Recent advances in the development of antibacterial potentiators / 中华检验医学杂志

Multidrug-resistant bacteria that can′t be treated with any common antibacterial drugs have become a global medical crisis. Therefore, there is an urgent need for new antibacterial potentiators to restore the sensitivity of bacteria to the antibacterial drug. This review elaborates on the novel antibacterial synergistic methods and their underlying mechanisms, clinical experimental data and efficacy, and the progress of drug research and development. This review aims to raise awareness about antibacterial potentiators among the public.

Newer ?-Lactam/?-Lactamase inhibitor for multidrug-resistant gram-negative infections: Challenges, implications and surveillance strategy for India

Antimicrobial resistance (AMR) is a major public health concern across the globe, and it is increasing at an alarming rate. Multiple classes of antimicrobials have been used for the treatment of infectious diseases. Rise in the AMR limits its use and hence the prerequisite for the newer agents to combat drug resistance. Among the infections caused by Gram-negative organisms, beta-lactams are one of the most commonly used agents. However, the presence of diverse beta-lactamases hinders its use for therapy. To overcome these enzymes, beta-lactamase inhibitors are being discovered. The aim of this document is to address the burden of AMR in India and interventions to fight against this battle. This document addresses and summarises the following: The current scenario of AMR in India (antimicrobial susceptibility, resistance mechanisms and molecular epidemiology of common pathogens); contentious issues in the use of beta-lactam/beta-lactamase inhibitor as an carbapenem sparing agent; role of newer beta-lactam/beta-lactamase inhibitor agents with its appropriateness to Indian scenario and; the Indian Council of Medical Research interventions to combat drug resistance in terms of surveillance and infection control as a national response to AMR. This document evidences the need for improved national surveillance system and country-specific newer agents to fight against the AMR.

Analysis on sensitivity of β-lactam/β-lactamase inhibitors to bifidobacteria and lactobacilli / 重庆医学

Objective To analyze the susceptibility situation of bifidobacteria and lactobacilli from child intestinal tract on β-lactam/β-lactamase inhibitor complex.Methods According to the method of the Bergey Bacterial Identification Manual,45 strains of bifidobacteria and 39 strains of lactobacilli were isolated from the stool specimens of 36 healthy children.The susceptibility tests of bifidobacteria and lactobacilli to ampicillin,amoxicillin/clavulanate,ampicillin/sulbactam,piperacillin,piperacillin/tazobactam,ticarcillin,ticarcillin/clavulanate,cefoperazone and cefoperazone/sulbactam were performed by adopting the E-test method.Then the statistical analysis was conducted.Results The sensitivity percentages of 45 strains of bifidobacteria to ampicillin,amoxicillin/clavulanate,ampicillin/sulbactam,piperacillin,piperacillin/tazobactam,ticarcillin,ticarcillin/clavulanate and cefoperazone were 77.78％,95.56％,88.89％,73.33％,91.11％,68.89％,84.44％ and 82.22％ respectively,which of 39 strains of lactobacilli to above antibiotic drugs were 74.36％,94.87％,92.31％,71.79％,92.31％,69.23％,89.74％ and79.49％,respectively.Except having no judgment due to without the CLSI drug susceptibility MIC interpretation criteria of cefoperazone/sulbactam,the sensitivity percentages of other β-lactam/β-lactamase inhibitor complex were higher than those of single β-lactam antibi otics,the sensitive number P values of bifidobacteria in ampicillin with amoxicillin/clavulanate and piperacillin with piperacillin/tazobactam were 0.01 and 0.03 respectively,which of lactobacilli in ampicillin with amoxicillin/clavulanate,ampicillin with ampicillin/sulbactam,piperacillin with piperacillin/tazobactam,ticarcillin with ticarcillin/clavulanate were 0.01,0.03,0.02 and 0.03 respectively.Conclusion β-lactam/β-lactamase inhibitors complex has stronger effect for inhibiting child intestinal tract bifidobacteria and lactobacilli than single β-lactam antibiotics.

