El desafio en la dosificación de colistin: actualización de las recomendaciones disponibles / The challenge in colistin dosing: updating available recommendations

Resumen Las polimixinas están disponibles desde la década de los 60; sin embargo, debido a sus efectos adversos su uso ha sido reservado para el tratamiento de infecciones provocadas por bacterias multi-resistentes. El aumento en la experiencia clínica adquirida en los últimos años y la literatura médica publicada han planteado dudas respecto de la información entregada del producto, poniendo en manifiesto la necesidad de actualizar las recomendaciones posológicas, su farmacocinética y la información farmacocinética/farmacodinámica. Además, las diferencias en cuanto a concentración y dosis entre los distintos productos del colistín pueden dar lugar a errores de indicación/administración y suponer un riesgo para los pacientes. El año 2013, la Agencia Europea de Medicamento (EMA) encargó al Comité de Productos Medicinales para uso Humano (CHPM) la revisión de los datos disponibles y que formulara recomendaciones actualizadas del uso de colistín. Dicho procedimiento arrojó un primer informe en 2014. Esta revisión destaca los aspectos críticos de seguridad y eficacia, revisa los recientes avances farmacocinéticos y de estabilidad, las formas farmacéuticas disponibles en Chile, proporcionando los esquemas actualmente recomendados por agencias sanitarias y expertos en el tema para distintos escenarios clínicos.

Polymyxins have been available since the 1960s, however, because of their adverse effects, their use has been reserved for the treatment of infections caused by multiresistant bacteria. The increase in the clinical experience acquired in recent years and the published medical literature have raised doubts about the information provided by the product, indicating the need to update dosage recommendations, pharmacokinetics and pharmacokinetic/pharmacodynamic information (PK/PD). In addition, differences in concentration and dose between the different products of colistin may lead to errors of indication/administration and pose a risk to patients. In 2013, the European Medicines Agency (EMA) commissioned the Committee for Medicinal Products for Human Use (CHPM) to review available data and to make updated recommendations on the use of colistin. This procedure yielded a first report in 2014. This review highlights critical safety and efficacy aspects, reviews the recent pharmacokinetic and stability advances, the available pharmaceutical forms in Chile, providing the schemes currently recommended by health care agencies and experts in the field.

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

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

Ventriculitis post-quirúrgica por Pseudomonas aeruginosa extensamente resistente tratada con colistina intratecal. Comunicación de un caso pediátrico y revisión de la literatura científica / Post-surgical ventriculitis due to extensively resistant Pseudomonas aeruginosa treated with intrathecal colistin. Pediatric case report and literature review

Resumen El uso de colistina por vía intratecal se ha consolidado como una opción terapéutica para el manejo de infecciones del sistema nervioso central causadas por bacilos gramnegativos multi-resistentes. La evidencia del éxito terapéutico y del perfil de seguridad es creciente, particularmente en infecciones por Acinetobacter baumanii multi-resistente en adultos. La evidencia en niños es escasa. Se presenta el caso clínico de una niña de 11 años de edad, con una ventriculitis post-quirúrgica por Pseudomonas aeruginosa extensamente resistente tratada con colistina intravenosa e intratecal. Se revisa su uso en niños con meningitis nosocomial causada por bacilos gramnegativos multi-resistentes.

Use of Intrathecal colistin has increased in recent years and has become an alternative for the management of infections of the central nervous system caused by multidrug resistant (MDR) bacteria. Evidence of therapeutic success and safety profile is increasing, particularly in MDR Acinetobacter baumanii infections in adults. Conversely, evidence in children is limited. We present a case of an 11-year-old female with postsurgical meningitis caused by an extensively resistant Pseudomonas aeruginosa strain and treated with venous and intrathecal colistin. The evidence of its use in children with nosocomial meningitis by MDR Gram negative bacteria is reviewed.

