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Clinical use of ceftriaxone: a pharmacokinetic-pharmacodynamic perspective on the impact of minimum inhibitory concentration and serum protein binding.

Ceftriaxone is a third-generation cephalosporin that is used for a variety of infections such as meningitis, gonorrhoea and community-acquired pneumonia. The most important aspects of its pharmacokinetics include a long half-life, excellent tissue penetration and saturable (dose-dependent) serum protein binding of the drug. A pharmacodynamic analysis [total area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC)] was performed in several populations (healthy volunteers, children, the elderly, and patients with renal and hepatic impairment) against various bacterial species (Streptococcus pneumoniae, the Enterobacteriacieae, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa). AUC/MIC [area under the inhibitory time curve (AUIC)] was chosen as the pharmacodynamic parameter for this analysis since ceftriaxone is a time-dependent killer and high peak concentrations are not needed. In addition, there is a significant correlation between AUIC, time when concentration exceeds the MIC (t > MIC) and time to eradication. Total and free AUICs (assuming a free fraction = 10%) were calculated since it is highly protein bound. It was postulated that a free AUIC of at least 125 would be required to achieve efficacy. From our analysis of these various populations, we were able to conclude that the free AUIC values support the use of Ig daily in infections where MIC values are below 2 mg/L. In addition, consistent with its reported good activity against CSF organisms with MICs < or =1.0 mg/L and marginal activity against organisms with MICs > or =2.0 mg/L, we also recommend the target free AUIC values of at least 125 for patients with severe infections such as meningitis. Patients with mild infections may recover with values below 125 but they may remain at risk of the development of resistant organisms. Furthermore, it is essential to further validate these findings in patients who have received treatment, calculate AUICs and correlate these parameters with both clinical and microbiological outcomes.

Adult↗

Drug-usage evaluation: a system for the prospective evaluation of antibiotic utilization in minimum inhibitory concentration documented infections.

Large hospitals appear to have advantages in using specialized clinical practitioners to provide prospective reviews on drug therapy. Using the PRMC pharmacy service as a model, a prospective DUE program can be duplicated in small hospitals with four or five fulltime pharmacists. The minimal requirements are a microbiology laboratory, administrative support, and a pharmacy service committed to providing prospective patient oriented care.

Anti-Bacterial Agents↗

Effect of beta-lactamase inhibitors on minimum inhibitory concentration of ampicillin and amoxicillin for Staphylococcus aureus strains.

Seventy strains of Staphylococcus aureus isolated from the nasopharynx (80%), urinary tract (16%), skin (1 strain) and eyes (2 strains) of patients at the clinical laboratory "El eritrocito" were analyzed. Susceptibility to 12 antibiotics was tested by the method of Kirby-Bauer. Minimal inhibitory concentration (MIC) of ampicillin, ampicillin + sulbactam, amoxicillin and amoxicillin + clavulanic acid were determined by plate dilution. Percentages of resistance were: Penicillin and ampicillin (100%), ceftazidime (81.4%), erythromycin (68.6%), tetracycline (31.4%) trimethoprim-sulphametoxasol (25.7%), dicloxacillin and pefloxacin (12.8%), cefuroxime and cefotaxime (4.3%), gentamicin (2.8%), cephalothin (0%). All strains were resistant to three or more antibiotics, with higher percentages of resistance to four (31.4%), three (27.1%), five (21.4%) and six (12.9%) drugs. One strain was resistant to nine antibiotics and 5.9% were resistant to seven. 97.5% of the strains were beta-lactamase-positive. The MIC50 of ampicillin and amoxicillin was 500 micrograms/ml and the MIC90 were 1727 micrograms/ml and 2000 micrograms/ml, respectively. beta-lactamase inhibitors sulbactam and clavulanic acid reduced these values eightfold, except for the MIC50 of ampicillin + sulbactam whose reduction was sixteen fold. These results show that the combination of beta-lactamic + beta-lactamase inhibitor was more efficient than cephalosporins for killing these beta-lactamase-positive strains.

