International manufacturing and trade in colistin, its implications in colistin resistance and One Health global policies: a microbiological, economic, and anthropological study.

BACKGROUND: The emergence of colistin-resistant Enterobacterales is a global public health concern, yet colistin is still widely used in animals that are used for food as treatment, metaphylaxis, prophylaxis, and growth promotion. Herein, we investigate the effect of colistin-resistant Enterobacterales in Pakistan, global trade of colistin, colistin use at the farm level, and relevant socioeconomic factors. METHODS: We conducted a microbiological, economic, and anthropological study of colistin-resistant Escherichia coli in humans, animals, and the environment and international trade and knowledge of colistin in Pakistan, Bangladesh, Nigeria, China, India, and Viet Nam. We collected backyard poultry cloacal swabs, commercial broiler cloacal swabs, cattle and buffalo rectal swabs, human rectal swabs, wild bird droppings, cattle and buffalo meat, sewage water, poultry flies, chicken meat, and canal water from 131 sites across Faisalabad, Pakistan, to be tested for mcr-1-positive and mcr-3-positive Escherichia coli. We recruited new patients admitted to Allied Hospital, Faisalabad, Pakistan, with abdominal pain and diarrhoea for rectal swabs. Patients with dysentery and those who were already on antibiotic treatment were excluded. Data for colistin trade between 2017 and 2020, including importation, manufacturing, and usage, were accessed from online databases and government sources in Pakistan, Bangladesh, and Nigeria. We recruited participants from poultry farms and veterinary drug stores in Pakistan and Nigeria to be interviewed using a structured questionnaire. International manufacturing, import, and export data; value analysis; and trade routes of colistin pharmaceutical raw material (PRM), feed additive, and finished pharmaceutical products (FPPs) were accessed from 2017-21 export data sets. FINDINGS: We collected 1131 samples between May 12, 2018, and July 1, 2019: backyard poultry cloacal swabs (n=100), commercial broiler cloacal swabs (n=102), cattle and buffalo rectal swabs (n=188), human rectal swabs (n=200), wild bird droppings (n=100), cattle and buffalo meat (n=100), sewage water (n=90), poultry flies (n=100), chicken meat (n=100), and canal water (n=51). We recruited 200 inpatients at Allied Hospital, Faisalabad, Pakistan, between Nov 15, 2018, and Dec 14, 2018, for rectal swabs. We recruited 21 participants between Jan 1, 2020, and Dec 31, 2020, from poultry farms and drug stores in Pakistan and Nigeria to be interviewed. 75 (7%) of 1131 samples contained mcr-1-positive E coli, including wild bird droppings (25 [25%] of 100), commercial broiler cloacal swabs (17 [17%] of 100), backyard poultry cloacal swabs (one [1%] of 100), chicken meat (13 [13%] of 100), cattle and buffalo meat (two [2%] of 100), poultry flies (eight [8%] of 100), sewage water (six [7%] of 90), and human rectal swabs (three [2%] of 200). During 2017-20, Pakistan imported 275·5 tonnes (68·9 tonnes per year, 95% CI 41·2-96·6) of colistin as PRM, all sourced from China, 701·9 tonnes (175·5 tonnes per year, 140·9-210·1) of colistin as feed additives from China and Viet Nam, and 63·0 tonnes (15·8 tonnes per year, 10·4-21·1) of colistin as FPPs from various countries in Asia and Europe. For Bangladesh and Nigeria, colistin PRM and FPPs were imported from China and Europe. Colistin knowledge and usage practices in Pakistan and Nigeria were unsatisfactory in terms of understanding of the effects on human medicine and usage other than for treatment purposes. China is the major manufacturer of PRM and feed additive colistin and exported a total of 2664·8 tonnes (666·2 tonnes per year, 95% CI 262·1 to 1070·2) of PRM and 2570·2 tonnes (642·6 tonnes per year, -89·4 to 1374·5) of feed additive in 1330 shipments during 2018-21 to 21 countries. INTERPRETATION: Regardless of 193 countries signing the UN agreement to tackle antimicrobial resistance, trading of colistin as PRM, FPPs, and feed additive or growth promoter in low-income and middle-income countries continues unabated. Robust national and international laws are urgently required to mitigate the international trade of this antimicrobial listed on WHO Critically Important Antimicrobials for Human Medicine. FUNDING: Pakistan Agricultural Research Council and INEOS Oxford Institute for Antimicrobial Research TRANSLATION: For the Urdu translation of the abstract see Supplementary Materials section.

Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation.

BACKGROUND: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. RESULTS: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%). CONCLUSIONS: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

Cost-effectiveness of selective digestive decontamination (SDD) versus selective oropharyngeal decontamination (SOD) in intensive care units with low levels of antimicrobial resistance: an individual patient data meta-analysis.