Opportunities to optimise colistin stewardship in hospitalised patients in South Africa: Results of a multisite utilisation audit

Background. Colistin is an old antibiotic that has been reintroduced as salvage therapy in hospitalised patients because it is frequently the only agent active against Gram-negative bacteria. Various guidelines for colistin administration have led to confusion in establishing the appropriate dose, which has potential for adverse consequences including treatment failure or toxicity. The emergence and spread of colistin resistance has been documented in South Africa (SA), but no local information exists on how and why colistin is used in hospitals, and similarly, compliance with current dosing guidelines is unknown.Objectives. To evaluate the current utilisation of colistin in SA hospitals, in order to identify stewardship opportunities that could enhance the appropriate use of this antibiotic.Methods. Electronic patient records of adult patients on intravenous (IV) colistin therapy for >72 hours in four private hospitals were retrospectively audited over a 10-month period (1 September 2015 - 30 June 2016). The following data were recorded: patient demographics, culture and susceptibility profiles, diagnosis, and indication for use. Compliance with six colistin process measures was audited: obtaining a culture prior to initiation, administration of a loading dose, administration of the correct loading dose, adjustments to maintenance dose according to renal function, whether colistin was administered in combination with another antibiotic, and whether de-escalation following culture and sensitivity results occurred. Outcome measures included effects on renal function, overall hospital mortality, intensive care unit length of stay (LoS), and hospital LoS.Results. Records of 199 patients on IV colistin were reviewed. There was 99.0% compliance with obtaining a culture prior to antibiotic therapy, 93.5% compliance with prescription of a loading dose, and 98.5% compliance regarding prescription of colistin in combination with another agent. However, overall composite compliance with the six colistin stewardship process measures was 82.0%. Non-compliance related to inappropriate loading and maintenance doses, lack of adjustment according to renal function and lack of de-escalation following culture sensitivity was evident. Significantly shorter durations of treatment were noted in patients who received higher loading doses (p=0.040) and in those who received maintenance doses of 4.5 MU twice daily v. 3 MU three times daily (p=0.0027). In addition, compared with patients who survived, more patients who died received the 3 MU three times daily maintenance dose (p=0.0037; phi coefficient 0.26).Conclusions. The study identified multiple stewardship opportunities to optimise colistin therapy in hospitalised patients. Urgent implementation of a stewardship bundle to improve colistin utilisation is warranted

Colistin asociado a bloqueo neuromuscular postanestésico prolongado. reporte de caso clínico / Colistin associated postanesthetic prolonged neuromuscular blockade: case report

En los últimos años se ha reconsiderado la utilización de antibióticos como el colistin en infecciones por microorganismos multiresistentes, esta situación ha ocasionado el resurgimiento de las reacciones adversas como la nefrotoxicidad y neurotoxicidad que provocaron su abandono en los 80s. Se presenta caso clínico de paciente femenina de 75 años que manifiesta toxicidad neurológica con bloqueo neuromuscular residual postanestésico asociado a tratamiento con colistin.

In recent years there has been reconsidered the use of antibiotics such as colistin in infections caused by multiresistant microorganisms, this situation has caused the resurgence of adverse reactions such as nephrotoxicity and neurotoxicity that led to its abandonment in the 80s. Herein, we present a case of a 75 years old woman with neurotoxicity associated with colistin treatment manifested by postanesthesia prolonged neuromuscular blockade.

Inhaled Colistin for Treatment of Pneumonia due to Colistin-Only-Susceptible Acinetobacter baumannii

