.

Background: Patients undergoing solid organ transplantation are at a higher risk of multi-drug resistant (MDR) bacterial infections especially during the immediate post operative period. Objective: To audit the usage, dosage appropriateness and safety of colistin use in abdominal solid organ transplant recipients to treat immediate post-transplant bacterial infections. Methods: After completion of 1000 abdominal solid organ transplants at our institute, data of the transplant recipients who received colistin between October 2010 and December 2019 was extracted from the hospital health information system. Data of all microbiological culture isolates, the minimum inhibitory concentration (MIC) of colistin, appropriateness of colistin dosing and nephrotoxicity associated with colistin use was assessed. Results: Of the 1170 (732 liver and 438 renal) solid organ transplant recipients, 82 (66 liver and 16 renal) received colistin to treat posttransplant MDR bacterial infections. Nearly 60% received colistin as definitive therapy and 87.81% received colistin as combination. Mean duration of colistin therapy was found to be higher in renal than liver transplant recipients. Out of the total 89 bacterial isolates, there were 2 colistin resistant Klebsiella strains. Colistin in combination with meropenem (36.4%) was the most commonly used dual therapy. Out of the total 89 bacterial isolates, there were 2 colistin resistant Klebsiella strains. Overall in-hospital mortality of patients who received colistin was 43.9%. Renal impairment occurred in 28.8% of liver transplant recipients. Conclusion: Infection necessitating colistin use increases mortality by three folds in liver transplant recipients and by five percentage points in renal transplant recipients.