bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Staphylococcus aureus endocarditis in rats with coumermycin A1 and ciprofloxacin, alone or in combination
Authors: Perronne C M , Malinverni R , Glauser M P
Published: June 2012

The efficacy of a 5-day treatment with coumermycin A1 (hereafter referred to as coumermycin) (at three dosage regimens), with ciprofloxacin, or with coumermycin plus ciprofloxacin was tested in experimental aortic valve endocarditis induced in rats by a strain of methicillin-susceptible Staphylococcus aureus and was compared with the efficacy of a 5-day treatment with cloxacillin plus gentamicin. While coumermycin was far less effective than cloxacillin plus gentamicin in reducing the bacterial counts in vegetations (P less than 10(-8), ciprofloxacin was as effective as cloxacillin plus gentamicin. Coumermycin plus ciprofloxacin was less effective than ciprofloxacin alone (P = 0.01). For endocarditis induced by two additional methicillin-susceptible S. aureus strains, the high-dosage regimen of coumermycin (12 mg/kg every 12 h) had the same low efficacy. Coumermycin-resistant variants of S. aureus emerged in most of the vegetations during coumermycin treatment. The ciprofloxacin susceptibility of S. aureus was unchanged during ciprofloxacin treatment. The addition of ciprofloxacin to coumermycin in the treatment did not prevent the emergence of coumermycin-resistant variants. Twelve additional S. aureus strains isolated from the blood of patients with endocarditis were tested in vitro against coumermycin with precautions to avoid carry-over of the antibiotic. Coumermycin exhibited a bacteriostatic activity at very low concentrations (MIC, less than 0.004 microgram/ml) but only a weak bactericidal activity (MBC for 90% of strains, 8 micrograms/ml), a finding contrasting with that of others. Furthermore, coumermycin-resistant mutants could be selected in vitro from the 15 S. aureus strains tested. These results indicated no evidence in vivo of a synergistic activity of coumermycin and ciprofloxacin. More importantly, these results suggested that coumermycin might not be adequate for the treatment of serious s. aureus infections in humans.
Selective gut decontamination with nalidixic acid or trimethoprim-sulfamethoxazole for infection prophylaxis in neutropenic cancer patients: relationship of efficacy to antimicrobial spectrum and timing of administration
Authors: Bow E J , Rayner E , Scott B A , Louie T J
Published: June 2012

Eighty-four cancer patients at risk of infection because of neutropenia were randomized to receive nalidixic acid as an alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for infection prophylaxis. Infections were documented significantly earlier and more often among patients who entered the trial with neutrophil counts of less than 0.1 X 10(9)/liter. TMP-SMX recipients experienced fewer microbiologically documented infections and bacteremias and were free of infection for a higher proportion of days with severe neutropenia (less than 0.1 X 10(9)/liter) than nalidixic acid recipients. Gram-negative bacillary and Staphylococcus aureus infections accounted for the major differences. Although the majority of aerobic gram-negative bacilli were eliminated from the feces after 1 week of prophylaxis with either agent, TMP-SMX was proved superior to nalidixic acid in this regard and was associated with acquired drug resistance by gram-negative bacilli less frequently. Both agents selected for colonization and subsequent infection by gram-positive cocci. Our data suggest that prophylaxis is most likely to be effective if administered to patients for at least 1 week before they become severely neutropenic. Nalidixic acid used as a single agent in doses of 4 g daily, however, cannot be recommended as an alternative to TMP-SMX for infection prophylaxis in neutropenic cancer patients.
Antimicrobial activity and spectrum of LY146032, a lipopeptide antibiotic, including susceptibility testing recommendations
Authors: Jones R N , Barry A L
Published: June 2012

