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PubMed2003

In vitro activity of beta-lactams in combination with other antimicrobial agents against resistant strains of Pseudomonas aeruginosa.

Using the chequerboard titration method, the activity in combination of beta-lactams, fluoroquinolones and aminoglycosides was investigated against 24 Pseudomonas aeruginosa isolates resistant to these antibiotics. Synergy was detected with one or more antimicrobial combinations against 15 of 24 (63%) isolates and partial synergy was detected with one or more combinations against all 24 isolates. No antagonism was seen with any combination. Ceftazidime and cefepime with aztreonam, amikacin and isepamicin showed synergy or partial synergy against 12-20 (50-80%) isolates. Imipenem and meropenem with amikacin and isepamicin showed synergy or partial synergy against eight to 12 (33-50%) isolates. The results of this study indicate that against P. aeruginosa, synergy may occur between beta-lactams, fluoroquinolones and aminoglycosides although the strains are resistant to the individual antibiotics.

Anti-Bacterial Agents↗
PubMed2003

Effect of siliconized latex urinary catheters on the activity of carbapenems against Pseudomonas aeruginosa strains with defined mutations in ampC, oprD, and genes coding for efflux systems.

The decreased activity of carbapenems against Pseudomonas aeruginosa in the presence of eluates from siliconized latex urinary catheters is related to the loss of OprD and the expression of a new outer membrane protein (OMP). To understand this phenomenon, the activity of carbapenems and quinolones against P. aeruginosa strains, some producing AmpC beta-lactamase (BL), OprD, MexA-MexB-OprM and MexE-MexF-OprN, were determined in Mueller-Hinton broth (MH) and in MH-containing eluates. OMP profiles and BL activities were also studied. Resistance to imipenem in P. aeruginosa grown in eluate is due to both the loss of OprD and expression of BL. For meropenem this phenomenon is related to both the loss of OprD and the integrity of MexA-MexB-OprM.

Anti-Infective Agents↗
PubMed1999

Carbapenems in clinical practice: a guide to their use in serious infection.

Meropenem and imipenem/cilastatin, currently the only available carbapenem agents in Europe and the United States, are characterised by a broad spectrum of antimicrobial activity and stability to beta-lactamase-mediated resistance mechanisms. A guide to the use of carbapenems in clinical practice is presented; the role of carbapenems in the treatment of several types of serious bacterial infection and an up-to-date account of their clinical efficacy and safety profiles are discussed. The good clinical efficacy and favourable safety profiles of the carbapenems make them valuable as initial empirical therapy in the treatment of ventilator-associated pneumonia, sepsis of unknown origin, post-operative peritonitis, paediatric meningitis, and febrile neutropenia. However, to maintain superior efficacy, the carbapenems should be used appropriately for definitive therapy.

Bacterial Infections↗
PubMed1999

Antimicrobial activity of quinupristin/dalfopristin, a new injectable streptogramin with a wide Gram-positive spectrum.

Quinupristin/dalfopristin (Synercid) is a new injectable streptogramin antibiotic proposed for the treatment of severe antimicrobial infections, that has been shown to be active against Gram-positive, multi-resistant cocci. We compared the in vitro activity of quinupristin/dalfopristin with that of amoxycillin, ampicillin, penicillin, cefixime, ceftriaxone, clindamycin, erythromycin, imipenem, meropenem, oxacillin, piperacillin/tazobactam, teicoplanin and vancomycin. The susceptibility of 37 Staphylococcus aureus (14 MS, 23 MR), 26 Staphylococcus epidermidis (16 MS, 10 MR), 20 Streptococcus pneumoniae, 33 Group A Streptococcus pyogenes, 15 Streptococcus agalactiae, 10 Enterococcus faecalis (1 vancomycin-resistant), 15 Enterococcus faecium (9 van A) was evaluated. Quinupristin/dalfopristin was active against all Gram-positive species tested, including met-R S. aureus (MIC < or = 2 mg/l), met-R S. epidermidis (MIC < or = 2 mg/l), S. pneumoniae (MIC < or = 1 mg/l), ery-R and ery-S streptococci (MIC < or = 1 mg/l). The strains of E. faecalis were generally less susceptible. Time-kill studies confirmed that quinupristin/dalfopristin at 4 x MIC concentration showed a complete bactericidal effect (3 log reduction) in about 4 6 h against all strains tested. A post-antibiotic effect (PAE) of 3.9-5.2 h was observed at 4 x MIC concentration of quinupristin/dalfopristin against staphylococci. A prolonged PAE was obtained for S. pneumoniae (8 h), S. pyogenes (9 h) and S. agalactiae (7 h), while the shortest PAE was seen for E. faecalis and E. faecium (about 4 h).

