B. Wiedemann

Prevalence of fluoroquinolone resistance in Europe

SummarySince 1984, when the first fluoroquinolone, norfloxacin, was marketed in Europe, there has been a marked increase in the usage of this class of drugs. In order to evaluate the influence of this drug usage on the prevalence of resistance to fluoroquinolones in clinical isolates of the familyEnterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, coagulase-negative staphylococci andEnterococcus faecalis we reviewed the susceptibility data from four collaborative surveys conducted between 1983 and 1990 by the Study Group ‘Bacterial Resistance’ of the Paul-Ehrlich-Society for Chemotherapy. All participating laboratories used the same standardized methods. Miminal inhibitory concentrations were determined by the broth microdilution method. More than 20,000 bacterial strains were tested. The results are presented for ciprofloxacin, which is regarded as the representative of the fluoroquinolones. Using ≥ 4 mg/l as a breakpoint for resistance to ciprofloxacin, the prevalence of resistant strains of the familyEnterobacteriaceae in Central Europe between 1983 and 1990 remained below 1%. In contrast, the resistance rates inP. aeruginosa were 0.7%, 1.0%, 3.8% and 7.0%, inS. aureus 0%, 0.5%, 6.6% and 6.8%, and inE. faecalis 2.2%, 0.7%, 4.9% and 7.7% in 1983, 1986, 1989 and 1990, respectively. The latest study carried out in cooperation with 78 laboratories from 12 European countries revealed great differences in the prevalence of resistance to fluoroquinolones from one species to another ranging from 0% withProteus vulgaris andSalmonella spp. to 26.7% withProvidencia stuartii. The highest rates of resistance were recorded for oxacillin-resistant strains ofS. aureus (70.6%) and oxacillin-resistant coagulase-negative staphylococci (51.2%). Resistance levels for individual species varied between countries, but they were consistently higher in Southern Europe than in Northwest and Central Europe. Resistance inS. aureus andE. faecalis was more prevalent in isolates from intensive care patients than in isolates from patients on normal wards. In addition,S. aureus isolates displayed a considerable difference in the resistance rates for blood (9.3%) and urine (34.4%).ZusammenfassungSeit 1984, als das erste Fluorchinolon, Norfloxacin, auf dem europäischen Markt eingeführt wurde, hat der Verbrauch an Substanzen dieser Stoffklasse in erheblichem Umfang zugenommen. Um den Einfluß dieses Verbrauchs auf die Ausbreitung der Resistenz gegenüber Fluorchinolonen bei klinischen Isolaten der Familie Enterobacteriaceae,Pseudomonas aeruginosa, Staphylococcus aureus, Koagulase-negativen Staphylokokken undEnterococcus faecalis feststellen zu können, haben wir die Empfindlichkeitsdaten von vier multizentrischen Studien analysiert, die zwischen 1983 und 1990 von der Arbeitsgemeinschaft „Resistenz“ in der Paul-Ehrlich-Gesellschaft für Chemotherapie durchgeführt wurden. Alle an der Studie beteiligten Institute verwendeten die gleichen standardisierten Methoden. Die minimalen Hemmkonzentrationen wurden unter Verwendung der Mikro-Bouillondilutionsmethode ermittelt. Es wurden mehr als 20 000 Bakterienstämme untersucht. Die Ergebnisse wurden für Ciprofloxacin dargestellt, das als repräsentatives Fluorchinolon angesehen wird. Wenn für Ciprofloxacin ein Grenzwert von ≥ 4 mg/l für die Bewertung resistent benutzt wird, blieb in Mitteleuropa die Prävalenz resistenter Stämme der FamilieEnterobacteriaceae zwischen 1983 und 1990 unterhalb von 1%. Demgegenüber betragen die Resistenzraten in 1983, 1986, 1989 und 1990 fürP. aeruginosa 0,7%, 1,0%, 3,8% and 7,0%, fürS. aureus 0%, 0,5%, 6,6% und 6,8% sowie fürE. faecalis 2,2%, 0,7%, 4,9% und 7,7%. Die 1990 in Kooperation mit 78 Laboratorien in 12 europäischen Ländern durchgeführte Studie ergab, daß hinsichtlich des Ausmaßes der Fluorchinolonresistenz zwischen den einzelnen Spezies erhebliche Unterschiede bestehen können. So beträgt die Resistenzhäufigkeit beiProteus vulgaris undSalmonella sp. 0%, aber beiProvidencia stuartii 26,7%. Die höchsten Resistenzraten wurden für oxacillinresistente Stämme vonS. aureus (70,6%) und Oxacillin-resistente Koagulase-negative Staphylokokken (51,2%) bestimmt. Das Resistenzniveau der einzelnen Bakterienspezies variiert zwischen den Ländern, wobei der Anteil resistenter Stämme in Südeuropa stets höher war als in Nordwest- und Mitteleuropa. Resistente Stämme vonS. aureus undE. faecalis wurden häufiger von Intensivpatienten als Patienten auf Normalstationen isoliert. Darüber hinaus zeigte sich fürS. aureus ein erheblicher Unterschied zwischen den Resistenzraten für Blut- (9,3%) und Urinisolate (34,4%).

