Evaluation of in-vitro susceptibility of ß-lactam-resistant Gram-negative bacilli to ceftazidime-avibactam and ceftolozane-tazobactam from clinical samples of a general hospital in southern Brazil

ABSTRACT Background: The spread of carbapenemase- and extended-spectrum β-lactamase (ESBL)-producing gram-negative bacilli (GNB) represent a global public health threat that limits therapeutic options for hospitalized patients. This study aimed to evaluate the in-vitro susceptibility of β-lactam-resistant GNB to ceftazidime-avibactam (C/A) and ceftolozane-tazobactam (C/T), and investigate the molecular determinants of resistance. Methods: Overall, 101 clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected from a general hospital in Brazil were analyzed. Susceptibility to the antimicrobial agents was evaluated using an automated method, and the minimum inhibitory concentrations (MIC50/90) of C/A and C/T were determined using Etest®. The β-lactamase-encoding genes were investigated using polymerase chain reaction. Results: High susceptibility to C/A and C/T was observed among ESBL-producing Enterobacterales (100% and 97.3% for CLSI and 83.8% for BRCAST, respectively) and carbapenem-resistant P. aeruginosa (92.3% and 87.2%, respectively). Carbapenemase-producing Klebsiella pneumoniae exhibited high resistance to C/T (80%- CLSI or 100%- BRCAST) but high susceptibility to C/A (93.4%). All carbapenem-resistant K. pneumoniae isolates were susceptible to C/A, whereas only one isolate was susceptible to C/T. Both antimicrobials were inactive against metallo-β-lactamase-producing K. pneumoniae isolates. Resistance genes were concomitantly identified in 44 (44.9%) isolates, with bla CTX-M and bla SHV being the most common. Conclusions: C/A and C/T were active against microorganisms with β-lactam-resistant phenotypes, except when resistance was mediated by metallo-β-lactamases. Most C/A- and C/T-resistant isolates concomitantly carried two or more β-lactamase-encoding genes (62.5% and 77.4%, respectively).

Effect of Modified Gualou Zhishitang Combined with Piperacillin Sodium and Tazobactam Sodium on Immune Function and Serum Levels of Inflammatory Cytokines in Patients with Stroke-associated Pneumonia with Syndrome of Phlegm-heat Accumulation in Lung / 中国实验方剂学杂志

ObjectiveTo explore the effects of modified Gualou Zhishitang combined with piperacillin sodium and tazobactam sodium on the immune function and serum levels of inflammatory cytokines in the patients with stroke-associated pneumonia （SAP， syndrome of phlegm-heat accumulation in lung）. MethodEighty SAP patients with the syndrome of phlegm-heat accumulation in lung were randomized into a control group （40 cases） and a study group （40 cases）. The SAP patients in the control group were treated with piperacillin sodium and tazobtam sodium， while those in the study group were treated with modified Gualou Zhishitang on the basis of the treatment in the control group for 2 consecutive weeks. The clinical therapeutic effects， immune function indexes， inflammation indexes， and lung function of SAP patients in the two groups before and after treatment were determined and compared. ResultAfter treatment， the scores of lesion， pulmonary rales， cough， fever， phlegm color， and constipation in both groups decreased （P<0.05）. After treatment， the ratio of forced expiratory volume in the first second to forced expiratory volume （FEV1/FVC） and forced expiratory volume in the first second as percentage of predicted value（FEV1%） in both groups improved （P<0.05）， and the study group outperformed the control group （P<0.05）. The treatment decreased the neutrophil to lymphocyte ratio （NLR） in the two groups （P<0.05）， and the study group had lower NLR than the control group after treatment （P<0.05）. The serum levels of procalcitonin （PCT） and hypersensitive C-reactive protein （hs-CRP） in both groups declined after treatment （P<0.05）， and the declines were more significant in the study group than in the control group （P<0.05）. After treatment， the study group was better than the control group （P<0.05）. The treatment in both groups elevated the levels of CD3+， CD4+， and CD4+/CD8+ in the peripheral blood and lowered the level of CD8+ （P<0.05）， and the changes were more significant in the study group than in the control group （P<0.05）. The total response rate of the study group was 95.00% （38/40）， which was higher than that （80.00%， 32/40） of the control group （χ2=4.114，P<0.05）. There was no significant difference in the incidence of adverse reactions between the two groups. ConclusionModified Gualhou Zhishitang combined with piperacillin sodium and tazobactam sodium demonstrates a significant therapeutic effect on the SAP patients with the syndrome of phlegm-heat accumulation in lung. This therapy can mitigate the clinical symptoms， improve the lung function， lower the serum levels of inflammatory cytokines， and improve the immune capacity， with high safety.

Real-life comparison of three intravitreal antibiotic drug regimens in endophthalmitis

Purpose: Real?life comparison of three intravitreal drug regimens used in cases of endophthalmitis at a tertiary care center in India. Methods: In this prospective, comparative study, patients of bacterial endophthalmitis were grouped according to intravitreal antibiotic drug regimens into Group 1 (ceftazidime and vancomycin), Group 2 (piperacillin + tazobactam and vancomycin), and Group 3 (imipenem and vancomycin). Forty?eight hours after injection nonresponding/worsening patients underwent vitrectomy. Vitreous samples were subjected to microbiological and pharmacokinetic tests. Results: A total of 64 patients were included and divided into Group 1: 29, Group 2: 20, and Group 3: 15 cases. Also, 75% of patients were post?surgical endophthalmitis, whereas 25% were post?traumatic. Improvement in vision (V90?0) and vision at 3 months (V90) were comparable between the three groups. Visual recovery was poorer in post?traumatic cases. In post?surgical cases, visual recovery was poorer in those presenting beyond 72 h of onset of symptoms (P = 0.0002). Polymerase chain reaction (PCR) positivity (66%) was higher than BACTECTM (33%) and culture (14%). Antibiotic resistance was comparable amongst the three groups. Most patients (62/64) further underwent vitrectomy. Ceftazidime and vancomycin achieved vitreous concentrations more than the minimum inhibitory concentration (MIC) at 48 h after the first injection. Conclusion: The choice of antibiotics did not affect the rate of vitrectomy and final vision in a real?life scenario. Ceftazidime and vancomycin can still be used as first?line intravitreal antibiotics owing to their comparable microbial sensitivity profile and adequate ocular bioavailability

Clinical study of lactitol powder combined with piperacillin sodium and tazobactam sodium in the treatment of spontaneous bacterial peritonitis / 中国医师进修杂志

