Margret Oethinger

Triclosan targets lipid synthesis

Triclosan is a broad-spectrum antibacterial and antifungal agent,, which acts by previously undetermined mechanisms, that is used in products such as antiseptic soaps, toothpastes, fabrics and plastics. Here we show that triclosan blocks lipid synthesis in Escherichia coli, and that mutations in, or overexpression of, the gene fabI (which encodes enoyl reductase, involved in fatty acid synthesis) prevents this blockage. This is, to our knowledge, the first evidence that triclosan acts on a specific bacterial target, rather than as a nonspecific ‘biocide’.

Ineffectiveness of Topoisomerase Mutations in Mediating Clinically Significant Fluoroquinolone Resistance in Escherichia coli in the Absence of the AcrAB Efflux Pump

ABSTRACT Fluoroquinolone-resistant mutants, selected from a wild-typeEscherichia coli K-12 strain and its Mar mutant by exposure to increasing levels of ofloxacin on solid medium, were analyzed by Northern (RNA) blot analysis, sequencing, and radiolabelled ciprofloxacin accumulation studies. Mutations in the target genegyrA (DNA gyrase), the regulatory gene marR, and additional, as yet unidentified genes (genes that probably affect efflux mediated by the multidrug efflux pump AcrAB) all contributed to fluoroquinolone resistance. Inactivation of the acrAB locus made all strains, including those with target gene mutations, hypersusceptible to fluoroquinolones and certain other unrelated drugs. These studies indicate that, in the absence of the AcrAB pump, gyrase mutations fail to produce clinically relevant levels of fluoroquinolone resistance.

Non-Target Gene Mutations in the Development of Fluoroquinolone Resistance in Escherichia coli

ABSTRACT Mutations in loci other than genes for the target topoisomerases of fluoroquinolones, gyrA and parC, may play a role in the development of fluoroquinolone resistance inEscherichia coli. A series of mutants with increasing resistance to ofloxacin was obtained from an E. coli K-12 strain and five clinical isolates. First-step mutants acquired agyrA mutation. Second-step mutants reproducibly acquired a phenotype of multiple antibiotic resistance (Mar) and organic solvent tolerance and showed enhanced fluoroquinolone efflux. None of the second-step mutants showed additional topoisomerase mutations. All second-step mutants showed constitutive expression of marAand/or overexpressed soxS. In some third-step mutants, fluoroquinolone efflux was further enhanced compared to that for second-step mutants, even when the mutant had acquired additional topoisomerase mutations. Attempts to circumvent the second-step Mar mutation by induction of the mar locus with sodium salicylate and thus to select for pure topoisomerase mutants at the second step were not successful. At least in vitro, non-target gene mutations accumulate in second- and third-step mutants upon exposure to a fluoroquinolone and typically include, but do not appear to be limited to, mutations in the mar or soxregulons with consequent increased drug efflux.

Ochrobactrum anthropi Bacteremia: Report of Four Cases and Short Review

SummaryOchrobactrum anthropi, formerly“Achromobacter” CDC group Vd, is a nonfermentative, nonfastidious gram-negative bacillus, that only recently has been given attention as a potential human pathogen. Over a 2-year period, we observed four patients with multiple blood cultures that were positive for the organism. The patients had acute leukemia as underlying disease, and presented with clinical and microbiologic features consistent with catheter-related bacteremia. In three of the patients the infection initially appeared to be unrelated to chemotherapy-associated profound neutropenia and occurred early after, or was the reason for, hospital admission. The antimicrobial susceptibility of the isolates varied: unlike previously reported cases, resistance in some of our isolates included aminoglycosides, newer fluoroquinolones, and trimethoprim-sulfamethoxazole. Despitein vitro susceptibility to imipenem in initial isolates, treatment of two patients with this agent obviously failed to eradicate the organism, and the patients either relapsed with bacteremia shortly after discontinuation of treatment or remained persistently febrile and bacteremic.O. anthropi appears to be increasingly recognized as a human opportunist pathogen associated with intravascular catheters and unpredictable multiple antibiotic resistance.ZusammenfassungOchrobactrum anthropi, früher als„Achromobacter“-Gruppe CDC Vd bezeichnet, ist ein nicht-fermentatives, anspruchslos wachsendes gram-negatives Stäbchen, das erst seit kurzer Zeit als potentiell humanpathogen gilt. Während einer 2-Jahresperiode beobachteten wir vier Patienten, bei denen dieses Bakterium aus mehreren Blutkulturen isoliert wurde. Die Patienten hatten als Grunderkrankung eine akute Leukämie. Bei drei Patienten trat die Infektion jedoch unabhängig von einer schweren Neutropenie auf. Vielmehr war sie hier entweder die Ursache der Krankenhausaufnahme, oder sie trat bereits sehr kurz nach Krankenhausaufnahme auf. Die Infektion erschien nach klinischen und mikrobiologischen Befunden in allen Fällen als Katheter-assoziierte Bakteriämie. Die antimikrobielle Empfindlichkeit der Isolate war sehr uneiheitlich: im Unterschied zu früheren Berichten waren einige unserer Isolate auch resistent gegenüber Aminoglykosiden, neueren Fluorochinolonen und gegenüber Trimethoprim-Sulfamethoxazol. Die Therapie mit Imipenem bei zwei Patienten war trotzIn-vitro-Empfindlichkeit nicht erfolgreich. Ein Patient hatte erneute Bakteriämien durch den Erreger jeweils kurz nach Ende der Therapie, der andere Patient blieb unter Therapie febril und bakteriämisch.Ochrobactrum anthropi muß als nicht selten multiresistenter, opportunistischer humanpathogener Erreger vor allem Katheter-assoziierter Infektionen angesehen werden.