OBJECTIVE: To determine the cost-effectiveness of selective digestive decontamination (SDD) as compared to selective oropharyngeal decontamination (SOD) in intensive care units (ICUs) with low levels of antimicrobial resistance. DESIGN: Post-hoc analysis of a previously performed individual patient data meta-analysis of two cluster-randomised cross-over trials. SETTING: 24 ICUs in the Netherlands. PARTICIPANTS: 12 952 ICU patients who were treated with ≥1 dose of SDD (n=6720) or SOD (n=6232). INTERVENTIONS: SDD versus SOD. PRIMARY AND SECONDARY OUTCOME MEASURES: The incremental cost-effectiveness ratio (ICER; ie, costs to prevent one in-hospital death) was calculated by comparing differences in direct healthcare costs and in-hospital mortality of patients treated with SDD versus SOD. A willingness-to-pay curve was plotted to reflect the probability of cost-effectiveness of SDD for a range of different values of maximum costs per prevented in-hospital death. RESULTS: The ICER resulting from the fixed-effect meta-analysis, adjusted for clustering and differences in baseline characteristics, showed that SDD significantly reduced in-hospital mortality (adjusted absolute risk reduction 0.0195, 95% CI 0.0050 to 0.0338) with no difference in costs (adjusted cost difference €62 in favour of SDD, 95% CI -€1079 to €935). Thus, SDD yielded significantly lower in-hospital mortality and comparable costs as compared with SOD. At a willingness-to-pay value of €33 633 per one prevented in-hospital death, SDD had a probability of 90.0% to be cost-effective as compared with SOD. CONCLUSION: In Dutch ICUs, SDD has a very high probability of cost-effectiveness as compared to SOD. These data support the implementation of SDD in settings with low levels of antimicrobial resistance.

Cost-effectiveness analysis of ceftazidime/avibactam compared to imipenem as empirical treatment for complicated urinary tract infections.

Ceftazidime/avibactam (CAZ-AVI) is a novel, fixed-dose combination antibiotic that has been approved in Europe and the United States for patients with complicated urinary tract infections (cUTIs) based on results of a Phase III, randomized, comparative study (RECAPTURE study). The present analysis evaluated cost-effectiveness of CAZ-AVI as an empirical treatment for hospitalized patients with cUTIs from the Italian publicly funded healthcare (third-party payer) perspective. A sequential, patient-level simulation model was developed that followed the clinical course of cUTI and generated 5000 pairs of identical patients (CAZ-AVI or imipenem as empirical treatment). The model included additional impact of resistant pathogens; patients who did not respond to empirical treatment were switched to second-line treatment of colistin+high dose carbapenem in both groups. The time horizon of the model was five years, with an annual discount rate of 3% applied to both costs and quality-adjusted life-years (QALYs). The analysis demonstrated that an intervention sequence (CAZ-AVI followed by colistin+high dose carbapenem) compared with a comparator sequence (imipenem followed by colistin+high dose carbapenem) was associated with a net incremental cost of €1015 per patient but provided better health outcomes in terms of clinical cure (97.65% vs. 91.08%; ∆ = 6.57%), shorter hospital stays (10.65 vs. 12.55 days; ∆ = 1.90 days), and QALYs gained per patient (4.190 vs. 4.063; ∆ = 0.126). The incremental cost-effectiveness ratio was €8039/QALY, which is well below the willingness-to-pay threshold of €30 000/QALY in Italy. The results showed that CAZ-AVI is expected to be a cost-effective treatment compared with imipenem for cUTI in Italy.

Colistin and polymyxin B for treatment of nosocomial infections in intensive care unit patients: pharmacoeconomic analysis.

Background The emergence and rapid spread of multidrug-resistant gram-negative bacteria related to nosocomial infections is a growing worldwide problem, and polymyxins have become important due to the lack of new antibiotics. Objectives To evaluate the outcomes and pharmacoeconomic impact of using colistin and polymyxin B to treat nosocomial infections. Setting Neurosurgical, cardiovascular, or transplantation intensive care unit (ICU) at the Clinical Hospital of the University of Campinas (São Paulo, Brazil). Method A retrospective cohort study was conduct in patients in the ICU. The renal function was determined daily during treatment by measuring the serum creatinine. A cost minimization analysis was performed to compare the relative costs of treatment with colistin and polymyxin B. Main outcomes measure The outcomes were 30-day mortality and frequency and onset of nephrotoxicity after beginning treatment. Results Fifty-one patients treated with colistin and 51 with polymyxin B were included. 30-day mortality was observed in 25.49% and 33.33% of patients treated with colistin and polymyxin B, respectively; Nephrotoxicity was observed in 43.14% and 54.90% of patients in colistin and polymyxin B groups, respectively; and onset time of nephrotoxicity was 9.86 ± 13.22 days for colistin and 10.68 ± 9.93 days for polymyxin B group. Colistin treatment had a lower cost per patient compared to the cost for polymyxin B treatment (USD $13,389.37 vs. USD $13,639.16, respectively). Conclusion We found no difference between 30-day mortality and nephrotoxicity between groups; however, colistin proved to be the best option from a pharmacoeconomic point of view.