PURPOSE: Colistin is used for the treatment of pneumonia associated with multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. However, the best route of administration and dosage is not known. We report our experience with aerosolized colistin in twelve patients with pneumonia caused by colistin-only-susceptible (COS) A. baumannii. MATERIALS AND METHODS: We retrospectively reviewed patients' medical records who were treated with aerosolized colistin for the treatment of pneumonia. RESULTS: Ten patients were treated only with aerosolized colistin inhalation and two patients received a 3-day course intravenous colistin, and then switched to colistin inhalation therapy. The median duration of aerosolized colistin therapy was 17 days (5-31 days). Four patients were treated only with aerosolized colistin, whereas 4 patients received concomitant glycopeptides, and 4 received concomitant levofloxacin or cefoperazone/sulbactam. At the end of the therapy, the clinical response rate and bacteriological clearance rate was 83% and 50%, respectively. Colistin-resistant strains were isolated from 3 patients after aerosolized colistin therapy; however, all of them showed favorable clinical response. The median interval between inhalation therapy and resistance was 7 days (range 5-19 days). Acute kidney injury developed in 3 patients. Two patients experienced Clostridium difficile associated diarrhea. One patient developed fever and skin rash after aerosolized colistin therapy. No patient developed neurotoxicity or bronchospasm. CONCLUSION: Colistin inhalation therapy is deemed tolerable and safe, and could be beneficial as an adjuctive therapy for the management of pneumonia due to COS A. baumannii. However, the potential development of colistin resistance cannot be overlooked.

Colistina parenteral no tratamento de infeccoes graves: experiencia em centro unico / Parenteral colistin for the treatment of severe infections: a single center experience

Objetivo: Descrever a experiência de um único centro com o uso de colistina para tratar infecções hospitalares causadas por bactérias Gram-negativas resistentes a múltiplos fármacos e identificar fatores associados com lesão renal aguda e mortalidade. Métodos: Estudo longitudinal retrospectivo que avaliou pacientes gravemente enfermos, com infecções causadas por bactérias Gram-negativas resistentes a múltiplos fármacos. Foram considerados elegíveis para este estudo, durante o período compreendido entre janeiro e dezembro de 2008, todos os pacientes adultos com necessidade de tratamento com colistina endovenosa (colistimetato de sódio). As informações coletadas incluem dados demográficos, diagnóstico, duração do tratamento, presença de lesão renal aguda e mortalidade em 30 dias. Resultados: A colistina foi utilizada para tratar uma infecção em 109 de 789 pacientes (13,8%) admitidos à unidade de terapia intensiva. A mortalidade em 30 dias observada nestes pacientes foi de 71,6%. Vinte e nove pacientes (26,6%) tinham lesão renal prévia ao tratamento com colistina, sendo que seis deles conseguiram recuperar a função renal, mesmo durante o tratamento com colistina. Vinte e um pacientes (19,2%) desenvolveram lesão renal aguda durante o tratamento com colistina, sendo que 11 destes pacientes necessitaram ser submetidos à diálise. A variável independentemente associada com a presença de lesão renal aguda foi a pontuação segundo o sistema Sequential Organ Failure Assessment no início do tratamento com colistina (OR=1,46; IC95%=1,20-1,79; p<0,001). Idade (OR=1,03; IC95%=1,00-1,05; p=0,02) e uso de vasopressores (OR=12,48; IC95%=4,49-34,70; p<0,001) foram fatores associados a óbito, segundo um modelo de regressão logística. ...

Objective: To describe a single center experience involving the administration of colistin to treat nosocomial infections caused by multidrug-resistant Gram-negative bacteria and identify factors associated with acute kidney injury and mortality. Methods: This retrospective longitudinal study evaluates critically ill patients with infections caused by multidrug-resistant Gram-negative bacteria. All adult patients who required treatment with intravenous colistin (colistimethate sodium) from January to December 2008 were considered eligible for the study. Data include demographics, diagnosis, duration of treatment, presence of acute kidney injury and 30-day mortality. Results: Colistin was used to treat an infection in 109 (13.8%) of the 789 patients admitted to the intensive care unit. The 30-day mortality observed in these patients was 71.6%. Twenty-nine patients (26.6%) presented kidney injury prior to colistin treatment, and six of these patients were able to recover kidney function even during colistin treatment. Twenty-one patients (19.2%) developed acute kidney injury while taking colistin, and 11 of these patients required dialysis. The variable independently associated with the presence of acute kidney injury was the Sequential Organ Failure Assessment at the beginning of colistin treatment (OR 1.46; 95%CI 1.20-1.79; p<0.001). The factors age (OR 1.03; 95%CI 1.00-1.05; p=0.02) and vasopressor use (OR 12.48; 95%CI 4.49-34.70; p<0.001) were associated with death in the logistic-regression model. Conclusions: Organ dysfunction at the beginning of colistin treatment was associated with acute kidney injury. In a small group of patients, we were able to observe an improvement of kidney function during colistin treatment. Age and vasopressor use were associated with death. .