Anti-Bacterial Agents↗
PubMed2000

Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety.

The synthesis and biological activity of a series of new 1beta-methylcarbapenems 1a-g containing 5'-isoxazolopyrrolidin-3'-ylthio derivatives as C-2 side chain are described. Most compounds exhibited potent and well-balanced antibacterial activity as well as high stability to DHP-I comparable to that of meropenem. 1e and 1c showed the best combination of antibacterial activity and stability to DHP-I, respectively.

Anti-Bacterial Agents↗
PubMed2003

CP0569, a new broad-spectrum injectable carbapenem. Part 1: synthesis and structure-activity relationships.

A series of 1beta-methylcarbapenems bearing an (imidazo[5,1-b]thiazolium-6-yl)methyl moiety, a 5,5-fused heterobicycle, at the C-2 position was synthesized and evaluated for in vitro antibacterial activities. CP0569 (1r) and its analogues showed potent antibacterial activities against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Gram-negative bacteria, including Pseudomonas aeruginosa. Moreover, CP0569 (1r) exhibited stronger antibacterial activity against MRSA and higher resistance to renal dehydropeptidase-1 (DHP-1) than any currently marketed carbapenems, that is, imipenem (IPM), panipenem (PAPM), and meropenem (MEPM).

Animals↗
PubMed2000

Two-year assessment of the pathogen frequency and antimicrobial resistance patterns among organisms isolated from skin and soft tissue infections in Latin American hospitals: results from the SENTRY antimicrobial surveillance program, 1997-98. SENTRY Study Group.

OBJECTIVES: This study was conducted to evaluate the frequency of occurrence and antimicrobial susceptibility of bacterial isolates collected from patients with skin and soft tissue infections (SSTI) in Latin American hospitals, as part of the SENTRY Antimicrobial Surveillance Program. The dissemination of multidrug-resistant methicillin-resistant Staphylococcus aureus (MDR-MRSA) among the Latin American countries also was studied. MATERIAL AND METHODS: A total of 885 bacterial isolates were analyzed. At the monitoring laboratory, antimicrobial susceptibility testing utilizing the reference broth microdilution method and confirmation of species identification were performed. Enterobacteriaceae possibly producing extended-spectrum beta-lactamases (ESBL) and MDR-MRSA isolates were genotyped by ribotyping using the RiboPrinter and by pulsed-field gel electrophoresis. RESULTS: Staphylococcus aureus (31%) was the most common etiologic agent causing SSTI, followed by Escherichia coli (13.4%) and Pseudomonas aeruginosa (11%). Thirty-one percent of S. aureus isolates were resistant to oxacillin (methicillin). The presence of ESBL phenotypes was markedly higher among the Klebsiella pneumoniae (35.5%) than E. coli isolates (10. 2%). Meropenem was the compound with the highest susceptibility rate among the Enterobacteriaceae (100%) and P. aeruginosa (95%) isolates. A great genetic similarity was observed among the MDR-MRSA in Latin America. CONCLUSION: High resistance rates to antimicrobial drugs among the most frequent bacterial pathogens were observed in 10 medical centers in Latin America. This study also demonstrated a clonal dissemination of a MDR-MRSA strain in several nations.

Anti-Bacterial Agents↗
PubMed2005

Management of anthrax meningitis.

Meningitis due to infection with Bacillus anthracis is considered an infrequent manifestation of the disease but one associated with high mortality. The bioterrorism event in the USA in the autumn of 2001 demonstrated our need for a better understanding of anthrax meningitis, as well as management and antimicrobial therapy. However, human clinical trials are not possible and animal experiments to guide such therapy are limited. An approach to the treatment of anthrax meningitis, based on the pathogenicity of B anthracis, the pharmacokinetics and pharmacodynamics of individual antimicrobial agents, studies of anthrax post-exposure prophylaxis in non-human primates, experience with antimicrobial susceptibility patterns of the 2001 outbreak strain, and the clinical experience with inhalational anthrax cases during the 2001 outbreak is presented. These outbreak data, the failure of previous single-drug regimens, the concerns of resistance, and the need for coverage for other causes of bacterial mengingitis suggest initial treatment of suspected anthrax meningitis should anchor on an intravenous fluoroquinolone and should include one or two other agents with activity against B anthracis and good penetration into the central nervous system. Such other agents include penicillin, ampicillin, meropenem, vancomycin, and rifampicin.