Objective:To investigate the effect of the lactitol powder combined with piperacillin sodium and tazobactam sodium in patients with spontaneous bacterial peritonitis (SBP), and the influence on the body microenvironment.Methods:The clinical data of 135 patients with SBP from January 2017 to December 2019 in Huxi Hospital Affiliated Jining Medical College were retrospectively analyzed. Among them, 68 patients were treated with lactitol powder combined with piperacillin sodium and tazobactam sodium (observation group), 67 patients were treated with piperacillin sodium and tazobactam sodium (control group). The curative effect was compared between 2 groups. The recovery time of clinical symptoms and signs (disappearance time of abdominal pain, disappearance time of abdominal distension, disappearance time of abdominal tenderness, recovery time of body temperature and recovery time of ascites white blood cell), liver function indexes (alanine aminotransferase, ALT; total bilirubin; albumin; aspartate aminotransferase, AST), microcirculation indexes (haptoglobin; procalcitonin; interleukin-6, IL-6; neutrophil gelatinase-associated lipocalin, NGAL), intestinal mucosal permeability indexes (endotoxin, blood ammonia, diamine oxidase) and adverse reactions (diarrhea, nausea and skin itching) were recorded.Results:The total effective rate in observation group was significantly higher than that in control group: 95.59% (65/68) vs. 82.09% (55/67), and there was statistical difference ( P<0.05). The disappearance time of abdominal pain, disappearance time of abdominal distension, disappearance time of abdominal tenderness, recovery time of body temperature and recovery time of ascites white blood cell in observation group were significantly shorter than those in control group: (6.15±1.34) d vs. (8.26±1.19) d, (5.34±1.29) d vs. (7.18±1.35) d, (7.59±1.65) d vs. (9.86±1.80) d, (5.28±1.20) d vs. (6.39±1.12) d and (10.87±2.25) d vs. (12.18±1.67) d, and there were statistical differences ( P<0.01). The ALT, total bilirubin, AST, haptoglobin, procalcitonin, IL-6, NGAL, endotoxin, blood ammonia and diamine oxidase 1 and 2 weeks after treatment in observation group were significantly lower than those in control group, and there were statistical differences ( P<0.01); there was no statistical difference in albumin between 2 groups ( P>0.05). There was no statistical difference in incidence of adverse reactions between2 groups ( P>0.05). Conclusions:The lactitol powder combined with piperacillin sodium and tazobactam sodium for SBP patients can more significantly improve the liver function and intestinal mucosal permeability, and promote the body microenvironment and the recovery of symptoms.

Exantema intertriginoso y flexural simétrico por fármacos: presentación de un caso / Symmetrical drug-related intertriginous and flexural exanthema: a case report

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a benign, self-limited, immune-mediated, symmetric erythematous rash involving the buttocks and other intertriginous/flexural areas, observed after systemic exposure to a drug in an individual with or without prior sensitization. We present a 70-year old patient, who presented SDRIFE after the administration of piperacillin-tazobactam which improved rapidly after its suspension.

El exantema intertriginoso y flexural simétrico relacionado con fármacos (SDRIFE, por su sigla en inglés) es una erupción eritematosa simétrica, inmunomediada, benigna y autolimitada, que compromete glúteos y otras áreas intertriginosas, flexurales o ambas, y que se observa luego de la exposición sistémica a un fármaco en un individuo con sensibilización previa o sin ella. Se comenta el caso clínico de un paciente de 70 años de edad, que presentó SDRIFE posterior a la administración de piperacilina-tazobactam y que mejoró rápidamente luego de su suspensión.

Efetividade da infusão estendida de Piperacilina-tazobactana - Meropenem no tratamento de pacientes sépticos adultos queimados através da modelagem farmacocinética farmacodinâmica, PK/P / Meropenem and piperacillin/tazobactam by extended infusion and PK/PD approach for drug effectiveness

Introdução: Meropenem (MER) e Piperacilina/Tazobactana (PTZ) são agentes antimicrobianos largamente prescritos para pacientes grandes queimados internados em Unidade de Terapia Intensiva (UTI) com infecções nosocomiais causadas por Gram-negativos sensíveis CIM 2 mg/L, Enterobacteriaceae, EB e Non-enterobacteriaceae, NEB. A síndrome da resposta inflamatória sistêmica (SRIS) que ocorre durante o choque séptico no grande queimado pode causar alteração na farmacocinética do paciente em terapia intensiva, de modo que a dose recomendada pode não atingir o alvo desejado contra Gram-negativos de sensibilidade intermediária CIM >2 mg/L. Objetivo: Investigar a efetividade dos beta-lactâmicos piperacilina e meropenem na infusão estendida comparada à infusão intermitente recomendada, para os pacientes sépticos grandes queimados através da abordagem farmacocinética-farmacodinâmica (PK/PD). Ética, casuística e procedimentos: Autor e co-autores declararam não haver conflito de interesse. O protocolo foi aprovado, registro CAAE 07525118.3.0000.0068. No presente protocolo de estudo investigaram-se 36 pacientes sépticos grandes queimados, ambos os gêneros (12F/24M) em terapia intensiva do choque séptico com piperacilina-tazobactana 4,5g q6h ou meropenem 1g q8h. Os pacientes incluídos foram estratificados em dois grupos com base na administração através da infusão intermitente, 0,5 h (G1) ou da infusão estendida, 3 h (G2), ambos com 16 pacientes cada. Duas amostras sanguíneas (1,5mL/cada) foram coletadas no estado de equilíbrio (Steady State), 3ª e 5ª hora do início da infusão. Os níveis séricos de PTZ e MER foram mensurados através de cromatografia líquida, e a farmacocinética (PK) dos dois grupos de pacientes foi comparada aos dados reportados em voluntários sadios. A abordagem PK/PD foi aplicada para avaliação da cobertura do antimicrobiano a partir da estimativa do índice de predição de efetividade (% fΔT>CIM) e da probabilidade de alcançar o alvo terapêutico (PTA) com base no alvo PK/PD recomendado, 100%fΔT>CIM. Resultados e discussão: As características de admissão dos pacientes G1/G2 foram expressas através de mediana e interquartil: Clcr 115 (90-148) / 127 (90-170) ml/min; 30 (24-31) / 27 (24- 33,5) anos, 70 (61-75) / 71 (65-75) kg, 30 (20-42) / 33,9 (18-38,4)% área total de superfície queimada, SAPS3 53 (45-57) / 48 (37,8-59,5). Na admissão dos pacientes na UTI registrou-se G1/G2: trauma térmico (17/16), trauma elétrico (1/2), lesão inalatória (11/11), ventilação mecânica (16/9) e vasopressores foram necessários em 15/8 pacientes, G1/G2. Ocorreram diferentes alterações na farmacocinética dos dois beta-lactâmicos após a infusão estendida versus a infusão intermitente quando comparadas com dados relatados em voluntários sadios. Evidenciou-se prolongamento da meia vida decorrente do aumento do volume de distribuição. Estes resultados impactaram diferentemente a cobertura. O monitoramento de biomarcadores inflamatórios expressos em medianas (G1/G2) evidenciou aumento do PCR: 232/183mg/L e leucocitose (leucócitos 11/14 mil cel/mm3, neutrófilos 9/10 mil cel/mm3) na fase precoce do choque séptico. Relativamente à microbiologia dos isolados, a erradicação dos patógenos ocorreu para todos os pacientes após a infusão estendida contra Gram-negativos sensíveis (CIM: 2 mg/L), e de sensibilidade intermediária (CIM 4mg/L) como a K. pneumoniae e P. aeruginosa, enquanto a infusão intermitente garantiu erradicação de patógenos apenas até CIM 2 mg/L. Conclusão: Evidenciou-se a superioridade da infusão estendida frente à infusão intermitente na cobertura dos dois antimicrobianos, no alvo terapêutico considerado 100%fΔT>CIM. Registraram-se alterações na farmacocinética destes agentes nos pacientes frente aos dados reportados para voluntários sadios. Diferença significativa entre grupos (G1/G2) foi encontrada com relação meia vida biológica, e ao volume de distribuição tanto pata a piperacilina quanto para o meropenem