Eficacia y seguridad de ceftolozano/tazobactam en pacientes adultos con enfermedad renal crónica e infección del tracto urinario por pseudomonas xdr con sensibilidad demostrada a ceftolozano/tazobactam / Efficacy and safety of ceftolozano / tazobactam in adult patients with chronic kidney disease and urinary tract infection by pseudomonas xdr with demonstrated sensitivity to ceftolozano / tazobactam

INTRODUCCIÓN: La resistencia antimicrobiana es una amenaza creciente para la salud pública mundial debido al aumento en costos médicos que genera, las estancias hospitalarias más prolongadas y el aumento de la mortalidad. Pseudomona aeruginosa es un bacilo aeróbio gramnegativo que se caracteriza por ser un microorganismo comúnmente resistente a los antibióticos y de ser causante de infecciones graves usualmente a nivel intrahospitalario, siendo el tercer patógeno más frecuente de infecciones del tracto urinario (ITU) intrahospitalaria después de Escherichia coli y Enterococcus spp. OBJETIVO: El objetivo del presente dictamen fue la evaluación de la eficacia y seguridad de ceftolozano/tazobactam comparado con colistina, amikacina y gentamicina, en pacientes adultos con enfermedad renal crónica (estadio 3 a 5) e infección del tracto urinario (ITU) por pseudomonas XDR con sensibilidad demostrada a ceftolozano/tazobactam, colistina, amikacina y gentamicina. METODOLOGÍA: Tras una búsqueda sistemática de literatura, se identificaron cuatro documentos: una guía de práctica clínica (GPC) elaborada por la European Urology Association, dos evaluaciones de tecnologías sanitarias (ETS) realizadas por el Scottish Medicines Consortium (SMC) y la Canadian Agency for Drugs and Technologies in Health (CADTH), una sinopsis de estudio de la National Institute for Health and Care Excellence (NICE) y un ensayo clínico aleatorizado (ECA) de fase III (el estudio ASPECT-cUTI). Cabe precisar que las ETS y la sinopsis basan sus recomendaciones o resultados en relación al estudio ASPECT-cUTI, que es un ensayo clínico de fase III que evaluó la eficacia y seguridad de ceftolozano/tazobactam en comparación con levofloxacino en pacientes con ITU complicada o pielonefritis aguda. Debido a que a la fecha no existe un ensayo que permita responder la pregunta PICO de interés de manera directa, en el presente dictamen se incluye el estudio ASPECT-cUTI como evidencia indirecta. RESULTADOS: La GPC incluida no establece recomendaciones específicas para la población de interés. Sin embargo, refiere la necesidad de disponer de un cultivo de orina para orientar la terapia según el perfil de susceptibilidad encontrado. Además, menciona que no existe evidencia para apoyar la superioridad de la eficacia de ningún agente o clase de agentes sobre otro en el caso que el microorganismo infeccioso sea susceptible a las terapias disponibles. Las ETS de SMC1 y CADTH y la sinopsis de estudio de NICE señalan que los resultados del estudio ASPECT-cUTI no son generalizables a la población de interés de la pregunta PICO del presente dictamen, incluyendo los pacientes con daño renal. Además, las ETS de SMC y CADTH señalan que, en general, la terapia con ceftolozano/tazobactam sería, en general, de mayor costo en comparación con otras alternativas disponibles para el tratamiento de ITU por pseudomonas considerando su contexto local. El estudio ASPECT-cUTI, fue un ensayo clínico aleatorizado, doble ciego, doble simulación, controlado de no inferioridad, fase III en pacientes con ITU complicada o pielonefritis aguda. Los resultados mostraron que ceftolozano/tazobactam no era inferior a levofloxacino en el desenlace compuesto de curación (curación clínica más erradicación microbiológica). Además, los perfiles de seguridad para ambos grupos fueron similares. Los hallazgos finales no incluyeron la valoración de la función renal, por lo que no fue posible evaluar los efectos de ceftolozano/tazobactam sobre la función renal. CONCLUSIÓN: En el presente documento, se evaluó la evidencia científica disponible hasta la actualidad sobre la eficacia y seguridad de ceftolozano/tazobactam comparado con colistina, amikacina y gentamicina, en pacientes adultos con enfermedad renal crónica (estadio 3 a 5) e ITU por pseudomonas XDR con sensibilidad demostrada a ceftolozano/tazobactam, colistina, amikacina y gentamicina. A la fecha, no se han identificado un ECA que evalúe directamente el uso de ceftolozano/tazobactam comparado con colistina, amikacina o gentamicina para