Animals↗
PubMed2005

Direct evidence that the reaction intermediate of metallo-beta-lactamase L1 is metal bound.

In an effort to probe the structure of the reaction intermediate of metallo-beta-lactamase L1 when reacted with nitrocefin and other beta-lactams, time-dependent absorption and rapid-freeze-quench (RFQ) EPR spectra were obtained using the Co(II)-substituted form of the enzyme. When using nitrocefin as the substrate, time-dependent absorption spectra demonstrate that Co(II)-substituted L1 utilizes a reaction mechanism, similar to that of the native Zn(II) enzyme, in which a short-lived intermediate forms. RFQ-EPR spectra of this intermediate demonstrate that the binding of substrate results in a change in the electronic properties of one or both of the Co(II)'s in the enzyme that is consistent with a change in the coordination sphere of this metal ion. This observation provides evidence that the reaction intermediate is a metal-bound species. RFQ-EPR studies also demonstrate that other beta-lactams, such as cephalothin, meropenem, and penicillin G, proceed through an electronically similar complex and that the role of metal is similar in all cases. EPR spectroscopy has also identified distinct product-bound species of L1, indicating that reversible product binding must be considered in all future kinetic mechanisms. Consideration of the time-dependent optical and EPR studies in light of available crystallographic information indicates the intimate involvement of the metal ion in the Zn(2)-binding site of L1 in the hydrolytic reaction.

Bacterial Proteins↗
PubMed1998

Application of logistic growth model to pharmacodynamic analysis of in vitro bactericidal kinetics.

A new pharmacodynamic model for the analysis of in vitro bactericidal kinetics was developed based on the logistic growth model, with the bacterial phases divided into two compartments. The model equations are expressed as nonlinear simultaneous differential equations, and the Runge-Kutta-Gill method was adopted to numerically solve the equations in both the simulation and the least squares curve-fitting procedures. The model can describe the initial killing and the regrowth phases and can explain the nonlinear dependence of the killing rate on the drug concentration. The model can also explain the plateau in the bacterial growth curve that is often observed in in vitro experiments. The model was applied to analysis of the in vitro time-killing data of beta-lactam antibiotics, S-4661, meropenem, imipenem, cefpirome, and ceftazidim against three types of bacteria, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The results of curve-fitting using the least squares program MULTI (Runge) showed good fits for all types of drugs and bacteria. The relationship between the characteristics of the drug-bacteria interactions and the estimated pharmacodynamic parameters is discussed.

Anti-Bacterial Agents↗
PubMed2003

New bromotyrosine derivatives from an association of two sponges, Jaspis wondoensis and Poecillastra wondoensis.

Three new bromotyrosine derivatives (4-6) were isolated from an association of two sponges, Jaspis wondoensis and Poecillastra wondoensis, along with the previously described (E,E)-psammaplin A (1), (E,Z)-psammaplin A (2), psammaplin D (3), bisaprasin (7), and (3-bromo-4-hydroxyphenyl)acetonitrile (8). The structures of the new compounds were established on the basis of NMR and MS spectroscopic analysis. The compounds 1, 3, and 5-7 displayed significant cytotoxicity against human lung (A549), ovarian (SK-OV-3), skin (SK-MEL-2), CNS (XF498), and colon (HCT15) cancer cell lines. Compounds 3-7 were further evaluated for antibacterial activity against methicillin- or ofloxacin-resistant Staphylococcus strains. Compound 4 exhibited more potent antibacterial activity than meropenem against several strains.

Animals↗
PubMed2026

Molecular characterization and antimicrobial resistance profiles of Shigella flexneri isolates from pediatric clinical cases in Ahvaz, Iran.

