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W V Kern

Publications and source records attributed to W V Kern.

At least 55 records · Page 3Linked to original sources
PubMed2000

Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump.

Fluoroquinolone-resistant mutants, selected from a wild-type Escherichia 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 gene gyrA (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.

Anti-Infective Agents↗
PubMed2000

Non-target gene mutations in the development of fluoroquinolone resistance in Escherichia coli.

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 in Escherichia 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 a gyrA 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 marA and/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 sox regulons with consequent increased drug efflux.

Anti-Infective Agents↗
PubMed2000

Zinc serum level in human immunodeficiency virus-infected patients in relation to immunological status.

In human immunodeficiency virus (HIV) infection, serum level of zinc, an important micronutrient for immune function, is frequently diminished. The aim of this study was to determine the zinc status in relation to immunological parameters and disease stage in 79 HIV-1 seropositive patients. The median serum level of zinc was within normal limits (12.5 micromol/L) but in 23% of patients, zinc deficiency was seen. Decreased serum zinc was associated with a low CD4 cell count, high viral load, and increased neopterin and IgA levels. According to current treatment recommendations, the majority of patients received antiretroviral triple therapy. Zinc levels in treated and untreated patients were comparable. Referring to disease stage (CDC classification, 1993), the mean zinc level was highest in stage C and lowest in stage A. In conclusion, even under antiretroviral triple therapy, zinc deficiency is still of great importance in HIV infection, and zinc substitution in zinc deficient individuals should be taken into account to optimize therapeutical success.

Adult↗
PubMed1999

Prospective, randomised, double blind trial of prophylaxis with single dose of co-amoxiclav before percutaneous endoscopic gastrostomy.

OBJECTIVE: To determine the efficacy of antibacterial prophylaxis in preventing infectious complications after percutaneous endoscopic gastrostomy. DESIGN: Prospective, randomised, placebo controlled, double blind, multicentre study. SETTING: Departments of internal medicine at six German hospitals. SUBJECTS: Of 106 randomised adult patients with dysphagia, 97 received study medication, and 84 completed the study. The median age of the patients was 65 years. Most had dysphagia due to malignant disease (65%), and many (76%) had serious comorbidity. INTERVENTIONS: A single intravenous 2.2 g dose of co-amoxiclav or identical appearing saline was given 30 min before percutaneous endoscopic gastrostomy performed by the thread pull method. MAIN OUTCOME MEASURES: Occurrence of peristomal wound infections and other infections within one week after percutaneous endoscopic gastrostomy. RESULTS: The incidence of peristomal and other infections within one week after percutaneous endoscopic gastrostomy was significantly reduced in the antibiotic group (8/41 (20%) v 28/43 (65%), P<0.001). Similar results were obtained in an intention to treat analysis. Several peristomal wound infections were of minor clinical significance. After wound infections that required no or only local treatment were excluded from the analysis, antibiotic prophylaxis remained highly effective in reducing clinically important wound infections (1/41 (2%) v 11/43 (26%), P<0.01) and non-wound infections (2 (5%) v 9 (21%), P<0.05). CONCLUSIONS: Antibiotic prophylaxis with a single dose of co-amoxiclav significantly reduces the risk of infectious complications after percutaneous endoscopic gastrostomy and should be recommended.

Administration, Oral↗
PubMed1999

Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS: In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS: Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS: In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

Administration, Oral↗
PubMed1999

Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial.

We performed a prospective, randomized, multicenter trial to evaluate the effectiveness of prophylactic inhalations with aerosolized amphotericin B (aeroAmB) to reduce the incidence of invasive aspergillus (IA) infections in patients after chemotherapy or autologous bone marrow transplantation and an expected duration of neutropenia of at least 10 days. From March 1993 until April 1996, 382 patients with leukemias, relapsed high-grade non-Hodgkin lymphomas, or solid tumors were randomized with a 13:10 ratio to receive either prophylactic aeroAmB inhalations at a dose of 10 mg twice daily or no inhalation prophylaxis in an unblinded fashion. The incidence of proven, probable, or possible IA infections was 10 of 227 (4%) in patients who received prophylactic aeroAmB. This did not differ significantly from the 11 of 155 (7%) incidence in patients who received no inhalation prophylaxis (P =.37). Moreover, no differences in the overall mortality (13% v 10%; P =.37) or in the infection-related mortality (8% v 7%; P =.79) were found. In contrast to other nonrandomized trials, we observed no benefit from prophylactic aeroAmB inhalations, but the overall incidence of IA infections was low.