Background: Meropenem (MER) and Piperacillin/Tazobactam (PTZ), antimicrobial betalactam agents are widely prescribed to burn patients from the Intensive Care Unit (ICU) with nosocomial infections caused by Gram-negative strains. Change in the pharmacokinetics of critically ill patient occurs during the systemic inflammatory response syndrome (SIRS) at the course of septic shock. Then, the recommended dose administered by intermittent infusion, 0.5 hr cannot reach the target against gram-negative strains MIC > 2 mg/L. Subject: To investigate drug effectiveness of the beta-lactams piperacilin and meropenem in extended infusion compared to the recommended intermittent infusion in critically ill septic burn patients using pharmacokinetic-pharmacodynamic (PK/PD) approach. Ethics, Casuistry and Methods: All authors declared there is no conflict of interests. Ethical approval CAAE, register 07525118.3.0000.0068. It was investigated in the study protocol 36 septic burn patients of both genders (12M / 24F), undergoing antimicrobial therapy with PTZ 4.5 g q6h or MER 1g q8h. Based on the chosen antimicrobial therapy and drug infusion prescribed by the physician, patients were stratified in groups with intermittent 0.5h infusion (G1) or with the extended 3h infusion (G2), both groups with 16 patients each. Two blood samples were collected at the steady state (1.5mL / each), at the 3rd and 5th hrs of starting the infusion. Serum levels were measured by liquid chromatography. Pharmacokinetics (PK) of MER or PTZ was compared to data reported in healthy volunteers for both groups of patients. PK/PD approach was applied to estimate the drug effectiveness index (fΔT> MIC) and to assess the probability of target attained (PTA) based on the recommended PK/PD target, 100% fΔT> MIC. Results and discussion: Characteristics of patients admission G1/G2 were: Clcr 115(90- 148)/127(90-170) ml/min; 30(24-31)/27(24-34) yrs, 70(61-75)/71(65-75) kg, 30(20- 42)/33.9(18-38.4)% total burn surface area, SAPS3 53(45-57)/48(37.8-59.5), medians (interquartile): thermal trauma occurred (17/16), electric trauma (1/2), inhalation injury (11/11), mechanical ventilation (9/16) and vasopressors required in 15/8 patients. It was demonstrated that different PK changes occurred for both beta-lactam agents after the extended or intermittent infusion by comparison with data reported in healthy volunteers. PK changes were related to the prolongation of biological half-life and increases on volume of distribution with impact on pharmacodynamics. On the other hand, meropenem total body clearance reduced by 50% at the earlier period of septic shock could be explained by the reduction of MER-transporters expression in the tubular renal secretion, once only patients with renal function preserved were included in the study protocol. Inflammatory biomarkers increased at the earlier period of septic shock: C-rp 232/183mg/L; leukocytes 11/14*103cel/mm3, neutrophils 9/10*103cel/mm3, medians, G1/G2. Clinical and microbiological cure was obtained for all patients of G1 against MIC < 2mg/L after intermittent 0.5 h infusion; while PK/PD target was attained for G2 patients undergoing antimicrobial therapy with MER or PTZ by extended infusion against gram negative strains K. pneumoniae, P. aeruginosa up to MIC 4mg L. Conclusion: Superiority of the extended infusion over intermitent infusion was obtained for the two antimicrobials was evidenced, in the therapeutic target considered 100%fΔT>CIM. Changes in the pharmacokinetics of these agents were recorded in patients compared to data reported for healthy volunteers. A significant difference between groups (G1/G2) was found in relation to biological half-life and volume of distribution for both piperacillin and meropenem

Evaluation of the effect of antibiotics used during parenteral nutrition treatment on Candidemia

SUMMARY OBJECTIVE: Parenteral nutrition is an important risk factor for candidemia. In this risk analysis study, the effect of previous antibiotic administration apart from the length of hospital stay, duration of Parenteral nutrition treatment, and Candida score parameters on developing candidemia was evaluated in the non-neutropenic patients receiving Parenteral nutrition treatment. METHODS: In this double center, retrospective, and cross-sectional study, the data of patients who received Parenteral nutrition treatment were collected. Patients with or without candidemia after the initiation of Parenteral nutrition treatment were compared in terms of demographic features, Candida score, length of hospital stay, duration of Parenteral nutrition treatment, and previous use of antibiotics. Then, predictor factors affecting the probability of candidemia during Candida growth time were determined by the Cox regression analysis. RESULTS: A total of 148 patients (59.5% males) were included and 16 (10.81%) of these had candidemia after initiation of parenteral nutrition treatment. The median (min-max) duration of parenteral nutrition treatment was 11 (4-72) days and the Candida growth time was 13 (7-29) days. Statistically significant differences were found between patients with or without candidemia groups in terms of length of hospital stay (p<0.001), duration of parenteral nutrition treatment (p<0.001), and Candida score (p<0.001). To determine the effect of these variables and antibiotics on candidemia, length of hospital stay [Hazard Ratio 1.030; p=0.021] and piperacillin-tazobactam (Hazard Ratio 5.626; p=0.030) were found significant and independent risk factors on the development of candidemia. CONCLUSION: There are some well-known risk factors including length of hospital stay, duration of Parenteral nutrition treatment, and Candida score; the potential impact of piperacillin-tazobactam administration should also be considered since they may be effective on the development of candidemia.