4-Quinolones↗

[Minimum inhibitory concentrations of various antifungal agents against Basidiomycetes clinical isolates].

The basidiomycete yeasts are often isolated from clinical samples. A minimal inhibiting concentrations (MIC) of ten antifungals of different groups--azols, allilamines, polyens etc.--against isolates of Rhodotorula, Cryptococcus [symbol: see text] Trichosporon yeasts genera were estimated. No one of these cultures was sensitive to azoles at concentrations 0-256 mcg/ml. A vitality of cultures after incubation during 10 days with antifungals was investigated. Miramistin was the most potent fungicidal agent against all cultures.

Antifungal Agents↗

Increase in minimum inhibitory concentration to quinolones and ceftriaxone in salmonellae causing enteric fever.

Multidrug resistance among Salmonella typhi is well known. Reports of treatment failure in enteric fever with Ciprofloxacin made us undertake this study to determine the antibiotic susceptibility pattern of S. typhi and S. paratyphi A isolated from typhoid bacteremia cases, by disc diffusion and MIC by broth dilution method. A total of 50 strains were tested, 48 of Salmonella typhi and 2 of S. paratyphi A. The disc diffusion method was done using ampicillin, chloramphenicol, cotrimoxazole, tetracycline, ciprofloxacin, ofloxacin, cefuroxime and ceftriaxone as antibiotics. The MIC was performed using ciproloxacin, ofloxacin and ceftriaxone based on standard procedure. ACCOT resistance as determined by disc diffusion method was seen in 68% of isolates. All the strains remained susceptible to flouroquinolones cephalosporins and aminoglycosides. The MIC of ciprofloxacin, ofloxacin and ceftriaxone were in the recommended range of susceptibility as given by NCCLS, 14 (28%) strains had MIC of ciprofloxacin greater than 0.5 ug/ml with 4 strains having an MIC of 1.56 ug/ml; 25 (50%) strains had MIC of ofloxacin greater than 0.5 ug/ml and 20 (40%) strains had MIC of ceftriaxone greater than 0.5 ug/ml. The high levels of MIC of ciprofloxacin may account for treatment failure cases. The rising levels of MIC of ofloxacin and ceftriaxone in S. typhi and S. paratyphi is also of concern. We document here the emergence of high levels of MIC not only to ciprofloxacin, but also ofloxacin and ceftriaxone in S. typhi and S. paratyphi A. We recommend that MIC levels of ofloxacin and ceftriaxone should be monitored along with ciprofloxacin in treatment failure cases of enteric fever.

Anti-Bacterial Agents↗

[Results from a German interlaboratory test to establish the broth microdilution method for the determination of the minimum inhibitory concentration of bacteria from animals].

In accordance with NCCLS guideline M31-A2, the DVG working group "antimicrobial resistance" developed a standard operating procedure (SOP) for the determination of the minimal inhibitory concentration (MIC) of antimicrobial agents by broth microdilution. This SOP was evaluated for its fitness for use in a national interlaboratory test. A total of 32 participating laboratories tested five strains (including two internationally accepted reference strains and three field strains representing in total three different bacterial species) three times at a one week interval each, using uniform microtitre plates. In 31 of the 32 laboratories more than 80% of MIC determinations performed yielded values in the expected range. In total 94.0% of the results were reproducible, with a lesser deviation of 4.0% from the expected values for laboratories performing MIC determination as a matter of routine (46.9%), compared to 7.9% for laboratories without such routine (53.1%). Comparing the consistency of results on the basis of the tested strains, a higher reproducibility of the results was observed for reference strains (96.1%) than for field strains (92.6%). In particular results obtained for the Streptococcus uberis field strain were afflicted with a higher error ratio (98 deviations from the expected values). Among the tested antimicrobial agents, a higher variability of results was recorded only for gentamicin with 16.7% divergent MIC determinations (mean value 6.0%). The high reproducibility of the results confirmed by this interlaboratory study underlines the robustness of the developed SOP as well as broth microdilutions as the method of choice for MIC determina tion.