Administration, Inhalation↗
PubMed1999

[Infectiology].

Explore the source record for details and available documents.

Curriculum↗
PubMed1999

[Antibiotics, new pathogens, new drug resistance].

The 20th century is the century of the discovery of numerous pathogenic microorganisms. It is also the century of discovery of antimicrobial drugs and the beginning of the antibiotic era. While the development of antifungal drugs and of antivirals is on its rise, many infectious disease physicians and microbiologists feel that we might be on the edge of the beginning of the post-antibiotic era--50 years after antibiotic use in man and animals. Antibiotics have certainly been a major progress in modern medicine. Mortality and morbidity from many infectious diseases have been substantially reduced by effective antimicrobial therapy. The use of antibiotics has also been a prerequisite for major advances in clinical oncology, transplantation medicine, and surgery. The emergence and spread of resistant pathogens, however, has necessitated the development of broader and more active drugs and has resulted in excessive antimicrobial drug use with consequent selective pressure. Every 3rd patient admitted to a hospital is given antibiotics--often in the form of stepwise escalated therapy eventually including combinations of expensive agents. If the aim is to minimize the emergence of resistance and to contain costs, a much more critical indication for antimicrobial drug therapy will be necessary. Also, programmes on a local, regional, and perhaps even national level will be needed to help rationalize antimicrobial drug use.

Animals↗
PubMed1999

Diagnostic value of procalcitonin serum levels in neutropenic patients with fever: comparison with interleukin-8.

We assessed the predictive value of procalcitonin (PCT) serum levels in neutropenic patients with fever and various types of infection, using a prospective 3 times weekly blood sampling protocol during 103 patient episodes. Compared with pre-fever levels, median PCT levels increased after fever onset from 0.16 ng/ml (day -1) to 0.34 ng/ml (day +1). In samples obtained within 32 h after fever onset, PCT levels differed significantly between (clinically or microbiologically) documented infection and unexplained fever (median 0.51 vs. 0.26 ng/ml), between bacteraemia and non-bacteraemic infection (median 0.8 vs. 0.27 ng/ml) and between Gram-negative bacteraemia and all other episodes (median 1.28 vs. 0.31 ng/ml). Receiver-operating-characteristic (ROC) curves indicated that the discriminatory power of PCT was best for predicting bacteraemia vs. non-bacteraemic infection (sensitivity 73%; specificity 86%; area under the ROC curve 0.795; cut-off value 0.5 ng/ml). Compared with interleukin-8 (IL-8) serum levels, test characteristics were similar in the prediction of bacteraemia vs. non-bacteraemic infection and in the prediction of documented infection vs. unexplained fever, while IL-8 was better than PCT in the prediction of Gram-negative bacteraemia (area under the ROC curve 0.965 vs. 0.758).

Adolescent↗
PubMed1998

Association of organic solvent tolerance and fluoroquinolone resistance in clinical isolates of Escherichia coli.

Fluoroquinolone resistance in Escherichia coli is principally caused by two kinds of mutation: those affecting the target proteins of the drugs, i.e. DNA gyrase and topoisomerase IV, and those affecting regulatory genes such as marA, soxS or robA. Recently, overexpression of the latter genes was linked to increased organic solvent tolerance in E. coli. Among 138 clinical fluoroquinolone-resistant and -susceptible clinical isolates of E. coli we found a high association between fluoroquinolone resistance and organic solvent tolerance. This finding suggests that E. coli may undergo an adaptive response to extrinsic substances other than quinolones, while mutating to fluoroquinolone resistance.

Anti-Infective Agents↗
PubMed1998

Overexpression of the marA or soxS regulatory gene in clinical topoisomerase mutants of Escherichia coli.