pacientes con ITU por pseudomonas XDR que presenten daño renal. Las agencias de ETS como NICE, SMC y CADTH analizan los resultados del ensayo clínico ASPECT-cUTI como única evidencia disponible para evaluar el uso de ceftolozano/tazobactam en pacientes con ITU complicada. Este ensayo clínico fue incluido como parte de la evidencia evaluada en el presente documento, teniéndose presente que el mismo aportaría evidencia indirecta para la pregunta PICO de interés debido a que no incluye ni a la población ni a los comparadores de interés. La GPC de EUA, destaca que a la fecha no se puede recomendar un antimicrobiano sobre otro en caso el microorganismo presente sensibilidad en el cultivo a dos o más antimicrobianos, siendo ceftolozano/tazobactam, amikacina y gentamicina alternativas terapéuticas para pacientes con ITU complicada. Las ETS del SMC y CADTH y la sinopsis de estudio del NICE realizaron la evaluación de la tecnología de interés con el análisis del estudio ASPECT-cUTI. Estas refieren que, dado las limitaciones del diseño del estudio, sus resultados no son generalizables a la población de pacientes con ITU complicada y pielonefritis, incluyendo a pacientes con disminución de la función renal, adultos mayores y varones. Las agencias señalan, además, que el empleo de ceftolozano/tazobactam representaría un costo muy superior comparado al uso de otras tecnologías con mayor experiencia de uso en sus sistemas sanitarios. SMC señala que levofloxacino no es un comparador ideal debido a que no es un antibiótico convencionalmente prescrito para los pacientes con ITU complicada en su medio sanitario. El estudio ASPECT-cUTI fue un ECA fase III, aleatorizado, doble ciego, doble simulación, multicéntrico, de no inferioridad que evaluó la eficacia y seguridad de ceftolozano/tazobactam, en comparación con levofloxacino, en pacientes adultos con infecciones complicadas del tracto urinario inferior o pielonefritis. El estudio reportó que Ceftolozano/tazobactam no era inferior a levofloxacino en el desenlace compuesto de curación (curación clínica más erradicación microbiológica). Los perfiles de seguridad para ambos grupos fueron similares. Los hallazgos finales no incluyeron la valoración de la función renal, por lo que no fue posible evaluar los efectos de ceftolozano/tazobactam sobre la función renal. Como limitaciones del estudio ASPECT-cUTI, la población evaluada incluyó únicamente 20 participantes con cultivo compatible con infección por P. aeruginosa en cada grupo de estudio, siendo la resistencia basal a levofloxacino mayor en el grupo de levofloxacino respecto a la resistencia basal a ceftolozano en el grupo de ceftolozano/tazobactam, situación que podría introducir sesgos. El estudio no reportó si los cultivos positivos a P. aeruginosa presentaban resistencia tipo XDR (siendo la infección por P. aeruginosa XDR condición de interés para el presente dictamen). Además, solo el 8 % de la población total tenía ERC moderada (estadio 3) y los pacientes con ERC avanzada (estadio 4 o 5) fueron excluidos. Otro punto a destacar es que el estudio ASPECT-cUTI empleó levofloxacino y no un comparador de interés para la pregunta PICO del presente dictamen y siendo que levofloxacino no es un antibiótico convencionalmente empleado para pacientes con la condición clínica de interés. De esta forma, la representatividad de pacientes adultos con ITU complicada e infección por pseudomonas XDR no está presente en este estudio, siendo además los resultados no útiles para realizar conclusiones para la población de interés del dictamen. Específicamente, existe incertidumbre respecto a la eficacia de ceftolozano/tazobactam en pacientes que presentan una ITU complicada causada por pseudomonas XDR, y en especial, en el grupo de pacientes con deterioro de la función renal. Además, no se tiene certeza acerca de la inocuidad renal del ceftolozano/tazobactam en pacientes con ITU complicada. Asimismo, la costo-oportunidad del empleo de ceftolozano/tazobactam sería inferior al de otras tecnologías disponibles actualmente en EsSalud para el tratamiento de la ITU por pseudomonas que han demostrado en el tiempo ser efectivas para la condición de interés del presente dictamen. El Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI no aprueba el uso de ceftolozano/tazobactam para el tratamiento de pacientes adultos con daño renal con infección del tracto urinario por pseudomonas XDR con sensibilidad demostrada al ceftolozano/tazobactam.