Incidence and risk factor analysis of antibiotic-associated diarrhea of pediatric patients with severe bacterial pneumo-nia / 临床儿科杂志

ObjectiveTo investigate the incidence and risk factors of antibiotic-associated diarrhea (AAD) of pediatric patients with severe bacterial pneumonia.MethodsClinical data of 1086 pediatric patients with severe bacterial pneumonia from January 2010 through January 2014 were recruited. The incidence and risk factors of AAD were retrospectively analyzed. ResultsThe incidence of AAD in 1086 pediatric patients with severe bacterial pneumonia was 36.74%. The incidence of AAD in patients younger than 2 years old were higher than that in those older than 2 years, once or more times of mechanical venti-lation history were higher than that with no arrangements of this treatment, administering of combined antibiotics therapy were higher than that with single antibiotics, and the incidence of AAD due to amoxicillin/clavulanate, piperacillin/tazobactam, cefo- perazone/sulbactam in pediatric patients were 43.55%, 43.75%, and 45.03%, respectively. Three β-lactam/β-lactamase inhibitors above were risk factors of AAD through multivariate Logistic regression analysis.ConclusionThe high incidence of AAD in pediatric patients with severe bacterial pneumonia was associated with some risk factors, including younger than 2 years old, me-chanical ventilation, combined antibiotics therapy and administration of β-lactam/β-lactamase inhibitor (amoxicillin/clavulanate, piperacillin/tazobactam, cefoperazone/sulbactam).

Susceptibility profile of Gram‑negative bacteremic isolates to beta lactam‑beta lactamase inhibitor agents in comparison to other antibiotics.

BACKGROUND: Comprehensive understanding about the local antibiogram is an essential requirement for preparation of hospital or unit based antibiotic policy. Bacteremic isolates are the most useful ones for this purpose, representing invasive disease. OBJECTIVE: To analyze susceptibility pattern of bacteremic Gram‑negative isolates in our center, to various antibiotics, including beta lactam‑beta lactamase inhibitor (BL‑BLI) agents and carbapenem. MATERIALS AND METHODS: This is a retrospective study done in Apollo Specialty Hospital, a tertiary care oncology center in South India. The susceptibility of Escherichia coli, Klebsiella, Acinetobacter and Pseudomonas blood culture isolates, identified between January 2013 and June 2014 to various antibiotics were analyzed. RESULTS: A total of 231‑Gram‑negative bacteremic isolates were analyzed. ESBL rate among E. coli isolates was 82.7% (67 out of 81) and 74.3% (58 out of 78) in Klebsiella. Carbapenem (imipenem) susceptibility rate in E. coli was 76.5%, Klebsiella 58.9%, Acinetobacter 32% and Pseudomonas 77.2%. Colistin susceptibility in E. coli was 96.2%, Klebsiella 93.5%, Acinetobacter 92.8% and Pseudomonas 97.7%. Difference in the susceptibility of Enterobacteriaceae to BL‑BLI agents (especially cefepime‑tazobactam) and carbapenem were minimal. In nonfermenters, BL‑BLI susceptibility was better than that of carbapenem. CONCLUSION: Findings of the study make a strong argument for using BL‑BLI agents and sparing carbapenem to curtail the spiraling scenario of carbapenem resistance.

Phenotypic detection of Extended Spectrum Beta-Lactamases and Amp C Beta- Lactamases among nosocomial isolates in a tertiary care hospital.

Background & objectives: Extended-Spectrum Beta-Lactamases (ESBLs) is an important resistance mechanism in Enterobacteriaceae infections. Lack of standard guidelines from Clinical Laboratory Standards Institute (CLSI) for Amp C beta-lactamase detection poses a problem. This study was undertaken to detect ESBLs by phenotypic tests and Amp C beta-lactamase by inhibitor based method. Material and Methods: 200 consecutive non-repetitive isolates of E.coli, Klebsiella and Proteus from clinical samples were screened for ESBLs as per CLSI guidelines and confirmed by PCDT, DDST and E-tests (AB Biodisk, Biomerieux). Amp C beta lactamases were screened by cefoxitin resistance and confirmed by inhibitor (Cloxacillin) based method. Simultaneous occurrence of Amp C and ESBLs was detected by combined disk test (Neo-Sensitabs and Diatabs). Descriptive and Kappa statistics were used. Results: Out of 200 isolates studied, 131 were initially screened as ESBL producers and later 114 (57%) were confirmed by phenotypic methods. E-Test was found most sensitive phenotypic test as compared to PCDT and DDST. 13 strains resistant to cefoxitin (30μg) were found to be pure Amp C producers. Combined disk test detected 36 to be ESBL and Amp C co-producers. Surprisingly, six isolates found sensitive to cefoxitin disk were confirmed as Amp C producers by cloxacillin disk inhibition test. Conclusion: 57% ESBLs and 27.5% Amp C producers were isolated from nosocomial pathogens showing significant resistance to 3rd generation cephalosporins. Phenotypic confirmation by E-test, PCDT & DDST were useful for ESBL identification and for detection of Amp C, cloxacillin was found to be an effective inhibitor.