LY146032, a new lipopeptide, was found to have a spectrum of gram-positive antimicrobial activity that includes activity against staphylococci (methicillin susceptible and resistant), beta-hemolytic Streptococcus spp., pneumococci, viridans group Streptococcus spp., anaerobic gram-positive cocci, Clostridium spp., and enterococci. The new lipopeptide was generally bactericidal and showed more rapid killing of Listeria spp. (MIC, 1 to 2 micrograms/ml) and staphylococci than either vancomycin or teicoplanin. The 30-micrograms disk was preferred to the 15-micrograms disk on the basis of the preliminary interpretive criteria for susceptibility which indicated zone diameters of greater than or equal to 16 mm for susceptible strains (MIC, less than or equal to 2.0 micrograms/ml) and greater than or equal to 12 mm for resistant strains (MIC, greater than or equal to 8.0 micrograms/ml). These criteria are valid pending the testing of additional gram-positive strains which have LY146032 MICs of greater than or equal to 8 micrograms/ml.
In vitro activity of BMY-28100 against common isolates from pediatric infections
Authors: Scribner R K , Marks M I , Finkhouse B D
Published: June 2012

The antibacterial activity of BMY-28100, a new oral cephalosporin, was measured against 300 bacterial isolates from pediatric infections by standard agar dilution methodology. The effect of inoculum size on activity was also assessed. BMY-28100 was more active than cephalexin or cefaclor against all bacterial species tested.
Broth dilution testing of Candida albicans susceptibility to ketoconazole
Authors: Hughes C E , Bennett R L , Beggs W H
Published: June 2012

We performed a detailed investigation of the kinetics of ketoconazole activity in the setting of broth dilution testing of Candida albicans susceptibility. Turbidimetric readings reflected parallel quantitative colony counts. The method of endpoint determination markedly affected the results. Determinations of 50% inhibitory concentrations clearly separated the ketoconazole-resistant strains from the susceptible strains.
Randomized double-blind evaluation of ceftazidime dose ranging in hospitalized patients with cystic fibrosis
Authors: Reed M D , Stern R C , O'Brien C A , Crenshaw D A , Blumer J L
Published: June 2012

Eighty-five patients with cystic fibrosis who were experiencing an acute infectious exacerbation of their disease were randomized in double-blind fashion to receive either 50 or 75 mg of ceftazidime per kg (body weight) per dose administered intravenously every 8 h for 14 days. Three patients were dropped from the study within 4 days of enrollment for reasons unrelated to drug administration. The total daily dose of ceftazidime administered was restricted by protocol design and was independent of the body weight of the patient. Thus, for datum analysis, patients were separated into three ceftazidime dosage groups (denoted as range of milligrams per kilogram per dose): group 1, 22 to 44.5; group 2, 46.3 to 56.6; and group 3, 66.7 to 80.6. Ceftazidime monotherapy had no effect on sputum colony counts for any Pseudomonas cepacia isolate. In contrast, a substantial reduction in Pseudomonas aeruginosa sputum colony counts was observed, and from 19 to 31% of isolates were suppressed greater than or equal to 10(5) CFU/ml after 14 days of therapy. Bacterial resistance in vitro was not observed, although a trend for increasing ceftazidime MICs was observed for group 1 patients (P less than 0.05). Overall, clinical response appeared independent of drug dose, and no relationship could be identified between the reduction in P. aeruginosa sputum colony counts and clinical outcome. Adverse effects of ceftazidime were mild and transient, necessitating drug discontinuation in one patient. These data suggest that the clinical response to ceftazidime in patients with cystic fibrosis may be maximal with 50 mg/kg per dose (150 mg/kg per day) up to a total daily dose of 6 g.
Sub-MICs of cefuroxime and ciprofloxacin influence interaction of complement and immunoglobulins with Klebsiella pneumoniae
Authors: Williams P
Published: June 2012

Growth of encapsulated (K+) and nonencapsulated (K-) Klebsiella pneumoniae strains in media containing sub-MICs of either cefuroxime or ciprofloxacin resulted in cell elongation but had little effect on the outer membrane protein or lipopolysaccharide profiles. Exposure to serum complement increased the surface hydrophobicity of a K- strain but failed to interact or to increase the surface hydrophobicity of the K+ strains. However, after growth of the K+ strains in sub-MICs of the antibiotics, complement increased their surface hydrophobicity and complement C3 was detected bound to their surface. Antisera raised against a K-O- strain agglutinated the K+ strains grown in the presence but not in the absence of cefuroxime or ciprofloxacin. These findings suggest that the filamentous morphology induced by these antibiotics influences the distribution or amount of capsular polysaccharide such that cell envelope components previously masked by the capsule become accessible to complement and immunoglobulins.
4-Quinolone drugs affect cell cycle progression and function of human lymphocytes in vitro
Authors: Forsgren A , Schlossman S F , Tedder T F
Published: June 2012