Cost-effectiveness analysis of low versus high dose colistin in the treatment of multi-drug resistant pneumonia in Saudi Arabia.

Background Gram negative pathogens are increasingly resistant to commonly used first line antibiotics and colistin is in most cases the only medicine available. There is very limited information available comparing the effectiveness and costs of low versus high dose colistin with studies showing efficacy with both doses and with variable levels of adverse effects. The absence of a definite dosing strategy makes a model to compare low dose and high dose colistin invaluable in making decisions regarding the appropriate use of colistin. Objective This study was designed to evaluate the cost effectiveness of low versus high dose colistin in the treatment of Pneumonia caused by colistin-only sensitive gram negative bacteria from the perspective of a tertiary care hospital in Saudi Arabia. Setting 300-bed tertiary care hospital in Saudi Arabia. Method A retrospective review was conducted to compare the costs and outcomes of treatment of pneumonia with low versus high dose colistin. The model followed an average patient from initiation of treatment until clinical cure or failure. Main outcome measures The main outcomes were cure, nephrotoxicity, total direct costs per episode, cost per additional cure and cost per nephrotoxicity avoided. Results There was no significant difference between high and low dose colistin with regards to clinical cure (30% vs. 21%; p = 0.292). Significantly more patients experienced nephrotoxicity with high versus low dose colistin (30% vs. 8%; p = 0.004). With low dose colistin the incremental costs per nephrotoxicity avoided was SAR-3056.28. One-way sensitivity analyses did not change the overall results. Conclusion Low dose was not inferior to high dose colistin in terms of clinical cure and had a lower incidence of nephrotoxicity resulting in significant cost avoidance.

Outcomes of adjunctive therapy with intrathecal or intraventricular administration of colistin for post-neurosurgical meningitis and ventriculitis due to carbapenem-resistant acinetobacter baumannii.

The efficacy and safety of intrathecal (ITH) or intraventricular (IVT) colistin in addition to intravenous (IV) colistin for meningitis and ventriculitis due to carbapenem-resistant Acinetobacter baumannii (CRAB) is unclear. In this retrospective observational study of 40 patients with post-neurosurgical meningitis and ventriculitis due to CRAB, 33 patients without concomitant infection received appropriate dosage regimens of IV colistin. Of the 33 patients, 17 received additional ITH/IVT colistin and 16 received only IV colistin. The 14-day, 30-day and in-hospital mortality rates were nominally lower for patients who received ITH/IVT colistin adjunctive therapy versus patients who received only IV colistin (24% vs. 38%, 29% vs. 56% and 29% vs. 56%, respectively). The costs of treatment were significantly lower, the lengths of hospital and intensive care unit (ICU) stay were significantly shorter, and the number of ventilator days was significantly less among patients who received ITH/IVT colistin compared with patients who did not receive ITH/IVT colistin. The initial Acute Physiology and Chronic Health Evaluation (APACHE) II and Glasgow Coma Scale (GCS) scores were associated with 30-day mortality with odds ratios (95% confidence intervals) of 1.21 (1.08-1.46) and 0.77 (0.44-0.85), respectively. Chemical meningitis from ITH/IVT colistin was mild and resolved spontaneously. Treatment of post-neurosurgical CRAB meningitis and ventriculitis with ITH/IVT colistin as an adjunct to IV colistin was associated with shorter lengths of hospital and ICU stay and a trend to lower mortality, especially among severely ill patients.

Antimicrobial consumption in five adult intensive care units: a 33-month surveillance study.

Background: Estimating the baseline antimicrobial consumption is extremely important to monitor the impact of antimicrobial stewardship activities that aim to reduce the burden and cost of antimicrobial consumption. Objectives: To quantify service-specific antimicrobial consumption using different metrics. Methods: A surveillance study was conducted at King Abdulaziz Medical City, Riyadh, Saudi Arabia, between October 2012 and June 2015 in five adult intensive care units (ICUs). Consumption data were collected manually on a daily basis by infection control practitioners. Data were presented as defined daily dose (DDD), days of therapy (DOT) per 1000 patient days, and frequency of daily consumption. Results: A total of 43,970 DDDs and 46,940 DOTs were monitored during 54,116 patient-days. For the most frequently consumed antimicrobials, the consumption of carbapenems, piperacillin/tazobactam, vancomycin, and colistin (respectively) in all ICUs combined were 255.9, 134.3, 98.2, and 13.6 DDDs per 1000 patient-days and 235.7, 145.9, 129.5, and 117.5 DOTs per 1000 patient-days. For the frequency of daily consumption, carbapenems were the most frequently consumed antimicrobial group in medical/surgical, burn, and step-down ICUs while piperacillin/tazobactam was the most frequently consumed antimicrobial in neuro-surgical and cardio-thoracic ICUs. Conclusion: High consumption of broad-spectrum antimicrobial agents such as meropenem and piperacillin/tazobactam is observed in multiple ICUs in a tertiary care hospital. Meropenem consumption is considerably higher than similar ICUs internationally. Future studies focusing on concurrent monitoring of antimicrobial resistance and identifying patient and physician characteristics associated with specific prescription patterns may help in improving judicious antimicrobial consumption.

A Retrospective Cohort Analysis Shows that Coadministration of Minocycline with Colistin in Critically Ill Patients Is Associated with Reduced Frequency of Acute Renal Failure.