Shigella is a highly invasive pathogen that causes dysentery and is associated with significant morbidity and mortality in children under five years of age. This agent is a major public health problem in developing countries. Multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA) is a reliable, cost-effective typing method with high discriminatory power and reproducible results. The rise of drug resistance in Shigella strains is a growing global health threat. Despite the significance of Shigella in Iran, there is limited knowledge about genetic diversity and drug resistance profiles of local strains. Therefore, the purpose of this study was to characterize the genetic diversity and drug resistance profiles of Shigella strains isolated in Ahvaz, Iran. A total of 49 Shigella flexneri isolates were recovered from 500 stool samples of pediatric patients. Routine biochemical tests were used to identify all isolates. Antimicrobial susceptibility testing was performed, and resistance genes were detected by polymerase chain reaction (PCR). Extended-spectrum &#x3b2;-lactamases (ESBL), carbapenemase, and Metallo-&#x3b2;-lactamase (MBL) production were detected phenotypically using combination disk assays and confirmed by the CLSI-recommended modified Carbapenem inactivation method (mCIM) and EDTA-modified carbapenem inactivation method (eCIM). MLVA based on seven VNTR loci was performed to characterize the genetic diversity of the isolates. All 49 isolates were resistant to ceftazidime, trimethoprim/sulfamethoxazole, ampicillin, and ceftriaxone (100% each). High resistance rates were also observed for imipenem 36/49 (73.5%), meropenem 36/49 (73.5%), azithromycin 21/49 (42.9%), and ciprofloxacin 16/49 (32.7%). Furthermore, phenotypic testing revealed ESBL production in 46/49 (93.9%) isolates and carbapenemase activity in 36/49 (73.5%), of which 22/49 (44.9%) were MBL. PCR analysis identified blaCTX-M 38/49 (77.6%) and blaSHV 35/49 (71.4%) as the most prevalent ESBL genes, whereas blaNDM 14/49 (28.6%), and blaOXA-48 14/49 (28.6%) were the most common carbapenemase genes. MLVA typing divided the isolates into 22 different MLVA types, including 10 clusters and 12 singletons, and locus ms21 showed the highest discriminatory power.&#xa0;The isolates exhibited high genetic diversity with a non-clonal distribution of resistance, which indicates dissemination through horizontal gene transfer. Our results demonstrated that mCIM/eCIM and MLVA are viable methods for investigating Shigella species as they are cost-effective, provide quick results, and allow for easy sharing of numerical data between laboratories.

Humans↗
PubMed2000

An outbreak of multiply resistant Serratia marcescens: the importance of persistent carriage.

An outbreak of multi-resistant Serratia marcescens involving 24 patients occurred in a bone marrow transplant and oncology unit, from September 1998 to June 1999, of whom 14 developed serious infection. This is the first such outbreak described in a BMT unit. All isolates demonstrated the same antimicrobial susceptibility pattern and were the same unusual serotype O21:K14. The antimicrobial susceptibility profile showed reduced susceptibility to ciprofloxacin, gentamicin and piperacillin-tazobactam. As the latter two antimicrobials are part of our empiric therapy for febrile neutropenia, they were substituted with meropenem and amikacin during the outbreak. Investigation revealed breaches in infection control practices. Subsequently, the outbreak was contained following implementation of strict infection control measures. A prominent feature of the outbreak was prolonged carriage in some patients. These patients may have acted as reservoirs for cross-infection. This report also indicates that patients who become colonised with Serratia marcescens may subsequently develop invasive infection during neutropenic periods.

Adult↗
PubMed2002

Changing pattern of bacterial susceptibility to antibiotics in hematopoietic stem cell transplant recipients.

UNLABELLED: Adequate infection prophylaxis and empirical antibiotic therapy are of critical importance after hematopoietic stem cell transplantation (HSCT). We examined the evolution of bacterial susceptibility to antibiotics in 492 patients (198 allografts and 294 autografts) transplanted between 1982 and 1999 and evaluated whether ciprofloxacin prophylaxis and an empirical antibiotic regimen (glycopeptide + third-generation cephalosporin) were still valid. We collected all susceptibility tests performed during the initial hospitalization on blood cultures as well as routine surveillance cultures and analyzed susceptibility to ciprofloxacin and to major antibiotics used in our unit. Gram-positive cocci rapidly became resistant to ciprofloxacin (susceptibility around 70% in 1990 to less than 20% in 1998) but sensitivity to glycopeptides remained unaltered. There was a rapid decline in the number of patients colonized with Gram-negative bacilli in the early years of ciprofloxacin prophylaxis. However, susceptibility to ciprofloxacin fell sharply from around 90% in 1990 to around 30% in 1999. In parallel, susceptibility to ceftazidime also decreased to less than 80% in recent years. Piperacillin (+/- tazobactam) did not show any variation over time and its efficacy remained too low (about 60%). Imipenem as well as recently introduced cefepim and meropenem showed stable and excellent profiles (>90% susceptibility). IN CONCLUSION: (1) quinolone prophylaxis has now lost most of its value; (2) the choice of a third-generation cephalosporin for empirical antibiotic therapy may no longer be the best because of the emergence of Gram-negative strains resistant to beta-lactamases, such as Enterobacter sp. More appropriate regimens of empirical antibiotic therapy in HSCT recipients may be based on the use of a carbapenem or fourth-generation cephalosporin.