Animals↗

A novel colorimetric broth microdilution method to determine the minimum inhibitory concentration (MIC) of antibiotics and essential oils against Helicobacter pylori.

Helicobacter pylori infections have been associated with the pathogenesis of a number of stomach and gastroduodenal diseases. In order to find alternative drugs for their treatment the search is increasingly focused on new antimicrobial products. However, no standardized methods are available to test the anti-Helicobacter pylori activity in particular of natural substances. Therefore we developed a broth microdilution assay to investigate the susceptibility of this fastidious slow growing bacterium against 15 essential oils widely used to treat disorders of the gastrointestinal tract. The MIC values were determined colorimetrically using p-iodonitrophenyltetrazolium violet (INT) as an indicator for bacterial cell viability. The test sytem was evaluated with three common antibiotics: amoxicillin, ampicillin and levofloxacin. The antibiotic MICs were controlled by Etest. The Helicobacter reference strain was remarkably susceptible to both the antibiotics (amoxicillin MIC: 0.02 microg/ml, ampicillin MIC: 0.064 microg/ml, levofloxacin MIC: 0.39 microg/ml) and the essential oils. Most of their MICs ranged from 0.015 to 0.064% (v/v) and about 140.0 to 280.0 microg/ml, respectively. Interestingly, chamomile oil, orange flower oil and ginger oil inhibited the bacterial growth in extraordinarily low concentrations of 0.0075% (v/v) and about 65 microg/ml, respectively. The bactericidal concentrations were generally one to two dilution steps higher. In conclusion, we could develop an innovative assay for the MIC determination of essential oils and antibiotics against Helicobacter pylori, which is simple to handle, accurate, reproducible and not as time- and material-consuming as traditional agar dilution techniques.

Anti-Bacterial Agents↗

Effects of minimum inhibitory concentrations of three antimicrobials on the growth cell and fimbriation of uropathogenic Escherichia coli.

Uropathogenic E. coli 36692 cells synthesize fimbriae during the first half of the exponential growth curve. The presence of the appendices was detected by electron microscopy and it was correlated with a high haemagglutination activity. Norfloxacin, amoxicillin and gentamicin supply 1/4 of their respective MICs, inhibiting the cell growth. Also all these drugs with the same sub MICs alter the haemagglutination titre and inhibit the fimbriation process of the uropathogenic E. coli. Gentamicin showed the highest inhibition of the haemagglutinating activity and fimbriae synthesis.

Adhesins, Escherichia coli↗

[Comparison of minimum inhibitory concentrations of group M penicillins against Staphylococcus aureus. Practical impact on diagnosis and treatment].

The MICs were determined in usual conditions and in special conditions for the detection of heterogeneous methicillin resistance. The study involved 40 strains of Staphylococcus aureus of the 3 categories of homogeneous resistant, heterogeneous resistant and sensitive strains. The MICs of the 4 main compounds of the group M penicillins, methicillin, oxacillin, cloxacillin and dicloxacillin, were lower in the presence of a higher number of chlorine atoms on the molecule. The heterogeneous strains were even sensitive to dicloxacillin. The MIC for a notable fraction of resistant strains were lower than the critical value, i.e. these strains entered the category of dicloxacillin sensitive even in reading conditions theoretically leading to the detection of heterogeneous resistance. These in vitro observations are of value in the presence of methicillin sensitive strains, since antibiotics containing one or two chlorine atoms will probably be more therapeutically effective. But the bacteriologist should pay more careful attention to the detection of methicillin resistant and heteroresistant strains, since the resistance in vivo is extended to other penicillinase-resistant penicillins or penicillins M.

Cloxacillin↗