Eficacia y seguridad del tratamiento empírico con piperacilina/tazobactan como monoterapia en episodios de neutropenia y fiebre en niños con cáncer: revisión sistemática y meta-análisis / Efficacy and safety of empirical treatment with piperacillin/tazobactan as monotherapy in episodes of neutropenia and fever in children with cancer: systematic review and meta-analysis

INTRODUCCIÓN: La neutropenia febril en niños con patología oncohematològica requiere un tratamiento empírico precoz y adecuado. Esta revisión sistemática se realizó para evaluar si piperacilina/tazobactam (PTZ) monoterapia es más efectiva y segura que los comparadores, en niños con episodios de neutropenia febril de causa oncológica. MATERIAL Y MÉTODOS: Se realizó una búsqueda bibliográfica en Embase, MEDLINE utilizando los términos de búsqueda (('febrile neutropenia' OR hemato oncology OR haemato oncology OR 'immunocompromised host' OR 'immunocompromised patient' OR 'chemotherapy-induced febrile neutropenia') AND (piperacillin OR tazobactam OR 'piperacillin plus tazobactam' OR 'piperacillin/tazobactam' OR 'piperacillin-tazobactam' OR tazocin OR 'piperacillin-tazobactam drug combination')). El criterio de valoración de eficacia fue la incidencia de fracaso terapéutico. El punto final de seguridad fue la ausencia de cualquier efecto adverso (EA). RESULTADOS: Se identificaron 1.388 estudios, de los cuales se incluyeron 11 que cumplían los criterios de elegibilidad. Los estudios presentaron notable homogeneidad ( I 2 0%) y no se detectó sesgo de publicación (p 0,36). El riesgo de fracaso terapéutico de PTZ no fue mayor que en los comparadores (RR global: 0,94; IC95% 0,83 a 1,07) como tampoco lo fue, la incidencia de EA. CONCLUSIONES: El riesgo de fracaso terapéutico no fue superior para la PTZ como monoterapia frente a los comparadores

BACKGROUND: Febrile neutropenia in children with onco-hematological diseases is an important cause of morbidity and mortality and requires early and adequate empirical treatment. This systematic review was conducted to evaluate if piperacillin/ tazobactan (PTZ) monotherapy leads to a lower incidence of therapeutic failures than comparators. METHODS: A literature search was carried out in Embase, and MEDLINE databases using the search terms ('febrile neutropenia' OR hemato oncology OR haemato oncology OR 'immunocompromised host' OR 'immunocompromised patient' OR 'chemotherapy-induced febrile neutropenia') AND (piperacillin OR tazobactam OR 'piperacillin plus tazobactam' OR 'piperacillin/tazobactam' OR 'piperacillin-tazobactam' OR tazocin OR 'piperacillin-tazobactam drug combination')), Efficacy endpoint was treatment failure rate. The safety end-point was absence of any adverse effects (AE). RESULTS: Eleven studies were included. No heterogeneity was detected ( I 2 0%). The risk of failure was not superior for piperacillin/tazobactan to comparators (Global RR: 0.94; IC95% 0.83 a 1.07). Rates of adverse events were similar among studies. No publication bias was detected (p 0.36). CONCLUSIONS: This systematic review and meta-analysis showed that treating episodes of febrile neutropenia in oncology pediatric patients, the risk of failure for PTZ was not superior to comparators. Adverse events were similar to the comparators.

Piperacillin and Its Compound Preparation-induced Anaphylactic Shock ：A Case Report and Literature Analysis / 中国药房

OBJECTIVE：To i nvestigate the clini cal ch aracteristics of anaphylactic shock induced by piperacillin and its compound preparation ，and to provide reference for prevention and treatment of the severe ADR. METHODS ：A case of anaphylactic shock induced by piperacillin and sulbactam were analyzed in our hospital ，meanwhile ADR literatures about piperacillin alone and its compound preparation-induced anaphylactic shock were collected from Medline ，CNKI，Wanfang database and VIP during the inception to Jul. 2020. Gender and age of patients ，allergic history ，primary disease and treatment ，skin test ， administration route and dosage of piperacillin and its compound preparation ，occurrence time and main manifestations of anaphylactic shock ，treatment measure and prognosis were analyzed ，then prevention and treatment suggestions were put forward. RESULTS：The patient in this case was transferred to the ICU after partial hepatectomy. The use of piperacillin and sulbactam to prevent postoperative infection caused anaphylactic shock. A total of 28 literatures about anaphylactic shock induced by piperacillin and its compound preparations were collected from the database （involving 28 patients）. Among totally 29 patients，there were 12 male and 17 female；the majority of patients were 50-59 years old （6 cases，20.69％）. Three patients had allergic history （food， latex gloves ，etc.），and most of the primary diseases were infectious diseases or the drug used in perioperative period. Skin tests were carried out in 22 patients（75.86％）before medication and the results were negative. The possible allergenic drugs of 27 cases which were administered by intravenous route included piperacillin ，piperacillin sulbactam and piperacillin tazobactam. The dosage was different according to the primary disease and severity. 14 patients（55.56％）developed anaphylactic shock within 5 minutes after drug exposure. The main symptoms were systemic allergic reaction ，mainly involving the circulatory system. Except for two death cases ，the other patients ’symptoms were relieved after treatment. CONCLUSIONS ：Allergic history and skin test results may have limitation in predicting anaphylactic shock induced by piperacillin and its compound preparation. Close monitoring needs to be taken in patients during these medications. Rescue therapy should be prepared in advance and countermeasures need to be carried out promptly in case of anaphylactic shock.

