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An assay of Staphylococcus epidermidis biofilm responses to therapeutic agents.

Implant-associated infections tend to become persistent, resisting host defences and antibiotic therapy. Routine clinical laboratory testing of bacterial isolates in the fluid phase for antibiotic susceptibility may not be predictive of therapeutic outcomes and therefore a number of antibiotic regimes have been formulated empirically. The resistance of implant-associated infections has been ascribed to the production by bacteria, when adherent to the implant surface, of a shielding matrix of polymerized carbohydrates protecting the enclosed bacteria from immune defences and antibiotics. This complex of surface, bacteria and matrix is termed a biofilm. We describe a technique to evaluate the efficacy of antimicrobial agents directed against biofilm-forming strains of Staphylococcus epidermidis (a major cause of implant infections) utilizing standardized biofilm preparations formed on glass. The impact of the antimicrobial agents was assessed quantally using the end-point of permanent cessation of metabolic activity (cell death) of the entire biofilm determined by the loss of ability to reduce 2,3,5-triphenyltetrazolium chloride to a visible red intracellular precipitate of formazan. The relative rate of action of differing antimicrobial agents could be determined by the minimum period of exposure of the biofilm to the agents that is required to bring about sterilization, the clinically relevant marker. A wide range of antimicrobial substances could be evaluated, including chemical disinfectants, immunoreactive substances, antibiotics; singly and in combination; and the modifying effects of interaction with non-antibacterial therapeutic agents and other environmental factors. The technique is simple, inexpensive, reproducible and readily adaptable to the clinical situation where evaluation of therapeutic regimes for individual cases of prosthetic device-associated infection is required routinely with despatch and ease of interpretation.

Anti-Bacterial Agents↗

[Effect of biologically active compounds on the resistance of bacteria to antibiotics].

A number of biologically active substances, i. e. main protamine proteins and histones, EDTA, lysozyme, methacyl and pentoxyl was studied with respect to their effect on the levels of the minimum inhibitory concentrations of antibiotics against E. coli and Staph. aureus and transfer of resistence to chloramphenicol in E. coli on conjugation. It was shown that the above substances lowered the minimum inhibitory concentrations of the antibiotics 2--10 times when added to the culture simultaneously with the latter. The results varied depending on the strain and the resistance nature. Marked inhibition of transfer of resistance to chloramphenicol in the presence of the main proteins and EDTA was found.

Anti-Bacterial Agents↗

In vitro interaction between clindamycin and trimethoprim in combination on staphylococci.

The in-vitro interaction between clindamycin and trimethoprim was tested on 10 staphylococcal clinical isolates by the checkerboard technique and by the time-kill curve. Indifference was demonstrated against seven of these strains and antagonism against three. The clindamycin/trimethoprim combination is of no value if the purpose of the combination is to obtain synergy against staphylococci. However, the combination is useful against mild polymicrobial infections due to Gram-positive aerobes, anaerobes and Enterobacteriaceae.

Clindamycin↗

Enhancement of the antitrichomonal activity of 5-nitroimidazole derivatives by hydrogen peroxide.

The in vitro sensitivity of nine Trichomonas vaginalis isolates to commonly employed 5-nitroimidazoles (metronidazole, nimorazole, ornidazole and tinidazole) was evaluated in absence and in presence of sub-inhibitory concentrations of hydrogen peroxide (H2O2). Co-incubation with H2O2 and 5-nitroimidazole compounds decreased the MIC values of the strains exhibiting cross-resistance to these drugs. It was suggested that H2O2 produced in the inflammatory process during trichomonal infection could enhance the therapeutic effect of 5-nitroimidazole drugs.

Animals↗

Advances in the treatment of superficial candida infections.

This article reviews recent controlled studies of treatment for candida infections of the skin and mucous membranes. In general, excellent agents are available for treatment, with reasonable alternatives for the uncommon emergence of resistant strains. Cutaneous infections in immunocompetent patients are effectively treated with topical agents. The major clinical problems that remain include frequently recurrent vulvovaginal candidiasis, and oroesophageal candida infections in patients with malignancies and immunosuppression. These often require systemic therapy. A number of treatment strategies have been investigated and are reviewed.

Acquired Immunodeficiency Syndrome↗

Clarithromycin is bactericidal against strains of Mycobacterium leprae resistant and susceptible to dapsone and rifampin.