Nonclinical studies have suggested that oxidative damage, caspase-mediated apoptosis, and inducible nitric oxide synthase levels may be involved in the pathogenesis of colistin (CST)-associated acute renal failure. MIN inhibits caspase 1, caspase 3, and inducible nitric oxide synthase, leading to the hypothesis that coadministration of CST with MIN (CST-MIN) may reduce the incidence of acute renal failure as well as produce additive or synergistic antimicrobial effects. A multicenter retrospective cohort study was conducted using the Premier Research database to examine the impact of CST-MIN on acute renal failure. Inclusion criteria were as follows: age of ≥18 years, intensive care unit admission at CST initiation, primary International Classification of Diseases 9 (ICD-9) diagnosis of pneumonia or sepsis, nondialysis at hospital admission, and discharge between January 2010 and December 2015. ICD-9 code 584.XX or ICD-10 code N17 was used to define acute renal failure. Baseline comparisons, 1:8 propensity score matching, and confirmatory logistic regression analyses were conducted. In total, 4,817 patients received CST and met inclusion criteria; 93 received CST-MIN. Unadjusted frequency of acute renal failure was significantly lower in patients receiving CST-MIN than CST (11.8% versus 23.7%, P = 0.007). Similar results were seen in propensity score matching (12.0% versus 22.3%, P = 0.031) and logistic regression analyses (odds ratio of 0.403, P = 0.006). Mortalities and 30-day readmission rates were similar between groups. The acute renal failure rate was not impacted by prevalence of baseline renal disease. CST-MIN in critically ill patients may reduce CST-associated acute renal failure. Further evaluation of this combination in prospective clinical studies is warranted.

Management of ventilator associated pneumonia with a new antibiotic adjuvant entity (ceftriaxone+sulbactam+disodium edetate) - A novel approach to spare carbapenems.

BACKGROUND: Ventilator associated pneumonia (VAP) is one of the most serious nosocomial infections in Intensive Care Unit (ICU). The aim of this study was to evaluate a new approach to spare the carbapenems for the management of patients diagnosed with VAP due to Acinetobacter baumannii (A. baumannii). METHOD: This retrospective study was conducted on VAP patients presenting for treatment at tertiary care centre between May 2014 and March 2016. The case sheets of patients who have been treated for VAP with meropenem, antibiotic adjuvant entity (AAE) and colistin were analysed. RESULTS: Out of 113 patients analysed, 24 (21.3%) patients were having VAP due to MDR A. baumannii. Microbial sensitivity has shown that 87.5% of patients were sensitive to AAE and colistin whereas all of them were resistant to meropenem, imipenem and gentamycin. The mean treatment durations were 12.4±2.1, 13.2±2.4 and 14.3±2.1days for AAE, meropenem+colistin and AAE+colistin treatment groups. In AAE susceptible patients, the mean treatment duration and cost could be reduced by 23-24% and 43-53% if AAE is used empirically. In AAE-resistant patients, the mean treatment duration and cost could be reduced by 21% and 26% if AAE+colistin regime is used empirically instead of meropenem followed by AAE+colistin. CONCLUSIONS: Clinical assessment with microbial eradication and pharmaco-economic evaluation clearly shows benefits in using AAE empirically in the management of A. baumannii infected VAP cases.

Organic acids in diets of weaned piglets: performance, digestibility and economical viability / Ácidos orgânicos em dietas para leitões desmamados: desempenho, digestibilidade e viabilidade econômica

Organic acids are used as feed additives to promote growth of weaned piglets since they prevent the occurrence of diarrhea. Thus, performance and digestibility assays were conducted and economic viability of diets was evaluated. In the performance assays, 64 hybrid piglets weaned with a mean weight of 5.87±0.31kg were divided in a randomized block design consisting of 4 treatments, 8 repetitions and 2 piglets per experimental unit (1 castrated male and 1 female). In the digestibility assay, 24 castrated male hybrid piglets with a mean weight of 8.21±0.79kg were individually assigned to 4 treatments and 6 repetitions. The treatments in the two assays were as follows: control, basal diet without addition of an acidifier; blend: inclusion of 0.5% of a mixture of organic acids; butyrate: inclusion of 0.1% of sodium butyrate; blend+butyrate: inclusion of 0.5% of a mixture of organic acids and 0.1% sodium butyrate. There was no effect (P>0.05) of the acidifiers on animal performance during the period studied. Organic acids exerted no effect (P>0.05) on the apparent digestibility coefficients of nutrients. Diets supplemented with sodium butyrate had an economic advantage for the period of 10-24 days. No episode of diarrhea was observed. This study demonstrated no effect of acidifier feed additives as growth promoters in complex diets for weaned piglets.(AU)