Colonization and infection with fluoroquinolone-resistantEscherichia coli among cancer patients: Clonal analysis

SummaryEscherichia coli with high-level fluoroquinolone resistance were isolated from feces and/or various body sites of 16 cancer patients who were on oral fluoroquinolone prophylaxis. Population analysis of fecal isolates in 11 patients showed that fluoroquinoloneresistantE. coli was the only aerobic gram-negative bacillus present and exhibited a relatively homogenous fluoroquinolone MIC distribution. Molecular typing by pulsed field gel electrophoresis of chromosomal DNA digests or by random amplified polymorphic DNA fingerprinting confirmed the clonal nature of gastrointestinal tract colonization withE. coli. Genotyping of ten colonies picked from the same fecal culture demonstrated identical strains in four of four patients examined. Identical genotypes from the same patient were isolated over prolonged periods of time in 12 of 12 cases examined, with one patient (with the longest follow-up of 14 months) who lost his initial genotype and became persistently colonized with a new genotype. In the 11 patients who developed infection due to fluoroquinolone-resistantE. coli, molecular typing also indicated that fecal colonization was associated with, and presumably preceded infection due to an indistinguishable genotype of fluoroquinolone-resistantE. coli.

Teicoplanin: 10 years of clinical experience

SummaryThe teichomycin antibiotics have been discovered and chemically purified in the late 1970s. Teicoplanin, one of the major derivatives of this group, has been introduced into clinical use in 1984. In Germany, teicoplanin was licensed in 1988 and now ranks among the antimicrobial agents most frequently used in intensive care units. Due to its reduced rate of side effects compared to vancomycin, its longer serum half-life and a simplified mode of application, teicoplanin has become the glycopeptide of choice in many hospitals. The present review summarizesin vitro activity data, pharmacokinetics, and clinical experience with teicoplanin, with special consideration of currently recommended doses and serum levels.ZusammenfassungDie Teichomycin-Antibiotika wurden Ende der 70er Jahre entdeckt und chemisch gereinigt. Das bisher wichtigste Derivat dieser Gruppe, Teicoplanin, wurde 1984 erstmals im Rahmen klinischer Studien angewandt. Nach seiner Zulassung in Deutschland, die Ende 1988 erfolgte, wurde Teicoplanin insbesondere in Intensivbereichen zu einem der meistverwendeten Antibiotika. Aufgrund seiner geringeren Nebenwirkungsrate im Vergleich zu Vancomycin, der längeren Serum-Halbwertszeit und eines vereinfachten Applikationsmodus (Bolus-Injektion), wurde Teicoplanin in vielen Kliniken als Glykopeptid erster Wahl eingeführt. In der vorliegenden Übersicht werden Daten zurIn-vitro-Aktivität, Pharmakokinetik sowie zu den klinischen Ergebnissen mit Teicoplanin zusammengefaßt, wobei insbesondere auf aktuelle Dosierungsempfehlungen und die Bestimmung von Serumspiegeln eingegangen wird.