The anti-Mycobacterium leprae activity of clarithromycin when administered alone and in combination with rifampin and dapsone in the diet was determined using the kinetic method of drug evaluation in mice. Clarithromycin when administered at a concentration of 0.1% (w/w) in the diet completely prevented growth of 2 pan-susceptible, 3 dapsone-resistant, 2 rifampin-resistant, and 2 rifampin and dapsone double resistant strains of M. leprae. A 0.03% (w/w) concentration also completely prevented growth of M. leprae in all mice infected with 2 of 7 strains tested, but in only some of the mice infected with the remaining 5 strains. No antagonistic drug interactions were observed between clarithromycin and dapsone or rifampin. The addition of clarithromycin to the currently recommended multidrug regimen should improve the rate of killing of M. leprae and help to prevent the growth of dapsone-resistant and rifampin-resistant strains.

Administration, Oral↗

Overview of the fluoroquinolone antibiotics.

The fluoroquinolones represent an important advance in antimicrobial therapy. Commercially available products in the United States now include norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin. Although they share a common mechanism of action, they differ significantly in their antimicrobial spectrum of activity, their pharmacokinetic characteristics, and, to a lesser degree, their safety profiles. These compounds are generally highly effective against aerobic gram-negative and many gram-positive isolates; their activity is more limited against anaerobic bacteria. Quinolone-resistant bacteria have been isolated, but most do not appear to pose a clinically significant problem at this time. The agents are effective in the treatment of a wide range of infections. Although some, such as ciprofloxacin and enoxacin, have been associated with clinically significant interactions with theophylline derivatives, others such as ofloxacin and lomefloxacin appear to have a limited propensity for such interactions.

Anti-Infective Agents↗

Metronidazole: utilization in the obstetric and gynecologic patient.

BACKGROUND: Obstetric and gynecologic complications associated with bacterial vaginosis and trichomoniasis have heightened awareness of these conditions, and thus metronidazole's role in obstetric and gynecologic practice continues to increase. GOAL OF THIS STUDY: To review the clinical indications for metronidazole in the obstetric and gynecologic setting, as well as the pharmacokinetics and potential adverse effects of the drug. STUDY DESIGN: Review of the current literature concerning metronidazole. RESULTS AND CONCLUSIONS: Metronidazole remains a valuable agent for the treatment of anaerobic and protozoal infections with little evidence of resistance. Although issues of mutagenicity and carcinogenicity remain theoretical concerns, current data do not support the existence of these risks in humans.

Antitrichomonal Agents↗

Modification by analgesics of the susceptibility to antibiotics in Serratia marcescens.

The influence of analgesics at low concentrations on permeability and beta-lactamase expression have been studied "in vitro". The effect of these drugs on major outer membrane proteins and the lipopolysaccharide was evaluated. Acetylsalicylate and paracetamol induced modifications in susceptibility to a large variety of antibiotics when tested at therapeutic concentrations. The results suggested that when analgesics and antibiotics are administered simultaneously, the interaction between both kinds of drugs can alter the response of microorganisms to antibiotics.

Acetaminophen↗

In vitro activity of a new rifamycin derivative against Mycobacterium leprae.

The antimicrobial effects of T9 (3-(4-cinamyl-1-piperazinyl)iminomethyl rifamycin SV) alone and in combination with ofloxacin, against strains of M. leprae were evaluated, using an in vitro cell-free culture system. The minimum inhibitory concentrations (MICs) of T9 against rifampin-sensitive and rifampin-resistant strains of M. leprae were 0.1 microgram/ml and 0.4 microgram/ml, respectively. Furthermore, in common with rifabutin, but not with rifamycin, T9 demonstrated synergy with ofloxacin against both rifampin-sensitive rifampin-resistant strains of M. leprae. The results suggest that T9, in combination with ofloxacin as part of multidrug regimens, warrants further evaluation as treatment for patients with leprosy.

Animals↗

HIV-1 protease inhibitors. A review for clinicians.