Ácidos orgânicos são utilizados como aditivos promotores de desempenho em leitões, pois podem prevenir a ocorrência de diarreias. Para tanto, foram conduzidos ensaios de desempenho, digestibilidade, e foi avaliada a viabilidade econômica das dietas. No desempenho, foram utilizados 64 leitões híbridos desmamados, com peso médio de 5,87±0,31kg, distribuídos em um delineamento em blocos ao acaso, com quatro tratamentos, oito repetições e dois leitões por unidade experimental (sendo um macho castrado e uma fêmea). Na digestibilidade, 24 leitões machos, castrados, híbridos, com peso médio de 8,21±0.79kg, foram alojados individualmente em quatro tratamentos e seis repetições. Em ambos os ensaios, os tratamentos foram: controle: dieta basal sem uso de acidificante; Blend: inclusão de 0,5% da mistura de ácidos orgânicos; butirato: inclusão de 0,1% de butirato de sódio; Blend+Butirato: inclusão de 0,5% da mistura de ácidos orgânicos e 0,1% butirato de sódio. Não houve efeito dos acidificantes (P>0,05) sobre o desempenho no período estudado. Não houve efeito dos ácidos orgânicos (P>0,05) sobre os coeficientes de digestibilidade aparente dos nutrientes. Dietas com suplementação de butirato de sódio apresentaram melhor vantagem econômica para o período de 10-24 dias. Não houve incidência de diarreia em nenhum período. Não ficou evidenciado o efeito dos aditivos acidificantes como promotores de crescimento em dietas complexas para leitões desmamados.(AU)

Use of colistin-containing products within the European Union and European Economic Area (EU/EEA): development of resistance in animals and possible impact on human and animal health.

Since its introduction in the 1950s, colistin has been used mainly as a topical treatment in human medicine owing to its toxicity when given systemically. Sixty years later, colistin is being used as a last-resort drug to treat infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae), for which mortality can be high. In veterinary medicine, colistin has been used for decades for the treatment and prevention of infectious diseases. Colistin has been administered frequently as a group treatment for animal gastrointestinal infections caused by Gram-negative bacteria within intensive husbandry systems. Given the ever-growing need to retain the efficacy of antimicrobials used to treat MDR infections in humans, the use of colistin in veterinary medicine is being re-evaluated. Despite extensive use in veterinary medicine, there is limited evidence for the development of resistance to colistin and no evidence has been found for the transmission of resistance in bacteria that have been spread from animals to humans. Since surveillance for colistin resistance in animals is limited and the potential for such transmission exists, there is a clear need to reinforce systematic monitoring of bacteria from food-producing animals for resistance to colistin (polymyxins). Furthermore, colistin should only be used for treatment of clinically affected animals and no longer for prophylaxis of diseases, in line with current principles of responsible use of antibiotics.

[Current strategies against multi-drug resistant organisms]. / Multiresistente Erreger - Infektionsmanagement 2015.

The global spread of multi-drug resistant organisms (MDRO) is a major threat to public health. Fighting MDRO spread requires a multi-faceted approach as summarized in the German Antibiotic Resistance Strategy (DART). In the hospital, this includes antibiotic stewardship concepts and strict infection control measures. Treatment of MDRO is sophisticated. Within the last years, several antibiotics with activity against MRSA were launched and facilitate an individual therapy according to site of infection and co-morbidities. In contrast, novel antibiotics against carbapenemase producing Gram-negatives are still lacking. Current studies have shown, that a colistin-based combination treatment can improve the prognosis in these patients. The following article reviews MDRO definitions, burden of disease, treatment options and general strategies against MDRO.

Multidrug-resistant Escherichia coli in Asia: epidemiology and management.

Escherichia coli has become multiresistant by way of production of a variety of ß-lactamases. The prevalence of CTX-M-producing E. coli has reached 60-79% in certain parts of Asia. The acquisition of CTX-M plasmids by E. coli sequence type 131, a successful clone of E. coli, has caused further dissemination of CTX-M-producing E. coli. The prevalence of carbapenemase-producing E. coli, especially Klebsiella pneumoniae carbapenemase, and New Delhi metallo-ß-lactamase (NDM)-producing E. coli has been increasing in Asia. K. pneumoniae carbapenemase and NDM have now been found in E. coli sequence type 131. The occurrence of NDM-producing E. coli is a major concern particularly in the Indian subcontinent, but now elsewhere in Asia as well. There are multiple reasons why antibiotic resistance in E. coli in Asia has reached such extreme levels. Approaches beyond antibiotic therapy, such as prevention of antibiotic resistance by antibiotic stewardship and protecting natural microbiome, are strategies to avoid further spread of antibiotic resistance.

Clinical, economic and societal impact of antibiotic resistance.