Colistin against colistin-only-susceptible Acinetobacter baumannii-related infections: Monotherapy or combination therapy.

Purpose: To evaluate the outcomes of the patients who were infected with colistin-only-susceptible (COS) Acinetobacter baumannii and treated with either colistin monotherapy or colistin combined therapy. Materials and Methods: This retrospective case-control study was conducted in the training and research hospital with an 800 beds between August 2008 and December 2011. The patients, who were infected with COS A. baumannii and received either colistin monotherapy or colistin combined therapy, were included into the study. Results: In total, 51 patients fulfilling study criteria were evaluated. Colistin monotherapy was found effective as much as colistin combined therapy in terms of clinical and microbiological responses in patients with ventilator associated pneumonia (VAP) and also in patients with blood stream infections. Conclusion: Although there is no randomised controlled study yet, colistin monotherapy and colistin combined therapy are likely to achieve similar treatment responses rates. Heteroresistant strains can emerge in patients who receive colistin monotherapy.

Utilidad de los antibióticos inhalados: más allá de la fibrosis quística / Inhaled antibiotic utility: more than cystic fibrosis

Inhalatory therapy is the preferred way for drugs targeting the lung, which permits to avoid adverse events associated to systemic use. Cystic fibrosis (CF) is the disease with the highest use of inhaled antibiotics, which has provided information extrapoled to other pathologies such as non-CF bronchiectasis and pneumonia associated to mechanical ventilation. The most studied antibiotics currently available in the market are tobramycin and colystin, both inhaled. This article analyzes the updated evidence and recommendations published regarding the use of inhaled antibiotics.

La terapia inhalatoria es la vía de elección para la administración de fármacos cuyo órgano diana es el pulmón, pues evita los efectos adversos asociados a su uso sistémico. La fibrosis quística (FQ) es la enfermedad en que se ha centrado la mayor utilización de antibióticos inhalados, aportando información que se ha extrapolado a otras patologías como las bronquiectasias no FQ y la neumonía asociada a ventilación mecánica. Los antibióticos más estudiados y actualmente disponibles en el mercado son la tobramicina y colistín inhalados. Este artículo revisa la evidencia actualizada y las recomendaciones publicadas en torno al uso de antibióticos por vía inhalatoria.

The Outcomes of Using Colistin for Treating Multidrug Resistant Acinetobacter Species Bloodstream Infections

Despite the identification of Acinetobacter baumannii isolates that demonstrate susceptibility to only colistin, this antimicrobial agent was not available in Korea until 2006. The present study examined the outcomes of patients with multidrug resistant (MDR) Acinetobacter species bloodstream infection and who were treated with or without colistin as part of their regimen. The colistin group was given colistin as part of therapy once colistin became available in 2006. The non-colistin group was derived from the patients who were treated with other antimicrobial regimens before 2006. Mortality within 30 days of the onset of bacteremia occurred for 11 of 31 patients in the colistin group and for 15 of 39 patients in the non-colistin group (35.5% vs 38.5%, respectively, P = 0.80). Renal dysfunction developed in 50.0% of the 20 evaluable patients in the colistin group, but in 28.6% of the 35 evaluable patients in the non-colistin group (P = 0.11). On multivariate analysis, only an Acute Physiological and Chronic Health Evaluation II score > or = 21 was associated with mortality at 30 days. This result suggests that administering colistin, although it is the sole microbiologically appropriate agent, does not influence the 30 day mortality of patients with a MDR Acinetobacter spp. bloodstream infection.