OBJECTIVE: The clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of HIV-specific protease inhibitors (PIs). The 4 PIs available are saquinavir mesylate, ritonavir, indinavir sulfate, and nelfinavir mesylate. Comparison studies have not been reported; therefore, an assessment of the available data to aid clinicians and patients in choosing appropriate treatment will be presented. DATA SOURCES: A systematic review of peer-reviewed publications, abstracts from national and international conferences, and product registration information through September 1996. STUDY SELECTION AND DATA EXTRACTION: Criteria used to select studies include their relevance to PIs, having been published in the English language, and pertinence for clinicians. Data quality and validity included the venue of the publication and relevance to clinical care. DATA SYNTHESIS: Oral adminstration of ritonavir, indinavir, or nelfinavir generates sustainable drug serum levels to effectively inhibit the protease enzyme; however, saquinavir may not generate sustained levels necessary to inhibit the protease enzyme. Patients treated with ritonavir, indinavir, or nelfinavir experience similar reductions in viral load and increases in CD4+ lymphocytes; smaller effects occur among those treated with saquinavir. Two randomized placebo-controlled studies conducted among patients with severe immune system suppression and substantial zidovudine treatment experience demonstrated reduced HIV disease progression and reduced mortality with PI treatment. Genotypic resistance to PIs occurs; the clinical relevance of resistance is unclear. The costs of these agents including required monitoring impose new and substantial costs. CONCLUSIONS: The PIs have emerged as critical drugs for people with HIV infection. Optimal use involves combination with reverse transcriptase inhibitors. Resistance develops to each agent, and cross-resistance is likely. These agents must be used at full doses with attention to ensuring patient compliance. The expense of these agents may be offset by forestalling disease progression and death and returning people to productive life. Selecting the initial PI must be individualized, and factors to consider include proven activity, possible toxicities, dosing regimens, drug interactions, and costs.

Anti-HIV Agents↗

[Determination of serum aminoglycoside and vancomycin concentrations by the microbiological method in the presence of other antimicrobials].

The determination of serum concentrations of antimicrobials with a narrow therapeutic range by microbiological method requires some modifications when the patient is under combined antimicrobial therapy. The methodological conditions for the appraisal of aminoglycosides and vancomycin in the presence of other drugs were evaluated by using strains with selective sensitivity to the antimicrobial to be tested or by the adding crude extracts of beta-lactamases for the inactivation of the beta-lactam antimicrobials. These beta-lactamases were obtained from Enterobacter cloacae P99 (derepressed mutant) cultures for the inactivation of penicillins and first, second and third generation cephalosporins, as well as from Stenotrophomonas (Xanthomonas) maltophilia M 1484 cultures for the hydrolysis of imipenem. The strains allowing vancomycin appraisal and indifferent to the synergic activity of other drugs in the mixture were S. aureus M 2120, when the accompanying antimicrobials were gentamicin, ciprofloxacin or rifampicin, and E. faecalis M 2113, E. avium M 2091 and S. aureus M 2101 when the drugs in the mixture were amikacin, lincomycin or trimethoprim-sulfamethoxazole, respectively. For the appraisal of gentamicin in the presence of vancomycin or fluoroquinolones (ciprofloxacin or norfloxacin), E. coli M 1376 was the most suitable strain, while the use of K. pneumoniae ATCC 10031 was required for the appraisal of amikacin or netilmicin. When rifampicin was the accompanying antimicrobial, E. coli M 1495 turned out more adequate. E. coli M 1462 proved to be more satisfactory for gentamicin, amikacin and netilmicin dosages in samples also containing chloramphenicol, trimethoprim-sulfamethoxazole or tetracycline.

Aminoglycosides↗

Meropenem, a new carbapenem antibiotic.

Meropenem is the second carbapenem antibiotic available in the United States. It has a broad spectrum of activity that includes moderate activity against gram-positive bacteria and excellent gram-negative aerobic and anaerobic activity. Meropenem has enhanced gram-negative activity relative to imipenem-cilastatin and often retains activity against strains resistant to third-generation cephalosporins and imipenem-cilastatin. The drug penetrates well into most body fluids and tissues, including cerebrospinal fluid. It is also stable against renal dehydropeptidase hydrolysis and does not require coadministration of a dehydropeptidase inhibitor. Meropenem showed excellent efficacy in clinical studies involving seriously ill patients with intraabdominal, central nervous system, lower respiratory tract, skin and soft tissue, urinary tract, and febrile neutropenic infections. It appears well tolerated and, relative to imipenem-cilastatin, may have reduced potential for causing seizures and other central nervous system toxicities. Although it has many favorable qualities and some potential advantages relative to other broad-spectrum agents, additional trials and clinical experience are necessary to define its optimal place in clinical practice.

Appendicitis↗