The concern over antibiotic resistance has been voiced since the discovery of modern antibiotics > 75 years ago. The concerns have only increased with time, with efforts to control resistance caused by widespread overuse of antibiotics in human medicine and far more than appreciated use in the feeding of animals for human consumption to promote growth. The problem is worldwide, but certain regions and selected health care institutions report far more resistance, including strains of Gram-negative bacteria that are susceptible only to the once discarded drugs polymyxin B or colistin, and pan-resistant strains are on the rise. One of the central efforts to control resistance, apart from antimicrobial stewardship, is the development of new antimicrobial agents. This has lagged significantly over the past 10 - 15 years, for a variety of reasons; but promising new agents are being developed, unfortunately none thus far addressing all potentially resistant strains. There is the unlikely, but not unreal, possibility that we could return to a pre-antibiotic era, where morbidity and mortality rates have risen dramatically and routine surgical procedures are not performed for fear of post-operative infections. The onus of control of resistance is a moral imperative that falls on the shoulders of all.

The cost effectiveness of dry powder antibiotics for the treatment of Pseudomonas aeruginosa in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) affects over 9,000 people in the UK and limits life expectancy. CF patients are susceptible to lung infections, most commonly Pseudomonas aeruginosa. Once infection is established, patients require lifetime treatment using nebulised antibiotics. Newer dry powder formulations of antibiotics may reduce treatment burden and improve compliance. OBJECTIVE: Our objective was to evaluate the cost effectiveness of (i) colistimethate sodium dry powder for inhalation (DPI) and (ii) tobramycin DPI versus nebulised tobramycin for the treatment of chronic P. aeruginosa lung infection in patients with CF from the perspective of the National Health Service (NHS) and Personal Social Services (PSS). METHODS: We developed a state transition model based on transitions between three strata of lung function measured in terms of forced expiratory volume in 1 second (FEV1) % predicted. Additional health states representing post-lung transplantation and dead are also modelled. The model structure was informed by systematic reviews of evidence concerning the plausibility of potential relationships between intermediate endpoints and final outcomes. The model assumes that treatment impacts on FEV1 trajectory, which manifest as changes in health-related quality of life. No survival benefit is assumed due to the absence of robust quantifiable evidence. Model parameters were informed by patient-level and aggregate data from two randomised controlled trials together with the best available evidence from the literature. Resource use and costs associated with drug acquisition, the management of exacerbations and reduced nebuliser maintenance were drawn from reference sources and expert opinion. Costs were valued at 2011/2012 prices. Costs and health outcomes were discounted at a rate of 3.5 %. Simple and probabilistic sensitivity analyses were undertaken, including additional analyses of Patient Access Scheme (PAS) price discounts offered by the manufacturers of both DPI products. RESULTS: Colistimethate sodium DPI is expected to produce fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Based on its list price, colistimethate sodium DPI is expected to be dominated by nebulised tobramycin. When the PAS is incorporated, the incremental cost-effectiveness ratio (ICER) for colistimethate sodium DPI versus nebulised tobramycin is expected to be approximately £288,600 saved per QALY lost. Based on its current list price, the ICER for tobramycin DPI versus nebulised tobramycin is expected to be approximately £124,000 per QALY gained. When the proposed PAS is included, tobramycin DPI is expected to dominate nebulised tobramycin. CONCLUSIONS: Under their list prices, neither DPI product is likely to represent good value for money for the NHS given current cost-effectiveness thresholds. The PAS discounts have a significant impact upon the economic attractiveness of both DPI products compared against nebulised tobramycin. The clinical effectiveness and cost effectiveness of the DPIs against other nebulised antibiotics, such as aztreonam and inhaled colistimethate sodium, remains unclear.

Biological cost of different mechanisms of colistin resistance and their impact on virulence in Acinetobacter baumannii.

Two mechanisms of resistance to colistin have been described in Acinetobacter baumannii. One involves complete loss of lipopolysaccharide (LPS), resulting from mutations in lpxA, lpxC, or lpxD, and the second is associated with phosphoethanolamine addition to LPS, mediated through mutations in pmrAB. In order to assess the clinical impacts of both resistance mechanisms, A. baumannii ATCC 19606 and its isogenic derivatives, AL1851 ΔlpxA, AL1852 ΔlpxD, AL1842 ΔlpxC, and ATCC 19606 pmrB, were analyzed for in vitro growth rate, in vitro and in vivo competitive growth, infection of A549 respiratory alveolar epithelial cells, virulence in the Caenorhabditis elegans model, and virulence in a systemic mouse infection model. The in vitro growth rate of the lpx mutants was clearly diminished; furthermore, in vitro and in vivo competitive-growth experiments revealed a reduction in fitness for both mutant types. Infection of A549 cells with ATCC 19606 or the pmrB mutant resulted in greater loss of viability than with lpx mutants. Finally, the lpx mutants were highly attenuated in both the C. elegans and mouse infection models, while the pmrB mutant was attenuated only in the C. elegans model. In summary, while colistin resistance in A. baumannii confers a clear selective advantage in the presence of colistin treatment, it causes a noticeable cost in terms of overall fitness and virulence, with a more striking reduction associated with LPS loss than with phosphoethanolamine addition. Therefore, we hypothesize that colistin resistance mediated by changes in pmrAB will be more likely to arise in clinical settings in patients treated with colistin.