Establishment of national reference standard of tazobactam impurity A / 中国药科大学学报

@#To improve the standard of quality control of tazobactam and its preparations in China, national reference standard of tazobactam impurity A was developed. After tazobactam impurity A was synthesized, its structure was validated by infrared (IR), mass spectrometry (MS) and nuclear magnetic resonance (NMR), and its content uniformity and short-term stability were measured and investigated. Then, water content and residue on ignition of impurity A were determined, and its purity was determined using high performance liquid chromatography (HPLC) with 10 mmol/L ammonium acetate solution-acetonitrile (98∶2) as the mobile phase. Mass balance method was used to determine the content of the first batch of tazobactam impurity A national standard substance. Meanwhile, nuclear magnetic quantitative method was used to calculate the content, which was mutually verified with the mass balance method. The developed reference material of tazobactam impurity A is consistent with the maximum degradation impurity in tazobactam system applicability solution and the reference material of tazobactam related substance A contained in USP41. Within the 95% confidence range, the ratio of inter- and intra-bottle variance of impurity A after separation was 0.61 (< F0.05(11,12)), proving that the uniformity was satisfying. The contents of organic impurity, water content and inorganic impurity in impurity A were 0.90%, 1.24% and 0.25%, respectively. The content of impurity A was determined to be 97.6% by mass balance method, which was basically consistent with the result of nuclear magnetic quantitative method (97.1%). Under the condition of 25 °C, the area normalized purity of impurity A was 99.1% at 0, 3, 5 and 10 days, proving that the sample was stable at room temperature for 10 days. Finally the first batch of national standard substance of tazobactam impurity A was established successfully.

Activity of ceftolozane-tazobactam and comparators against gram-negative bacilli: Results from the study for monitoring antimicrobial resistance trends (SMART - Brazil; 2016-2017)

Abstract Multi-drug resistant Gram-negative bacilli (GNB) have been reported as cause of serious hospital-acquired infections worldwide. The aim of this study was to investigate the in vitro activity of ceftolozane-tazobactam compared to other agents against GNB isolated from patients admitted to Brazilian medical centers between the years 2016 and 2017. Presence of β-lactamase encoding genes was also evaluated. Methods Antimicrobial susceptibility testing of GNB isolated from intra-abdominal (IAI), respiratory (RTI), and urinary tract infections (UTI) was performed according to ISO 227-1 guidelines and interpreted following CLSI and BrCAST/EUCAST guidelines. Qualifying Enterobacteriaceae isolates were screened for the presence of β-lactamase genes by PCR followed by DNA sequencing. Results 1748 GNB collected from UTI (45.2%), IAI (25.7%) and RTI (29.1%) were evaluated. Ceftolozane-tazobactam remained highly active (94.7%) against E. coli isolates. Among K. pneumoniae, susceptibility rates were 85.9% and 85.4% for amikacin and colistin, whereas ceftolozane-tazobactam (44.1% susceptible) and carbapenems (55.2-62.2% susceptible) showed poor activity due to bla KPC-2. Against E. cloacae amikacin, imipenem, and meropenem retained good activity (>90%). Ceftolozane-tazobactam was the most potent β-lactam agent tested against P. aeruginosa (90.9% susceptible), including ceftazidime and imipenem resistant isolates. β-lactamase encoding genes testing was carried out in 433 isolates. bla CTX-M variants were predominant in E. coli, P. mirabilis and E. cloacae. Among the K. pneumoniae molecularly tested, most carried bla KPC (68.5%), with all harboring bla KPC-2, except two isolates carrying bla KPC-3 or bla KPC-30. ESBL encoding genes, mainly CTX-M family, were frequently detected in K. pneumoniae, plasmid-mediated AmpC were rare. A variety of PDC encoding genes were detected in P. aeruginosa isolates with five isolates harboring MBL and one KPC encoding genes. Conclusion Ceftolozane-tazobactam was very active against E. coli, P. mirabilis and P. aeruginosa isolates and could constitute an excellent therapeutic option including for those isolates resistant to extended-spectrum cephalosporins and carbapenems but not producers of carbapenemases.

Concentraciones plasmáticas de piperacilina/tazobactam en pacientes pediátricos críticos sometidos a ECMO: análisis preliminar / Plasmatic concentracion of piperacillin/tazobactam in pediatric patients on ECMO support: preliminary analysis

Resumen Introducción: Se desconocen las alteraciones farmacocinéticas de piperacilina/tazobactam (PT) en pacientes pediátricos que requieren de membrana de oxigenación extracorpórea (ECMO) y cómo dosificar adecuadamente dicho antimicrobiano. Objetivo: Describir las concentraciones plasmáticas (CP)y evaluar el cumplimiento del objetivo farmacocinético/famacodinámico de piperacilina en pacientes pediátricos en soporte con ECMO. Métodos: Presentamos tres pacientes pediátricos en tratamiento con PT que requirieran de ECMO en los que se midieron CP de piperacilina en la mitad del intervalo de dosificación mediante cromatografía liquida de alta resolución. Resultados: Las CP fueron 51,7-14,1 y 6,5 μg/mL para los pacientes A, B y C, respectivamente. Sólo se alcanzaron CP adecuadas en un paciente. Conclusión: Estos resultados preliminares sugieren que la disponibilidad de CP de piperacilina podría optimizar el cumplimiento de los objetivos farmacocinéticos/farmacodinámicos en pacientes pediátricos en soporte con ECMO.

Abstract Background: Pharmacokinetics and optimal dosing of piperacillin tazobactam (PT) have not been well studied in pediatric patients undergoing extracorporeal oxygenation membrane (ECMO). Aim: To describe piperacillin plasmatic concentration and evaluate achievement of pharmaccokinetic/pharmacodinamic objective in patients on ECMO support. Method: We report three pediatric patients admitted to the Pediatric Intensive Care Unit, treated with PT undergoing ECMO. Plasmatic concentrations of piperacillin were obtained in the middle of the dosing interval using high performance liquid chromatography. Results: Plasmatic concentrations were 51,7-14,1 and 6,5 μg/mL for patient A, B and C respectively. Only one patient reached adequate concentrations. Conclusion: These preliminary results suggest that availability of plasmatic concentrations of piperacillin could optimize the achievement of pharmacokinetic/pharmacodynamic objectives in pediatric patients on ECMO support.