The contribution of regulatory genes to fluoroquinolone resistance was studied with clinical Escherichia coli strains bearing mutations in gyrA and parC and with different levels of fluoroquinolone resistance. Expression of marA and soxS was evaluated by Northern blot analysis of isolates that demonstrated increased organic solvent tolerance, a phenotype that has been linked to overexpression of marA, soxS, and rob. Among 25 cyclohexane-tolerant strains detected by a screen for increased organic solvent tolerance (M. Oethinger, W. V. Kern, J. D. Goldman, and S. B. Levy, J. Antimicrob. Chemother. 41:111-114, 1998), we found 5 Mar mutants and 4 Sox mutants. A further Mar mutant was detected among 11 fluoroquinolone-resistant, cyclohexane-susceptible E. coli strains used as controls. Comparison of the marOR sequences of clinical Mar mutants with that of E. coli K-12 (GenBank accession no. M96235) revealed point mutations in marR in all mutants which correlated with loss of repressor function as detected in a marO::lacZ transcriptional assay. We found four other amino acid changes in MarR that did not lead to loss of function. Two of these changes, present in 20 of the 35 sequenced marOR fragments, identified a variant genotype of marOR. Isolates with the same gyrA and parC mutations showed increased fluoroquinolone resistance when the mutations were accompanied by overexpression of marA or soxS. These data support the hypothesis that high-level fluoroquinolone resistance involves mutations at several chromosomal loci, comprising structural and regulatory genes.

Anti-Infective Agents↗
PubMed1997

Serum PCR of Pneumocystis carinii DNA in immunocompromised patients.

The detection of Pneumocystis carinii DNA in serum, a potentially useful and attractive tool for the diagnosis of P. carinii infection and for monitoring the success of therapeutic interventions, remains a controversial issue. In a prospective study of 29 immunocompromised patients, including 16 with HIV infection undergoing bronchoscopy and bronchoalveolar lavage, we examined 32 bronchoalveolar lavage fluids and multiple serum samples for the presence of P. carinii DNA by using mitochondrial rRNA gene fragments pAZ102-E as pAZ102-H as primers. Samples from 7 immunocompetent patients were analysed as a control. 13/32 bronchoalveolar lavage fluids of immunocompromised patients (41%), but none of the controls, had both microscopic evidence of P. carinii cysts as well as P. carinii DNA detection. In none of these patients were serum samples obtained before therapy positive for P. carinii DNA, while in 1 patient (8%), P. carinii DNA was detected in 2/5 serum samples obtained during therapy. Interestingly, PCR detected P. carinii DNA in sera of 3/15 immunocompromised patients without detection of P. carinii DNA or organisms in BAL. Two of these 3 patients were taking secondary prophylactics for P. carinii pneumonia. In conclusion, PCR for P. carinii DNA in serum, at least in certain circumstances, may be of little value for the diagnosis of P. carinii pneumonia.

Adult↗
PubMed1996

Levels of cytokines and cytokine inhibitors in the neutropenic patient with alpha-hemolytic streptococcus shock syndrome.

The pathogenesis of alpha-hemolytic streptococcus shock syndrome (SS), a life-threatening complication in neutropenic patients following aggressive chemotherapy that is caused by viridans streptococci, is unknown. We measured serum concentrations of proinflammatory and antiinflammatory cytokines and T cell activation markers in two patients with lethal alpha-hemolytic streptococcus SS. The results were compared with those for controls, two neutropenic patients with uncomplicated bacteremia due to gram-positive organisms and four patients with neutropenia and bacteremia due to gram-negative organisms (two of whom had lethal septic shock). In patients with alpha-hemolytic streptococcus SS, levels of interleukin (IL) 1 were undetectable, levels of tumor necrosis factor (TNF) alpha were only slightly elevated, and IL-6 was the only proinflammatory cytokine that was found in high concentrations and had a late peak level at the time of clinical deterioration. IL-6 levels were much higher in patients with alpha-hemolytic streptococcus SS than in controls with uncomplicated bacteremia due to gram-positive organisms but were comparable with those in controls with bacteremia due to gram-negative organisms. Soluble TNF receptor fragments and IL-1 receptor antagonist apparently were not protective despite high serum concentrations.

Adult↗
PubMed1996

gyrA mutations in high-level fluoroquinolone-resistant clinical isolates of Escherichia coli.

