Activity Of Third-generation Cephalosporins Research Articles

The evolution of antimicrobial resistance in Salmonella Typhi.

Increasing antimicrobial resistance in Salmonella Typhi is a serious public health concern, especially in industrializing countries. Here we review recent clinical and laboratory data concerning the evolution of antimicrobial resistance, with particular reference to the emergence resistance against fluoroquinolones, third generation cephalosporins, and azithromycin. The last 40 years have witnessed the sequential emergence of resistance to all first-line antimicrobials used in the treatment of S. Typhi infections. Multidrug resistance (MDR), defined by resistance to chloramphenicol, amoxicillin, and co-trimoxazole, emerged in the 1990s, followed rapidly by reduced susceptibility to fluoroquinolones. In the current decade, high-level fluoroquinolone resistance has emerged in south Asia and threatens to spread worldwide. Increasing reliance is now being placed on the activity of third generation cephalosporins and azithromycin, but resistance against these agents is developing. Carbapenems and tigecycline may be alternatives, although clinical data are sparse, and in some settings reversion to chloramphenicol and co-trimoxazole susceptibility is occurring. Therefore, older drugs may yet have a role in the treatment of S. Typhi infections. Good surveillance, improved diagnostics, more prudent use of antimicrobials, and effective vaccines will all be critical to reducing the burden of disease caused by S. Typhi.

Increased expression levels of chromosomal AmpC β-lactamase in clinical Escherichia coli isolates and their effect on susceptibility to extended-spectrum cephalosporins.

Forty-nine clinical Escherichia coli isolates, both extended-spectrum β-lactamase (ESBL) negative and ESBL positive, were studied to investigate whether increased AmpC expression is a mechanism involved in cefoxitin resistance and if this influences the third-generation cephalosporin activity. Nine of 33 (27.2%) cefoxitin-resistant (minimum inhibitory concentration [MIC] >8 mg/L) isolates showed hyperproduction of chromosomal AmpC (c-AmpC) based on (1) at least two positive tests using AmpC inhibitors, (2) mutations in the promoter/attenuator regions, and (3) a 6.1- to 163-fold increase in c-ampC expression by quantitative reverse transcription-polymerase chain reaction. In ESBL-negative isolates, MICs of ceftazidime and cefotaxime were mostly above the wild-type (WT) level, but below the S/I breakpoint (EUCAST guideline), except for one isolate with MICs of 4 mg/L. No plasmid-mediated AmpCs were found. Periplasmic extracts of nine c-AmpC hyperproducers were preincubated with or without cefuroxime or ceftazidime and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cefuroxime and ceftazidime were stable to hydrolysis but acted as inhibitors of the enzyme. None of these isolates showed loss of porins. Thus, cefoxitin resistance has low specificity for detecting upregulated c-AmpC production. c-AmpC hyperproducing E. coli is mostly still susceptible to third-generation cephalosporins but less than WT E. coli. Surveillance of cefoxitin-resistant E. coli to monitor developments in the activity of third-generation cephalosporins against c-AmpC hyperproducers is warranted.

A novel approach to prevent candidiasis associated with long term administration of cephalosporins

BackgroundAntibiotics play a critical role in the pathogenesis of Candida infections by invading the competent indigenous flora. Very little is known about the antifungal activity of third generation cephalosporins, but several new groups of cephalosporins were reported to show in vitro antifungal activity. EDTA, a chelating and permeable agent has been found to exhibit the effective antifungal activity. The purpose of the study was to evaluate the in vitro antifungal activity of Elores, a novel antibiotic adjuvant entity having combination of ceftriaxone, sulbactam and EDTA against ceftriaxone alone in Candida albicans in an attempt to prevent the risk of candidiasis after a prolonged cephalosporin antibiotic treatment. MethodsC. albicans (MTCC-227) procured from Institute of Microbial Technology (IMTECH) Chandigarh was used in the study. Antifungal susceptibility of the drugs was determined by agar well diffusion method. Agar dilution and tube dilution methods were used to assess the anti-proliferative activity of Elores and EDTA. ResultsElores containing EDTA equivalent to 6.25 and 12.5 μg/ml effectively suppressed the growth and the difference was 1318 CFU/ml between ceftriaxone and test sample, which is more significant in preventing overgrowth of Candida. ConclusionThe study showed that Elores effectively slowdown the Candida over growth at serum level EDTA concentrations and believed to prevent candidiasis, associated with prolonged cephalosporin antibiotic treatment therapies.