Actinomicetos produtores de inibidores de beta-lactamases com atividade antimicrobiana frente a isolados de mastite bovina / Actinomycetes producers of beta-lactamases inhibitors with antimicrobial activity against microorganisms isolated from bovine mastitis

Avaliou-se a capacidade de 71 actinomicetos isolados de líquens da região amazônica em produzir inibidores de β-lactamases com atividade antimicrobiana sobre Staphylococcus aureus, resistentes à penicilina, isolados de mastite bovina do estado de Pernambuco. A seleção dos actinomicetos produtores de inibidores de β-lactamases foi realizada pela técnica de bloco de gelose contra Klebsiella pneumoniae ATCC 29665, e os actinomicetos selecionados foram testados frente a 17 linhagens de Staphylococcus aureus resistentes à penicilina. Os melhores produtores de inibidores de β-lactamases foram Streptomyces sp. DPUA 1542 e Nocardia sp. DPUA 1571, os quais foram submetidos ao cultivo submerso para determinação da curva de crescimento, pH e atividade antimicrobiana. Os maiores halos de inibição foram obtidos pelos metabólitos produzidos após 96 horas de cultivo tanto para Nocardia sp. - 13,5 e 12,0mm - como para Streptomyces sp. - 8,0 e 14,0mm - com os testes de difusão nos discos e poços, respectivamente. Os resultados permitiram concluir que os actinomicetos são fonte promissora de inibidores de β-lactamases, com potencial uso no tratamento de mastites bovinas.

The ability of 71 actinomycetes, isolated from the Amazon lichens, to produce β-lactamase inhibitors with antimicrobial activity was evaluated against penicillin-resistant Staphylococcus aureus, isolated from bovine mastitis in Pernambuco State. The selection of actinomycetes producers of β-lactamase inhibitors was performed using agar-plug method against Klebsiella pneumoniae ATCC 29665 and the selected actinomycetes were tested against 17 penicillin-resistant Staphylococcus aureus strains. The best producers of β-lactamase inhibitors were Streptomyces sp. DPUA 1542 and Nocardia sp. DPUA 1571. They were submitted to the submerged cultivation to determine the growth and pH curve, and antimicrobial activity. The highest inhibition halo zonewas obtained by metabolites produced after 96 hours of cultivation for both Nocardia sp. (13.5 and 12.0mm) and Streptomyces sp. (8.0 and 14.0mm) with discs and well diffusion tests, respectively. The results showed that the actinomycetes are a promising source of β-lactamase inhibitors, with potential for use in the bovine mastitis treatment.

A Case of Immune Hemolytic Anemia Induced by Ceftizoxime and Cefobactam (Sulbactam/Cefoperazone) / 대한진단검사의학회지

Simultaneous drug-induced immune hemolytic anemia (DIIHA) caused by multiple drugs is rare. We report a case of a patient who developed DIIHA caused by 2 drugs. The patient's serum exhibited agglutination of ceftizoxime- or sulbactam-coated red blood cells (RBCs; via a drug-adsorption mechanism) and of uncoated RBCs in the presence of sulbactam (via an immune-complex mechanism). Although ceftizoxime is known to exhibit a positive reaction by an immune-complex method with or without reactivity with drug-coated RBCs, this patient's antibodies were reactive only against drug-coated RBCs. On the other hand, sulbactam, which is known to cause hemolytic anemia by nonimmunologic protein adsorption, exhibited positive reactions in tests with both drug-coated RBCs and in the presence of sulbactam. This is the first report of DIIHA due to a sulbactam-cefoperazone combination and the fourth report of DIIHA due to ceftizoxime. Owing to the patient's complicated laboratory results, DIIHA was suspected only at a late stage. We propose that for the prompt diagnosis of DIIHA, tests for all possible causative drugs should be conducted by 2 methods.

Adverse Drug Reactions Induced by ?-lactamase Inhibitor:Analysis of 155 Cases / 中国药房

OBJECTIVE:To explore the general pattern and the characteristics of the adverse drug reactions(ADR)induced by ?-lactamase inhibitor.METHODS:155 ADR cases induced by ?-lactamase inhibitor reported in 141 articles in the domestic periodicals between Jan.1996 and Jan.2008 retrieved from CHKD full-text data base were analyzed respectively.RESULTS:Among the total 155 ADR cases,81.94%(127 cases)were induced by sulbactam-contained ?-lactamase inhibitor.Systemic lesion was the most common manifestation of ADR,accounting for 42.58%(66 cases).The most serious manifestation of ADR was allergic shock,and death occurred in 9 cases.CONCLUSION:It is advisable to promote rational use of ?-lactamase inhibitor and strengthen ADR monitoring so as to reduce or avoid the occurrence of ADR.