Double mutations in the quinolone resistance determining region of the gyrase A gene (gyrA) have recently been reported to be associated with high-level resistance to fluoroquinolones in clinical isolates of Escherichia coli. We examined the type and frequency of such mutations in a large number of clinical isolates that were obtained from ten different geographical locations and had been genotypically characterized by pulsed field gel electrophoresis (PFGE) of chromosomal DNA digests. Of 36 isolates with ofloxacin MICs > or = 4 mg/L that represented at least 24 distinct genotypes, 35 had double mutations at amino acid codons 83 and 87 of gyrA, while two isolates with ofloxacin MICs of 0.5 and 4 mg/L, respectively, each had a single mutation at codon 83. Mutations at codon Ser-83 were uniform, resulting in substitution by Leu. The additional mutations at amino acid codon 87 in the 35 double-mutants were diverse, resulting in Asp-87 substitutions by residues Asn (23 isolates), Gly (7 isolates), Tyr (4 isolates), or His (1 isolate) without a discernable correlation with fluoroquinolone MICs or with phenotypic resistance to chemically unrelated antibacterial agents. Maximal differences between MICs of double-mutants with the same amino acid substitution were eight-fold. The changes of amino acid residues at codon Asp-87 differed between individual patient isolates with the same genotype (and similar MICs), suggesting that the amino acid codon 87 mutations (and possibly the development of high-level fluoroquinolone resistance) might have occurred after the transmission and sharing of a precursor strain carrying the Ser-83-->Leu mutation.

Anti-Infective Agents↗
PubMed1996

Molecular epidemiology of fluoroquinolone-resistant Escherichia coli bloodstream isolates from patients admitted to European cancer centers.

Previous reports have suggested an increasing incidence of highly fluoroquinolone-resistant Escherichia coli causing bacteremia among cancer patients on prophylactic therapy. We used genotyping by pulsed-field gel electrophoresis of chromosomal DNA digests and random amplified polymorphic DNA fingerprinting to study clonal relationships among such isolates obtained at 10 cancer centers located across Europe and the Middle East. Analysis by both methods indicated that isolates from different centers were genotypically unrelated to each other. There were five centers from which more than one individual patient isolate was available, and most demonstrated significant within-center genetic diversity of strains. Strains shared among patients could be identified at two centers. At the center with the largest number of bloodstream isolates from cancer patients available, fluoroquinolone-resistant control isolates from surgical patients and fluoroquinolone-susceptible control isolates from patients admitted to medical services during the same time period were unrelated to resistant cancer patient isolates and to each other as well. A substantial number of fluoroquinolone-resistant isolates (19 of 58) were nontypeable by pulsed-field gel electrophoresis. Fluoroquinolone resistance was commonly associated with multiple antibiotic resistance to chemically unrelated antibacterial agents irrespective of the origin of the isolates.

Anti-Infective Agents↗
PubMed1996

Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Infection Program.

Combinations of beta-lactams plus aminoglycosides have been standard therapy for suspected infections in granulocytopenic cancer patients, especially those with profound long-lasting granulocytopenia. With the advent of new broad-spectrum bactericidal antibiotics such as extended-spectrum cephalosporins or carbapenems, the need to combine beta-lactams with aminoglycosides became more controversial. The objective of this prospective randomized multicenter study was to compare the efficacy, safety, and tolerance of meropenem monotherapy with those of the combination of ceftazidime plus amikacin for the empirical treatment of fever in granulocytopenic cancer patients. Of 1,034 randomized patients, 958 were assessable in the intent-to-treat analysis for response to antibacterial therapy, including 483 in the meropenem group and 475 in the ceftazidime-plus-amikacin group. The median durations of neutropenia were 16 and 17 days, respectively. A successful outcome was reported in 270 of 483 (56%) patients treated with monotherapy compared with 245 of 475 (52%) patients treated with the combination group (P = 0.20). The success rates in the monotherapy group and the combination group were similar by type of infection (single gram-negative bacteremia, single gram-positive bacteremia, clinically documented infection, and possible infection). The occurrence of further infections assessed in patients for whom the allocated regimen was not modified did not differ between the two groups (12% in both groups). Mortality due to the presenting infection or further infection was relatively low (8 patients treated with the monotherapy compared with 13 patients treated with the combination). A total of 1,027 patients were evaluable for adverse events; the proportion of those who developed adverse effects was similar between the two groups (29% in both groups), and only 19 (4%) patients in the monotherapy group and 31 (6%) in the combination group experienced an adverse event related or probably related to the study drug. Allergic reactions were the only reason for stopping the protocol antibiotic(s) (3 and 5 patients, respectively). This study confirms that monotherapy with meropenem is as effective as the combination of ceftazidime plus amikacin for the empiric treatment of fever in persistently granulocytopenic cancer patients, and both regimens were well tolerated.

Adolescent↗