Evaluation of in vitro activity of ceftolozane-tazobactam against recent clinical bacterial isolates from Brazil - the EM200 study

ABSTRACT Background: The emergence of antibiotic resistance is increasing and there are few effective antibiotics to treat infections caused by resistant and multidrug resistant bacterial pathogens. This study aimed to evaluate the in vitro activity of ceftolozane-tazobactam against clinical bacterial isolates from Brazil. Methods: A total of 673 Gram-negative bacterial isolates including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and other Enterobacterales collected from 2016 to 2017 were tested, most of them isolated from patients in intensive care units. Minimum inhibitory concentrations (MIC50/90) were determined by broth microdilution for amikacin, aztreonam, cefepime, cefotaxime, cefoxitin, ceftolozane-tazobactam, ceftazidime, ceftriaxone, ciprofloxacin, colistin, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam using dried panels. Antimicrobial susceptibility results were interpreted according to Clinical and Laboratory Standards Institute criteria. Results: Susceptibility rates to ceftolozane-tazobactam ranged from 40.4% to 94.9%. P. aeruginosa susceptibility rate to ceftolozane-tazobactam was 84.9% (MIC50/90, 1/16 µg/mL) and 99.2% to colistin. For E. coli, ceftolozane-tazobactam inhibited 94.9% (MIC50/90, 0.25/1 µg/mL) of the microorganisms. The susceptibility rate of K. pneumoniae to ceftolozane-tazobactam was 40.4% (MIC50/90, 16/>32 µg/mL). Other Enterobacterales have shown susceptibility rates of 81.1% (MIC50/90, 0.5/16 µg/mL) to ceftolozane-tazobactam, 93.9% to meropenem, 90.9% to amikacin (90.9%), and 88.6% to ertapenem. In non-carbapenemase producing isolates, AmpC mutations were found three isolates. Conclusions: Ceftolozane-tazobactam has shown relevant activity against a large variety of the analyzed microorganisms collected from multiple centers in Brazil, showing promising results even in multidrug resistant strains.

Cost-effectiveness of ceftolozane/tazobactam for the treatment of complicated intraabdominal and urinary tract infections in Colombia / Costo-efectividad de ceftolozano/tazobactam para el tratamiento de las infecciones intraabdominales e infecciones del tracto urinario complicadas en Colombia

Objective: To evaluate the cost-effectiveness of ceftolozane/tazobactam + metronidazole (C/T+M) and ceftolozane/tazobactam (C/T) compared with 8 alternatives used in the treatment of complicated intraabdominal infection (cIAI) and complicated urinary tract infection (cUTI) respectively. Methods: A Monte Carlo simulation decision model was used for the estimation and comparison of treatment-related costs, and quality adjusted life years for patients with cIAI treated with C/T+M in comparison with cefepime + metronidazole, ciprofloxacin + metronidazole, doripenem, levofloxacin + metronidazole, meropenem, piperacillin/tazobactam, ceftazidime + metronidazole or imipenem/cilastatin and patients with cUTI treated with C/T in comparison with cefepime, ciprofloxacin, doripenem, levofloxacin, meropenem, piperacillin/tazobactam, ceftazidime or imipenem/cilastatin. Local costs were estimated using base cases identified by experts and consulting local databases. Sensitivity values of the PACTS (Program to Assess Ceftolozane/Tazobactam Susceptibility) study in Latin America were used in the model. Results: C/T+M and C/T obtained incremental cost-effectiveness ratios (ICER) that were below the Colombian cost-effectiveness threshold (3 GDP per capita) in most comparisons, and were dominated by meropenem, considering only gram-negative microorganisms. Sensitivity assessments were also carried out, in which only the population with P. aeruginosa infections was considered, showing positive results for C/T+M and C/T (cost-effective or dominant with regards to all comparators). Conclusions: C/T+M and C/T could be cost-effective alternatives in the treatment of CIAI and CUTI in Colombia, when there is an adequate and rational use of antibiotics. The results of the sensitivity analyses showed dominance and cost-effectiveness with regards to every comparator in patients infected with P. aeruginosa

Objetivo: Evaluar la costo-efectividad de ceftolozano/tazobactam + metronidazol (C/T + M) y ceftolozano/tazobactam (C/T) en comparación con 8 alternativas utilizadas en el tratamiento de las infecciones intraabdominales complicadas (IAAc) e infecciones del tracto urinario complicadas (ITUc) respectivamente. Métodos: Se usó un modelo de decisión de simulación de Monte Carlo para la estimación y comparación de los costos relacionados con el tratamiento y los años de vida ajustados por calidad para pacientes con IAAc tratados con C/T + M, en comparación con cefepima + metronidazol, ciprofloxacina + metronidazol, doripenem , levofloxacina + metronidazol, meropenem, piperacilina / tazobactam, ceftazidima + metronidazol o imipenem/cilastatina, y pacientes con ITUc tratados con C/T en comparación con cefepime, ciprofloxacina, doripenem, levofloxacina, meropenem, piperacilina / tazobactam, ceftazidima o imipenem/cilastatina . Los costos locales se estimaron por medio de casos base identificados por expertos y consultando bases de datos locales. Se utilizaron los valores de sensibilidad bacteriana del estudio PACTS (Programa para evaluar la susceptibilidad al ceftolozano/tazobactam) en América Latina para poblar el modelo. Resultados: C/T + M y C/T obtuvieron razones de costo-efectividad incrementales (RCEI) que estaban por debajo del umbral de costo-efectividad colombiano (3 PIB per cápita) en la mayoría de las comparaciones, y fueron dominados por meropenem, considerando solo microorganismos gran-negativos También se llevaron a cabo análisis de sensibilidad, en los que solo se consideró la población con infecciones por P. aeruginosa, mostrando resultados positivos para C/T + M y C/T (costo efectivo o dominante con respecto a todos los comparadores). Conclusiones: C/T + M y C/T podrían ser alternativas costo efectivas en el tratamiento de IAAc e ITUc en Colombia, cuando existe un uso adecuado y racional de antibióticos. Los resultados de los análisis de sensibilidad mostraron dominio y costo-efectividad en relación con todos los comparadores en pacientes infectados con P. aeruginosa.

Effectiveness analysis of clinical pharmacists intervention in the clinical application of piperacillin-tazobactam based on PDCA / 药学实践杂志

Objective To explore the effect of the intervention of clinical pharmacists on the rational use of piperacillin-tazobactam by using PDCA cycle, in order to provide reference for rational drug use. Methods The problems of piperacillin-tazobactam in our hospital was analyzed. PDCA cycle was used to manage the problems. Then, the data before and after PDCA cycle was compared and analyzed. Results After using PDCA cycle, the irrational use rate of piperacillin-tazobactam gradually decreased, from 9% in February 2018 to 2% in February 2019; the doses decreased from 4380 in February 2018 to 3346 in February 2019; and the frequency of usage decreased from 391 DDDs in February 2018 to 298 DDDs in February 2019. The effectiveness and continuous improvement of PDCA cycle in managing piperacillin-tazobactam were significant. Conclusion PDCA cycle can effectively improve the management effectiveness of piperacillin-tazobactam administration.