In vitro activity of cefpodoxime and ten other cephalosporins against gram-positive cocci, enterobacteriaceae and pseudomonas aeruginosa, including β-lactamase producers

SummaryCefpodoxime, the deesterified part of the orally available cefpodoxime proxetil, is active against mostEnterobacteriaceae with MIC50 of 0.06 to 2 mg/l. OnlyEnterobacter cloacae andCitrobacter freundii strains show MIC50 of 4 mg/l. Coagulase negative staphylococci have a MIC50 of 2, whileStaphylococcus aureus strains have a MIC of 4 mg/l. In comparison to other orally available cephalosporins cefpodoxime is slightly less active than cefixime and cefotiam against gram-negative bacteria but more active than cefuroxime, cefaclor, and cephalexin. Against staphylococci the activity of cefpodoxime is comparable to that of cefotiam and cefuroxime and superior to cefaclor and cephalexin, while cefixime does not have sufficient activity against these species. Like all cephalosporins cefpodoxime has no activity against enterococci.ZusammenfassungCefpodoxim entsteht durch Spaltung des Esters aus dem resorbierbaren Cefpodoxim-Proxetil und ist gegen die meistenEnterobacteriaceae mit MHK50-Werten von 0,06 bis 2 mg/l aktiv. Nur Stämme vonEnterobacter cloacae undCitrobacter freundii zeigen MHK50-Werte von 4 mg/l. Coagulase negative Staphylokokken haben eine MHK50 von 2, währendStaphylococcus aureus-Stämme eine MHK von 4 mg/l aufweisen. Im Vergleich mit anderen oral verfügbaren Cephalosporinen ist Cefpodoxim gegen gramnegative Bakterien etwas weniger aktiv als Cefixim und Cefotiam, aber aktiver als Cefuroxim, Cefaclor und Cephalexin. Gegen Staphylokokken ist die Aktivität von Cefpodoxim mit der von Cefotiam und Cefuroxim vergleichbar und der von Cefaclor und Cephalexin überlegen, während Cefixim keine ausreichende Aktivität gegen diese Spezies hat. Wie alle Cephalosporine weist Cefpodoxim keine Aktivität gegen Enterokokken auf.

Microbiological Evaluation of Cefpodoxime Proxetil

SummaryCefpodoxime, the active de-esterified molecule of the orally absorbable cephalosporin cefpodoxime proxetil, inhibits streptococci, Neisseria spp., and most Enterobacteriaceae, with MIC50 and/or MIC90 values of ⩽ 2 mg/L; with regard to the latter family of bacteria, the MIC50 and/ or MIC90 values of cefpodoxime are consistently ⩾ 4 mg/L for only Enterobacter cloacae, Citrobacter freundii, Senatia marcescens, and Morganella morganii. The MIC50 of cedpodoxime for coagulase-negative staphylococci is > 2 mg/L, while the MIC for Staphylococcus aureus strains is 4 mg/L. In comparison with other orally absorbable cephalosporins, cefpodoxime is slightly less active than cefixime, cefetamet, and cefotiam against Gram-negative bacteria, but more active than cefuroxime, cefaclor, and cefalexin. Against staphylococci, the activity of cefpodoxime is comparable to that of cefotiam and cefuroxime, and superior to that of cefaclor, while cefixime and cefetamet have insufficient activity against these species. In common with other cephalosporins, cefpodoxime has no activity against enterococci. In vitro models simulating human serum cefpodoxime concentrations demonstrate that a dosage regimen of 200mg is probably sufficient to treat most infections. However, further study is needed to clarify whether infections due to bacteria such as S. aureus, with higher cefpodoxime MICs, can be treated with this dose regimen.