Colistín en infecciones nosocomiales por bacilos gramnegativos pan-resistentes / Intravenous colistin in the treatment of infections due to pan-resistant Gram negative bacilli

La emergencia de bacilos gramnegativos pan-resistentes ha obligado a la reutilización progresiva de colistín. Objetivo: Describir la experiencia clínica con este compuesto. Metodología: Se efectuó un análisis retrospectivo de todos los tratamientos con colistín endovenoso administrados por más de 48 horas, analizando datos clínicos, microbiológicos, la respuesta terapéutica y evolución hasta el egreso. Resultados: Se aplicaron 24 tratamientos entre junio de 2005 y septiembre de 2006. Colistín endovenoso fue utilizado en eventos de neumonía asociada a VM (n = 10; 41,7 por ciento), colecciones o abscesos (12,5 por ciento), bacteriemias, neumonía no asociada a VM e infección urinaria (4,2 por ciento cada una, respectivamente). El tratamiento fue iniciado en promedio a 3,2 (± 2,85) días desde el diagnóstico de infección. Todos los pacientes tenían infecciones por Pseudomonas aeruginosa o Acinetobacter baumannii. Se evaluó la susceptibilidad por E-test en once aislados (CIM90 3,6 µg/mL, rango 0,38 a 4 µg/mL). Una cepa (9 por ciento) presentó resistencia. Se observó una respuesta favorable en 50 por cientoo de los casos (n = 12) con recaída en cinco de estos casos (41,7 por ciento). El único factor asociado a fracaso fue la presencia de neumonía (p = 0,04). Se observó erradicación en ocho casos (33,3 por ciento) y persistencia en once (45,8 por ciento). En cinco casos el resultado microbiológico no fue evaluable. Sobrevivió a la hospitalización 45,5 por ciento de los pacientes (n = 10). No se observó nefrotoxicidad. Conclusiones: Colistín endovenoso es un compuesto seguro para el tratamiento de infecciones por bacilos gramnegativos pan-resistentes. Sin embargo, su eficacia terapéutica es limitada, especialmente, entre aquellos pacientes tratados por neumonía.

Emergence of panresistant gram negative bacilli has lead to the progressive reintroduction of intravenous colistin. Aim: To describe the clinical experience observed with this compound. Methodology: A retrospective analysis was performed for all treatments lasting ≥ 48 hours. Medical records were analyzed to obtain clinical parameters and microbiological data, evaluate clinical response and evolution until discharge. Main results: 24 treatments lasting ≥ 48 hours were applied between June 2005 and September 2006. Intravenous colistin was indicated to treat cases of ventilator-associated (VA) pneumonia (n = 10; 41.7 percent), abscess or collections (12.5 percent), bloodstream infections, non-VA pneumonia or urinary tract infections (4.2 percent each one, respectively). Treatment was initiated on average at 3.2 days (± 2.85) from diagnosis of infection. All courses were microbiologically-guided, and involved P. aeruginosa or A. baumannii isolates. Susceptibility was evaluated by E-test in 11 isolates (MIC90 3.6 µg/mL, range 0.38 to 4 µg/mL). One isolate was resistant to colistin (9 percent). A favorable response was observed in 12 treatments (50 percent) with a relapse in 5 cases (41.7 percent). Being treated for pneumonia was the only factor associated to failure, (p = 0.04) Eradication was documented in 8 cases (33.3 percent) and persistence in 11 (45.8 percent). In 5 cases a microbiological follow-up was not available. Survival at time of discharge was 45.5 percent. (n = 10) None of the treatment courses was associated with nefrotoxicity. Conclusions: Intravenous colistin is a safe compound useful to treat various nosocomial infections due to pan-resistant gram negative bacilli. Nonetheless, its clinical efficacy is limited, especially among patients treated for nosocomial pneumonia.