Nuevos antibióticos en la era de la multiresistencia: revisión sobre ceftolozano/tazobactam y ceftazidima/avibactam / New antibiotics in the multiresistance era: review about ceftolozane/tazobactam and ceftazidime/avibactamISSN 2314-3193. Actualizaciones en sida e infectología. Buenos Aires. noviembre 2020. volumen 28. número 103: 57-71

En los últimos años se han desarrollado nuevos antimicrobianos destinados a combatir infecciones causadas por microorganismos multirresistentes a drogas (MDR), incluyendo combinaciones entre agentes ß-lactámicos (BL) e inhibidores de ß-lactamasas (IBL). En nuestro país se encuentran disponibles dos nuevas combinaciones de BL/IBL: ceftolozano/tazobactam (C/T) y ceftazidima/avibactam (CAZ/AVI). La adición de tazobactam a ceftolozano incrementa la actividad in vitro contra microorganismos productores de BL de espectro extendido (BLEE), por lo que la combinación presenta una potente actividad intrínseca frente a P. aeruginosa. Por su parte, CAZ/AVI conserva las características que definen el perfil de actividad de ceftazidima, por lo que con el agregado de avibactam presenta una potente actividad inhibidora frente a las BLEE y carbapenemasas (KPC, ß-lactamasas de clase C y algunas de clase D). Se presenta a continuación una revisión de la evidencia publicada. A partir de la misma, y considerando la situación actual de tasas crecientes de resistencia antimicrobiana, particularmente en bacilos Gram negativos, se considera que el uso de C/T o CAZ/AVI constituye una excelente alternativa para el manejo de infecciones graves causadas por microorganismos multirresistentes. Sin embargo, su utilización en forma empírica no es recomendable, salvo en situaciones puntuales y estrictamente seleccionadas, y en el contexto un programa de uso racional de antibióticos, bajo el control por parte del equipo de infectología responsable

In recent years, new antimicrobials have been developed to combat infections caused by multidrug-resistant microorganism (MDR), including combinations between ß-lactam agents (BL) and ß-lactamase inhibitors (IBL). Two new combinations of BL / IBL are available in our country: ceftolozano / tazobactam (C / T) and ceftazidime / avibactam (CAZ / AVI). The addition of tazobactam to ceftolozano increases in vitro activity against microorganisms producing extended spectrum BL (ESBL), so the combination has a potent intrinsic activity against P. aeruginosa. For its part, CAZ / AVI retains the characteristics that define the activity profile of ceftazidime, to which with the addition of avibactam it presents a potent inhibitory activity against ESBL and carbapenemases (KPC, ß-lactamases of class C and some of class D). A review of the published evidence is presented below. Based on this, and considering the current situation of increasing rates of antimicrobial resistance, particularly in Gram-negative bacilli, we consider that the use of C/T or CAZ/AVI is an excellent alternative for the management of serious infections caused by multi-resistant microorganisms. However, its use empirically is not recommended, except in specific and strictly selected situations, and in the context of a program for the rational use of antibiotics, under the control of the responsible infectious disease team

Evaluación de la sensibilidad de cepas de Pseudomonas aeruginosa multi-resistentes frente a ceftolozano/tazobactam / Evaluation of susceptibility of multidrug-resistant Pseudomonas aeruginosa strains against ceftolozane/tazobactam

Resumen Introducción: Pseudomonas aeruginosa es un patógeno oportunista asociado a alta morbi-mortalidad. Para cepas multi-resistentes (MDR), ceftolozano/tazobactam (CTZ) se ha autorizado por la Agencia Europea del Medicamento (EMA) para infecciones del tracto urinario complicadas, pielonefritis aguda e infecciones intra-abdominales complicadas. Objetivo: Determinar la sensibilidad a CTZ de P. aeruginosa MDR en muestras clínicas aisladas en el Hospital Universitario Puerto Real. Material y Métodos: Se estudió la sensibilidad según criterios EUCAST a CTZ de cepas de P. aeruginosa MDR, entre enero de 2015 y agosto de 2017. Los criterios de multi-resistencia fueron definidos por el Centers for Disease Control and Prevention. La sensibilidad antimicrobiana se obtuvo mediante sistema MicroScan® (Beckman Coulter). La sensibilidad a CTZ se determinó mediante tiras de gradiente (Liofilchem®, Werfen). Resultados: De 1253 cepas, 7% fueron MDR. Se estudió la sensibilidad de 78 cepas de P. aeruginosa MDR, de las cuales cinco (6,4%) resultaron resistentes a CTZ según criterios EUCAST. Conclusiones: En nuestro medio la resistencia in vitro a CTZ en cepas de P. aeruginosa MDR es aproximadamente 6%; CTZ es una opción de tratamiento de infecciones por cepas de P. aeruginosa MDR cuando no exista otra alternativa y se haya comprobado su sensibilidad in vitro.

Background: Pseudomonas aeruginosa is an opportunistic pathogen associated with high morbidity and mortality. For multidrug-resistant strains (MDR), ceftolozane/tazobactam (CTZ) has been authorized by the European Medicines Agency (EMA) for complicated urinary tract infections, acute pyelonephritis, and complicated intraabdominal infections. Aim: To determine the susceptibility to CTZ of P. aeruginosa MDR in isolated clinical samples at the University Hospital Puerto Real. Methods: The susceptibility according to the EUCAST to CTZ criteria of strains of P. aeruginosa MDR, between January 2015 and August 2017 has been studied. The multiresistance criteria were those defined by the Centers for Disease Control and Prevention. The antibiotic susceptibility was obtained by automated MicroScan® system (Beckman Coulter). Susceptibility to CTZ was determined using gradient strips (Liofilchem®, Werfen). Results: Of 1253 strains isolated, 7% presented MDR. We studied the susceptibility of a total of 78 strains of MDR P. aeruginosa, of which 5 (6.4%) were resistant to CTZ according to the EUCAST criteria. Conclusions: In our environment, the in vitro resistance to CTZ in MDR P. aeruginosa strains is approximately 6%. CTZ is an option for the treatment of infections by MDR P. aeruginosa when there is no other alternative and its in-vitro susceptibility has been proven.