Urine bactericidal activity of pefloxacin versus norfloxacin in healthy female volunteers after a single 800-mg oral dose

SummaryIn an open randomised crossover study the antibacterial activity of pefloxacin and norfloxacin was assessed in the urine after a single 800-mg oral dose in 14 healthy female volunteers. Pefloxacin demonstrated lower peak concentrations in the urine than norfloxacin (mean, 217.2 mg/l versus 492.9 mg/l as determined by the microbiological assay) but pefloxacin was present over a longer period of time in sufficient concentrations than norfloxacin. Mean urine levels of at least 2 mg/l were present for 7 days after pefloxacin administration and 2 days after norfloxacin administration as determined by the microbiological assay. Overall, the urinary recovery of pefloxacin and norfloxacin amounted to 49.3% and 25.1%, respectively, of the total administered dose. The average urine bactericidal activity against the five test organisms was as follows: against reference strainEscherichia coli ATCC 25922 susceptible to nalidixic acid (Nal-S) for 5 days with pefloxacin and 2 days with norfloxacin; against three clinical isolates, one strain each ofE. coli resistant to nalidixic acid (Nal-R),Klebsiella pneumoniae Nal-R, andStaphylococcus saprophyticus, for 3 days with pefloxacin and 24 h with norfloxacin; and against a clinical isolate ofEnterococcus faecalis for 2 days with pefloxacin and 12 h with norfloxacin. In conclusion, pefloxacin as a single dose proved to have sufficiently high and long-lasting urine bactericidal activity against urinary pathogens. These findings support the results of a meta-analysis of seven clinical trials in patients with uncomplicated lower UTI, demonstrating a single oral dose of 800 mg pefloxacin to be as effective as a conventional treatment with comparative drugs [21].

Pharmacodynamic Activity of Levofloxacin in an In Vitro Model Against Gram-Positive and Gram-Negative Bacteria

It is well established that fluoroquinolone antibiotics have a high activity against Gram-negative pathogens. However, treatment failures have occurred with older fluoroquinolones (i.e. ciprofloxacin) when used in patients infected with Gram-positive bacteria. Newer agents, such as levofloxacin, show high activity against Gram-positive and Gram-negative organisms. The in vitro susceptibility of bacteria to antibiotics, expressed as MIC values, does not necessarily reflect the therapeutic value of a drug, because these data are obtained by constant drug concentrations. Furthermore, the minimum inhibitory concentration (MIC) does not represent the real pharmacodynamic activity as the kinetics of the killing ability is neglected. Therefore, we evaluated the pharmacodynamic properties of levofloxacin against 5 respiratory tract pathogens in comparison with ciprofloxacin, using an in vitro model. Using this method, we were able to simulate the pharmacokinetic profile observed in humans after a standard antibiotic dosage regime (500mg levofloxacin or ciprofloxacin).

Quinolone Activity Against Respiratory Pathogens

Grepafloxacin has a broad spectrum of activity that includes all the important Gram-positive, Gramnegative and intracellular pathogens responsible for community-acquired respiratory tract infections.[1,2] Compared with older quinolones, grepafloxacin has significantly greater activity against Gram-positive bacteria.[1] Grepafloxacin-resistant mutants of Streptococcus pneumoniae and Staphylococcus aureus have been shown to occur less frequently, and to be associated with smaller increases in MICs, than ciprofloxacinor ofloxacin-resistant mutants.[3,4] This in vitro study evaluated the likely therapeutic activity of grepafloxacin and ciprofloxacin against S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. As comparisons of MICs and peak serum concentrations do not reflect the antibiotic pharmacodynamics, the study used an in vitromodel to simulate the in vivo pharmacokinetics of recommended doses of grepafloxacin and ciprofloxacin, i.e. 400 and 500mg, respectively.

Antibiotika-Resistenz und R-Faktoren bei Salmonellen-Spezies in der Bundesrepublik

ZusammenfassungIn der vorliegenden Arbeit wurden drei Kollektive von S. typhi murium und S. panama untersucht, die in den Jahren 1969–1970 in der Bundesrepublik Deutschland isoliert wurden. Folgende Ergebnisse wurden erzielt: 1. Gegenüber den Jahren 1965 bis 1968 zeigt sich bei den Stämmen menschlicher Herkunft keine wesentliche Veränderung in der Häufigkeit resistenter Anteile. 2. Vom Tier stammende Stämme, bei denen ein Vergleich mit Untersuchungen aus früheren Jahren nicht möglich war, zeigen zwei- bis dreifach höheren Anteil resistenter Stämme als diejenigen menschlicher Herkunft. 3. Der überwiegende Anteil der resistenten Stämme (75–90%) trug R-Faktoren. Dabei überwogen Tetracyclin, Ampicillin/Tetracyclin und Ampicillin/Streptomycin/Tetracyclin.SummaryThis study examined samples of S. typhi murium and S. panama which were isolated in 1969 and 1970 in three different institutes in West Germany. The following results were obtained: 1. In contrast to the years 1965–1968, strains isolated from man showed no appreciable change in the frequency of the resistant percentage. 2. Strains isolated from animals demonstrated a resistant percentage two or three times higher than strains isolated from man. A comparison with investigations from previous years was not possible for these animal strains. 3. The majority of resistant strains (75–90%) carried R-factors mostly to Tetracycline, Ampicillin/Tetracycline and Ampicillin/Streptomycin/Tetracycline.