Comparaison de la sensibilité aux antibiotiques de 1 217 isolats consécutifs de Escherichia coli responsables d’infections urinaires féminines en ville et à l’hôpital

The treatment of urinary tract infection (UTI) in women is based mainly on empirical antibiotic therapy. It requires up-to-date knowledge of the susceptibility patterns of the bacteria most commonly identified in that setting. The aim of this prospective study was to measure the antibiotic susceptibility of Escherichia coli isolates responsible for UTIs in women from a single area and to compare it in hospital and community settings. From May 2003 through April 2004, UTI was diagnosed in 1838 women around Rennes (France), 893 of them inpatients admitted to the teaching hospital and 945 outpatients in the community. We determined the susceptibility to 7 antibiotics of the resulting 1217 E. coli isolates. E. coli resistance rates in hospitalized and community patients were respectively 47.9% and 39.2% for aminopenicillins, 47.3% and 25.4% for coamoxiclav, 19.2% and 14.1% for cotrimoxazole, 14.3% and 5.7% for first-generation quinolones, and 8.9% and 3.7% for fluoroquinolones. All these rates were significantly higher among hospitalized patients (p<0.05). Conversely, resistance to injectable third-generation cephalosporins and fosfomycin was similar and infrequent in both groups. Comparisons with previous data show that activity of third-generation cephalosporins and fosfomycin on E. coli appears unchanged, in contrast to the increased resistance rates to other antibiotics usually prescribed for UTI.

Influence of penicillin/amoxicillin non-susceptibility on the activity of third-generation cephalosporins against Streptococcus pneumoniae

To study the influence of penicillin/amoxicillin non-susceptibility on the activity of third-generation cephalosporins, 430 consecutive penicillin non-susceptible Streptococcus pneumoniae 2007 isolates received in the Spanish Reference Pneumococcal Laboratory were tested. For comparative purposes, 625 penicillin-susceptible 2007 isolates were also tested. Susceptibility was determined by agar dilution using Mueller-Hinton agar supplemented with 5% sheep blood. Penicillin-susceptible strains were susceptible to amoxicillin, cefotaxime and ceftriaxone, 99.8% to cefpodoxime and 99.5% to cefdinir, and were inhibited by 0.12 microg/ml of cefditoren and 4 microg/ml of cefixime. Penicillin-intermediate strains were susceptible to cefotaxime and ceftriaxone, with <50% susceptibility to cefdinir and cefpodoxime. The MIC(50) and MIC(90) values of cefditoren were 0.25 microg/ml and 0.5 microg/ml, respectively, whereas cefixime exhibited only marginal activity (MIC(90)=16 microg/ml). Penicillin-resistant strains were resistant to cefdinir and cefpodoxime, with 74.8% and 94.1% susceptibility to cefotaxime and ceftriaxone, respectively. Cefditoren MIC(50)/MIC(90) (0.5/1 microg/ml) were lower than cefotaxime and ceftriaxone. Among amoxicillin non-susceptible strains, susceptibility to cefdinir and cefpodoxime was <10%, and susceptibility to cefotaxime decreased from 87.9% in the intermediate category to 63.0% in the resistant group. Cefditoren MIC(50)/MIC(90) (0.5/1 microg/ml) were lower than cefotaxime. In conclusion, the activity of cefixime, cefdinir and cefpodoxime was highly affected by penicillin/amoxicillin non-susceptibility, while parenteral third-generation cephalosporins exhibited higher intrinsic activity (MIC(90)=1 microg/ml for penicillin-resistant and 2 microg/ml for amoxicillin-resistant strains). Cefditoren exhibited one-dilution lower MIC(90) values for these strains, even against those of the most troublesome serotypes.

New insights into the activity of third-generation cephalosporins against pneumonia-causing bacteria