Delftia acidovorans pneumonia with lung cavities formation / Neumonia con formación de cavidades pulmonares causada por Delftia acidovorans

Abstract Case Description: A 52-year-old female patient was admitted to our clinic with complaints of cough, sputum, fever and fatigue. The patient has been receiving immunosuppressive therapy for thrombocytopenic purpura for 5 years. Clinical Finding: Inspiratory crackles were heard on both hemithorax. Oxygen saturation measured with the pulse oximeter was 97%. Chest X-ray showed diffuse reticular opacities that were more prominent in the upper zones of both lungs. WBC counts were 17,600 mm3 and Platelet counts were 29,000 mm3. Thorax CT showed that there were many thin-walled cavities and millimetric nodules accompanied by ground-glass infiltrates in the upper and middle lobes. Gram staining of bronchial fluid, taken by bronchoscopy, revealed Gram-negative bacilli and intense polymorphonuclear leukocytes. The bacteria were defined as Delftia acidovorans by BD Phoenix automated system. Treatment and outcomes: The patient was hospitalized with suspicion of opportunistic pulmonary infections and cavitary lung disease. After the empirical treatment of intravenous piperacillin-tazobactam and oral clarithromycin, her clinical and radiological findings significantly regressed, and she was discharged with outpatient follow-up. Clinical Relevance: This is the first example of cavitary pneumonia due to Delftia acidovorans in an immunocompromised patient. We would like to emphasize that Delftia pneumonia should be considered in the differential diagnosis of pulmonary cavitary involvement in such patients.

Resumen Descripción del caso: Una mujer de 52 años llegó a la clínica con tos, esputo, fiebre y fatiga. El paciente estuvo recibiendo terapia inmunosupresora durante 5 años para el tratamiento de la púrpura trombocitopénica. Hallazgo clínico: se escucharon crepitaciones inspiratorias en ambos hemitórax. La saturación de oxígeno fue del 97%. La radiografía de tórax mostró opacidades reticulares difusas que eran más prominentes en las zonas superiores de ambos pulmones. Los recuentos de leucocitos fueron de 17,600 mm3 y los recuentos de plaquetas fueron de 29,000 mm3. La TC de tórax mostró muchas cavidades de pared delgada y nódulos milimétricos acompañados de infiltrados vitrales en los lóbulos superior y medio. La tinción de Gram del líquido bronquial reveló bacilos gramnegativos y leucocitos polimorfonucleares. Las bacterias fueron identificadas como Delftia acidovorans. Tratamiento y resultados: La paciente fue hospitalizado con una sospecha de infección oportunista pulmonar y enfermedad pulmonar cavitaria. Después del tratamiento empírico de piperacilina-tazobactam intravenosa y claritromicina oral, los síntomas y signos retrocedieron significativamente, y fue dada de alta con seguimiento ambulatorio. Relevancia clínica: este es el primer registro de neumonía cavitaria causado por Delftia acidovorans en una paciente inmunocomprometida. Enfatizamos que la neumonía por Delftia debe considerarse en el diagnóstico diferencial de la afectación de la cavidad pulmonar en tales pacientes.

Piperacillin/tazobactam in continuous infusion versus intermittent infusion in children with febrile neutropenia

Abstract Background Febrile neutropenia (FN) is a common complication in children who receive chemotherapy for cancer. Objective The objective of this study was to evaluate the clinical efficacy of the continuous versus intermittent infusion of piperacillin/tazobactam (TZP) in febrile neutropenic pediatric patients. Methods This is a non-blinded randomized controlled clinical trial. Eligible group consisted of hemato-oncological patients with FN who were candidates to receive TZP. Patients were randomized to one of two groups: Group 1 received antibiotic treatment through intravenous intermittent infusion of TZP 300 mg/kg/day based on piperacillin, divided into four doses, not exceeding 16 g/day; Group 2 received an initial TZP loading dose of 75 mg/kg infusion over 30 min, and then a continuous infusion of TZP 300 mg/kg/day through central line with pump over 24 h. Results There were 176 episodes that could be assessed, 100 in Group 1 and 76 in Group 2. There was no statistically significant difference in treatment failure in the experimental group (continuous infusion) compared with the intermittent group, 21% versus 13% (p = 0.15). The increase in the absolute risk reduction was 0.08% (95% confidence interval 0.12-0.30), and the number needed to treat was 12.4. One patient in each group died. Conclusions There were no differences in fever resolution, clinical cure rate, or mortality when comparing the continuous with the intermittent TZP infusion.

Cefepime/tazobactam as a new treatment option for multidrug resistant gram negative bacilli

Background: Every time an antibiotic is used, whether appropriately or not, the probability of the development and spread of antibiotic resistant bacteria is increased. Thus, multidrug resistant bacteria particularly ESBL (Extended spectrum β­lactamase), Amp C and carbapenemases producing gram negative bacilli have emerged as a major health problem all over the world. Considering new treatment options as a carbapenems sparing and resistance prevention modality, this study was aimed to know the in vitro susceptibility pattern of Cefepime/Tazobactam (CPM/TZ) in comparison to other β-Lactam/ β-Lactamase inhibitors (BL/BLI) and carbapenems against GNB.Methods: A prospective study was conducted on all clinical samples received for a period of about 1 year. Identification and susceptibility of all isolates was done by Vitek 2 Compact system. Susceptibility of CPM/ TZ was done by disc diffusion method on the basis of CLSI guidelines. Both fermenters (E. coli and Klebsiella pneumoniae) and non-fermenters (Acintobacter baumanii and Pseudomonas aeruginosa) were included in the study.Results: Out of 550 GNB isolates the most common was E. coli (61.8%), Acintobacter baumanii (16%), Klebsiella pneumoniae (14.9%) and Pseudomonas aeruginosa (7.3%). Cefepime/tazobactam had a much higher susceptibility of 68% compared to cefepime (28%). Among the BL/BLI combinations tested cefepime/tazobactam (68%) showed the maximum percentage of susceptibility followed by cefoperazone/sulbactam (61.5%) and piperacillin/tazobactam (57.6%). Amongst all GNB isolates cefepime/tazobactam (68%) sensitivity was very much comparable to imipenem (71.8%) and meropenem (69.6%).Conclusions: CPM/TZ exhibited the best in vitro activity in comparison to the other BL/BLI. This new combination of cefepime/tazobactam appears to be a promising alternative therapeutic option to carbapenems. Clinical studies are needed to confirm this in vitro study result.