Clinical Application of ?-Lactamase Inhibitor Antibiotics / 中华医院感染学杂志

OBJECTIVE To know of the application status of ?-lactamase inhibitor antibiotics in our hospital,promote the compliance of Guideline for application of antibiotics,and cut down the abusing or irrationally using of antibiotics.METHODS Retrospective cohort research was used to review the medical records of 1184 patients left our hospital.Based on the inspection results,to select following 98 inpatients to do prospective research and correct those problems found in the retrospective research.RESULTS There were 71 cases in the prospective research who had applied antibiotics,in which 23 cases had used ?-lactamase inhibitor antibiotics;20 cases with precautious application,18 cases underwent type Ⅰ operation and used antibiotics for 2 to 10 days;2 cases underwent type Ⅱ operation and used antibiotics for 5 to 6 days;2 cases underwent type Ⅲ operation;3 cases of internal medicine patients had been treated with ?-lactamase inhibitor antibiotics for 10 days,not selected by the type of bacteria and the result of drug sensitivity test,and no analysis records in the progress note.CONCLUSIONS In surgical departments,use antibiotics as preventive measurements even after clean operation which lack indications and choose over estimated level of ?-lactamase inhibitor antibiotics and combine medication for post-operation preventive medicine.When treating ordinary infections,Internal department had chose antibiotics which should be used for difficult diseases caused by resistant microbes.Most patients do not have undergone bacteria cultivation and drug sensitivity test before applying antibiotics.Therefore the management of antibiotics should be enhanced.

Tandem Repeat Expression and Inhibitory Activity of a ?-lactamase Inhibitory Peptide / 中国生物工程杂志

?-lactamase inhibitor research is popular for its potential on ?-lactam antibiotics resistant strain.A ?-lactamase binding peptide SIPIS04-01 was obtained by the yeast two-hybid system.In vitro assay showed that it can inhibit the ?-lactamase activity.In order to improve the expression level of the recombinant peptide,a two-copy expression plasmid pYG563 was constructed by random orientation tandem repeat method after codon modification,the two-copy plasmid was successfully expressed and the product was increased by 48.4% than that of one-copy plasmid.Purified peptide showed inhibitory activity against TEM-1 ?-lactamase in vitro and the inhhibitory constant Ki was measured.

Role of β−lactamase in the susceptibility of clinical isolates to β−lactam antibiotics.

Combination of β−lactam antibiotic with β−lactamase inhibitor has been proven to overcome resistance caused by β−lactamase production. An evaluation to the MIC of some β−lactam antibiotics to β−lactamase producing isolates will be reported. A. anitratus, E. coli, K. pneumoniae, Proteus sp, Pseudomonas sp, S. aureus, S. epidermidis, S. pneumoniae, S. viridans, and β−hemolytic Streptococcus, were challenged to Ampicillin/Sulbactam (AMS), Amoxicillin/Clavulanic acid (AMC), Cefoperazone (CFP), Cefoperazone/Sulbactam (CSL), Ceftriaxone (CRO), dan Cefotaxime (CTX) using ETest techniques. β−lactamase production was identified using Cefinase disk. Sixtyfour percent of isolates were capable of producing β−lactamase. All E. coli and K. pneumoniae tested were β−lactamase producer, none of Proteus sp, Pseudomonas sp, and S. epidermidis tested produced β−lactamase. In β−lactamase producing group, Sulbactam was able to reduce resistance to CFP from 25% to 5%. About 20% of β−lactamase producing isolates which were resistant to CFP, were susceptible to CSL. Susceptibility of S.viridans to AMS, AMC, CFP, and CSL was higher than 80%, but less than 50% to CRO and CTX. S. pneumoniae was less susceptible to tested antibiotics, 50 to 60% susceptibility was shown to AMC, CFP, and CSL. S.aureus was 60 to 70% susceptible, while β−haemolytic Streptococcus showed good response to the tested antibiotics. Only 30% or less of K. pneumoniae and E. coli was susceptible to AMS and AMC. A. anitratus showed good susceptibility only to AMS (78%) and CSL (89%). Sixtyfour percent of isolate studied produced β−lactamase. β−lactamase inhibitor could reduce resistance of β−lactamase producing organism to β−lactam antibiotic from 25 to 5 percent.