Over 300 isolates representing all pathogens causing ≥ 4% of nosocomial or outpatient pneumonias were tested against currently used third-generation cephalosporins (cefotaxime, desacetylcefotaxime, ceftriaxone, ceftazidime, cefoperazone, and ceftizoxime) to determine differences in activity and effects of physiologic host and pharmacokinetic properties. Prevalent drug resistances were represented and tests were performed by reference methods of the National Committee for Clinical Laboratory Standards. Spectrums and potency of cefotaxime, desacetylcefotaxime, ceftriaxone, and ceftizoxime were most similar, but cefotaxime plus desacetylcefotaxime at in vivo ratios increased the cefotaxime spectrum (anaerobes and Pseudomonas) and potency. Ceftizoxime was least active because of current reduced activity against some Staphylococcus spp. and Pseudomonas aeruginosa. Ceftriaxone potency was adversely affected (≥ 4-fold decrease) by serum protein binding, thus reducing its susceptibility spectrum for pathogens with ≥ 4 μg/ml minimum inhibitory concentrations (MICs) and a 10.6% reduced spectrum overall. Ceftazidime provided poorest coverage against the significant and clinically increasing Gram-positive cocci and did not significantly inhibit aspiration pneumonia causing anaerobic strains. Ceftazidime and cefoperazone were more active against pseudomonas, but they were most labile to newer extended-spectrum β-lactamases. On empiric balance, the third-generation cephalosporins continue to provide the best therapeutic spectrum, particularly those favorably influenced by host factors (proteins and metabolism). These third-generation cephalosporin differences become more important since some agents (ceftazidime) have readily selected type-I enzyme mutants among intensive-care-unit respiratory tract pathogens at our institution. Cost containment will also influence drug choices for some third-generation cephalosporins, usually favoring the earliest introduced compounds such as cefotaxime.

Cellular uptake and cell-associated activity of third generation cephalosporins.

The ability of the third generation cephalosporins to penetrate human polymorphonuclear leukocytes (PMNs) and their antibacterial activity against cell-associated Staphylococcus aureus (SA) and Haemophilus influenzae, type b (Hib) were studied. Utilizing radioactive uptake experiments, the cellular to extracellular concentration ratios were determined to be less than one for all cephalosporins at 10 and 120 min: cefotaxime (0.08 +/- 0.02, 0.34 +/- 0.08), ceftizoxime (0.21 +/- 0.11, 0.52 +/- 0.18), ceftriaxone (0.12 +/- 0.04, 0.38 +/- 0.23), and N-formimidoyl thienamycin (0.18 +/- 0.09, 0.33 +/- 0.14). Third generation cephalosporins were similar to penicillin in their exclusion from PMNs. The killing of cell-associated SA and Hib were evaluated in a preopsonized cell-associated bacterial assay with radiolabelled SA/Hib (cfu/cpm) comparing activity of PMNs + antibiotics to the PMN cell control (no antibiotics) at 0.5, 2, and 4 h. PMNs alone killed less than or equal to 0.5 log SA/Hib over 4 h. Clindamycin killed significantly more SA (p less than 0.01) than all other antibiotics; nafcillin killed significantly fewer SA (p less than 0.05) than all other antibiotics. Although each third generation cephalosporin showed good activity against cell-associated Hib, chloramphenicol had a significantly greater effect (p less than 0.05). N-formimidoyl thienamycin demonstrated good activity only after the concentration was increased in vitro to 8 micrograms/ml. Although cellular penetration of antibiotics may be important in the eradication of cell-associated pathogens, the overall cellular activity would appear to be multifactorial.

Do we need the third-generation cephalosporins?

Third-generation cephalosporins have been available for the past 5 years. The continued increase in resistance of bacteria to older antimicrobial agents and the safety profile of a number of the third-generation agents have established situations in which these compounds are useful. Upper respiratory infections such as epiglottitis, lower respiratory tract infections due to Enterobacteriaceae are examples of illnesses in which third-generation cephalosporins would be preferred to older drug programmes. Bone and joint infections due to Enterobacteriaceae can be treated with third-generation cephalosporins with less risk of toxicity than that associated with aminoglycoside use. But this is an area in which resistance may develop. Meningitis in the elderly due to Escherichia coli or Klebsiella pneumoniae are best treated with cefotaxime and the third-generation cephalosporins are alternative therapy for neonatal and the other forms of meningitis except Listeria or Pseudomonas. These drugs have proved extremely useful in treatment of penicillinase-producing Neisseria gonorrhoeae. Hospital-acquired urinary tract infections in the elderly can be treated with these agents since they provide excellent urinary levels and have a low risk of nephrotoxicity. The need for third-generation cephalosporins in gynaecological and intra-abdomonal infections is less clear. Selected patients will benefit from their use. Closer attention to the excellent in vitro activity and pharmacological activity of third-generation cephalosporins should establish other areas of need for these compounds, but it will be necessary to follow closely the development of resistance to these compounds since species such as Enterobacter, Serratia and Citrobacter can become resistant.