Anti-Bacterial Agents↗
PubMed2001

Resistance to antibiotics and biocides among non-fermenting Gram-negative bacteria.

OBJECTIVE: To investigate the antibiotic and biocide susceptibilities of clinical isolates of rarely encountered Gram-negative, non-fermenting bacteria. METHODS: Thirty Gram-negative non-fermenting bacterial strains were isolated from blood cultures of oncology patients. These were studied for their resistance to 11 antibiotics. Their susceptibilities to seven biocides used in hospitals were also examined. RESULTS: Isolates of Stenotrophomonas maltophilia and Ochrobactrum anthropi were generally resistant to at least five of the antibiotics, whereas isolates of Comamonas acidivorans, Flavobacterium oryzihabitans, Aeromonas hydrophila, Sphingobacterium spiritivorum, Acinetobacter junii and Acinetobacter lwoffi were generally sensitive to at least nine of the antibiotics. Trovafloxacin and trimethoprim-sulfamethoxazole were the most effective antibacterial agents tested, with 0% and 7%, respectively, of isolates being resistant, whereas 63% of isolates were resistant to aztreonam. Some isolates, sensitive to meropenem and/or ceftazidime in vitro, possessed very high MBC/MIC ratios for these beta-lactams. Two out of three biocides used in hospital pharmacies showed lethal activity towards all strains tested when used at less than one-third of their recommended in-use concentration. Proceine 40 failed to give a 5 log reduction in bacterial cell number for the isolates tested when used at its "in-use" concentration. A concentration of > 500 mg/L chlorhexidine was required to achieve a 5 log reduction for the same isolates. CONCLUSIONS: We have examined the antibiotic susceptibilities of non-fermenting Gram-negative bacterial strains isolated from immunocompromised patients. Despite being sensitive to certain antibiotics in vitro, some isolates were still able to cause serious bacteremia. We have also reported for the first time the susceptibilities of non-fermenting Gram-negative bacteria to common biocides used in hospital infection control, and have shown that some strains are able to persist at the "in-use" concentration of particular biocides. It is therefore important to study further this particular group of organisms, and, in particular, to examine whether there exists a link between resistance to antibiotics and resistance to biocides.

Anti-Bacterial Agents↗
PubMed2000

Variations in antibiotic resistance profile in Enterobacteriaceae isolated from wild Australian mammals.

We carried out a retrospective analysis of 946 strains of Enterobacteriaceae isolated from wild Australian mammals between 1993 and 1997. The prevalence of resistance to fixed concentrations of 32 antimicrobial agents was determined, and the respective roles that taxonomic family of the host, state of origin and bacterial species play in defining prevalence and range of resistance were investigated. Our results demonstrated a low but widespread prevalence of antimicrobial resistance in wild isolates. Only amikacin, ciprofloxacin, meropenem and gentamicin inhibited growth in all 946 samples. There was extensive variation in the combination of antibiotics to which isolates were resistant, and multiple antibiotic resistance was common. Geographical location and host group significantly influenced the antibiotic resistance profile of an isolate, whereas bacterial species influenced both the resistance profile of an isolate and the number of antibiotics it was resistant to. The role of these factors in determining observed antibiotic resistance profiles suggests that any study measuring resistance in wild isolates should include the broadest possible range of bacterial species, host species and sampling locations. As such, this study provides an important new baseline for future measurements of antibiotic resistance in the Australian environment.

Aminoglycosides↗
PubMed2000

Recommendation for treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs).

Extended-spectrum beta-lactamase (ESBL)-producing organisms are a global problem. No randomized controlled trials have ever been performed to guide optimal treatment. However, in vitro studies and observational studies strongly suggest that carbapenems (imipenem or meropenem) should be regarded as drugs of choice for serious infections due to ESBL-producing organisms. Other beta-lactam antibiotics (cefepime, beta-lactam/beta-lactamase inhibitor combinations) are not suitable as first-line therapy. The increasing frequency of the association between quinolone resistance and ESBL production have greatly limited the role of this class of antibiotic against ESBL producers.

Anti-Bacterial Agents↗