In Vitro Antibacterial Activity of Azlocillin in Combination with Tazobactam against 168 Strains of Pathogenic Bacteria / 中国药房

OBJECTIVE:To compare the in vitro antibacterial activity of azlocillin given alone with azlocillin plus tazobactam against168strains of clinically isolated pathogenic bacteria.METHODS:The antibacterial activities of two antibac_ terials against168strains of clinically isolated pathogenic bacteria in vitro were detected by two-fold dilution method.RE-SULTS:The MIC 50 and the MIC 90 of the combined therapy of azlocillin/tazobactam(4∶1)were1/32and1/64,respectively that of azlocillin given alone.CONCLUSION:The concomitant therapy of azlocillin with tazobactam improves the antibacterial activity.

Effect of Empirically Applying ?-Lactam Antibiotics for Treatment of Hospital-acquired Pneumonia on Pathogenic Bacteria / 中华医院感染学杂志

OBJECTIVE To approach the effect of empirically applying ?-lactam antibiotics for treatment of hospital-acquired pneumonia on distribution and antibiotic-resistance of pathogenic bacteria.METHODS To investigate 141 patients with hospital-acqired pneumonia in intensive care unit during Jan 2001-Oct 2005,and divide into 3 groups:third generation cephalosporin group;lactamase inhibitor group;and other lactam antibiotics group according to different initial antibacterial strategy,then analyze difference in distribution and antibiotic-resistance of pathogens among each group.RESULTS We acquired 164 strains of pathogens.Comparing with other two groups,the proportion of Gram-positive cocci in lactamase inhibitor group was higher significantly(P

Analysis of Consumption of Antibiotic/Beta-Lactamase Inhibitor Preparations in18Hospitals of Chongqing During the2001～2003Period / 中国药房

OBJECTIVE:To survey and evaluate the current situation and developing trend of antibiotic/beta-lactamase inhibitor(BLI)preparations consumed.METHODS:The antibiotic/BLI preparations used in18hospitals of Chongqing in2001～2003were collected in respect to the compositions,dosage forms,specifications,drug name,manufacturers and sum of money for consumption,and the clinical application information was analysed.RESULTS:The sum of money for these antibi?otics/BLI consumed in the years2001,2002and2003were2229,2937and4119ten-thousand yuan(RMB),respectively,with an average annual increase rate of26.41%.Among them the consumption costs of antibiotics plus sulbactam,clavulanate and tazobactam were6280,2276and729ten-thousand yuan(RMB),accounting for67.64%,24.51%and7.85%of the total consumption sum,with an annual increase rates of32.20%,35.93%and94.50%,respectively.CONCLUSION:The consump?tion of the antibiotic/BLI preparations was increasing fast in these years and the more requirement for the antibiotic/BLI preparations by market would be expected in the future.

Study on the In Vitro Antibacterial Activity of Amoxicillin/tazobactam Against Clinically Isolated 128 Strains of Bacteria / 中国药房

OBJECTIVE:Using in vitro studies,we evaluated the antibacterial activity of amoxicillin/tazobactam against 128 strains of pathogens isolated from patients and compared with amoxicillin/clavulanic acid and amoxicillin/sulbactam.METHODS:To detect the minimum inhibitory concentrations (MIC)of four ?-lactams against 128 clinically isolated strains with agar dilution method.RESULTS:The results indicated that the in vitro antibacterial activity of amoxicillin/tazobactam(2∶1) was the best.The MIC50 of amoxicillin/tazobactam(2∶1) is 1/4～1/8 times than those of amoxicillin/sulbutam and amoxicillin/clavulanic acid.The MIC90 of amoxicillin/tazobactam(2∶1) was 1/2～1/4 of those of amoxicillin/sulbutam and amoxicillin/clavulanic acid.The combination ratio 2∶1(amoxicillin/tazobactam)of the two compounds was more suitable than other combination ratios(4∶1 and 8∶1)for inactivating ?-lactamase.CONCLUSION:The in vitro antibacterial activities of amoxicillin/tazobactam(2∶1) against MRSA,MRSE,MSSA and E.coli are high.It showed that amoxicillin/tazobactam(2∶1)is stable to ?-lactamase and is an effective bactericidal agent.

A CLINICAL STUDY ON TREATING BACTERIAL INFECTIONS WITH MEZLOCILLIN/SULBACTAM / 解放军医学杂志

patients were treated with mezlocillin/sulbactam, among them there were 59 cases of respiratory infection, 36 cases of urinary system infection,13 cases of abdominal infection, and 2 cases of septicemia. 84 patients were successfully cured, and 25 patients were markedly improved. The total effective rate was 99.9%, and the side effect rate was only 4.5%, which included one case of skin rash and two cases of abnormally high GPT. The study in vitro showed that antibacterial activity of mezlocillin was markedly enhanced against most ordinary pathogens with the help of sulbactam in the clinic.