Most antibacterial agents do not affect human lymphocyte function, but a few are inhibitory. In contrast, a pronounced increase in the incorporation of [3H]thymidine in the presence of 4-quinolones was observed in these studies. The uptake of [3H]thymidine into DNA (trichloroacetic acid precipitable) was significantly increased in phytohemagglutinin-stimulated human lymphocytes when they were exposed to eight new 4-quinolone derivatives, ciprofloxacin, norfloxacin, ofloxacin, A-56619, A-56620, amifloxacin, enoxacin, and pefloxacin, at 1.6 to 6.25 micrograms/ml for 5 days. Four less antibacterially active 4-quinolones (nalidixic acid, cinoxacin, flumequine, and pipemidic acid) stimulated [3H]thymidine incorporation only at higher concentrations or not at all. Kinetic studies showed that incorporation of [3H]thymidine was not affected or slightly inhibited by ciprofloxacin 2 days after phytohemagglutinin stimulation but was increased on days 3 to 6. The total incorporation of [3H]thymidine from day 1 to day 6 after phytohemagglutinin stimulation was increased by 42 to 45% at 5 to 20 micrograms of ciprofloxacin per ml. Increased [3H]thymidine incorporation was also seen when human lymphocytes were stimulated with mitogens other than phytohemagglutinin. Ciprofloxacin added at the start of the culture had a more pronounced effect on [3H]thymidine incorporation than when added later. In spite of the apparent increase in DNA synthesis, lymphocyte growth was inhibited by 20 micrograms of ciprofloxacin per ml, and cell cycle analysis showed that ciprofloxacin inhibited progression through the cell cycle. In addition, immunoglobulin secretion by human lymphocytes stimulated by pokeweed mitogen for Epstein-Barr virus was inhibited by approximately 50% at 5 micrograms of ciprofloxacin per ml. These results suggest that the 4-quinolone drugs may also affect eucaryotic cell function in vitro, but additional studies are needed to establish an in vivo relevance.
Penetration of ceftazidime into heart valves and subcutaneous and muscle tissue of patients undergoing open-heart surgery
Authors: Frank U , Kappstein I , Schmidt-Eisenlohr E , Schlosser V , Spillner G , Schindler M , Daschner F D
Published: June 2012

Patients undergoing open-heart surgery were given an intravenous bolus injection of 2 g of ceftazidime as a single dose over a period of 5 min. Within 12 h, ceftazidime concentrations in serum declined from 55.8 to 3.9 mg/liter. Subcutaneous tissue concentrations of the drug decreased from 21.0 to 2.7 micrograms/g, and muscle concentrations decreased from 34.5 to 2.5 micrograms/g. Ceftazidime concentrations in cardiac valvular tissue were even higher than those in muscle or fat, declining from 37.4 to 6.3 micrograms/g within 10 h.
In vitro susceptibility of Citrobacter species to various antimicrobial agents
Authors: Samonis G , Ho D H , Gooch G F , Rolston K V , Bodey G P
Published: June 2012

The in vitro activities of 16 antimicrobial agents against 14 clinical isolates of Citrobacter diversus and 27 isolates of Citrobacter freundii were studied. C. freundii isolates were more resistant, being susceptible only to amikacin, netilmicin, gentamicin, imipenem, ciprofloxacin, and enoxacin. C. diversus isolates were susceptible to many more of the agents tested.
Does prolonged exposure to antibiotic-resistant bacteria increase the rate of antibiotic-resistant infection?
Authors: Parsonnet K C , Kass E H
Published: June 2012

The magnitude of the risk of acquiring infections due to antibiotic-resistant bacteria, as a consequence of prolonged contact with such bacteria, is unclear. We compared antibiotic resistance patterns of Escherichia coli isolated from the urine of bacteriuric female abattoir workers with resistance patterns of E. coli cultured from 190 poultry taken from the processing line. We found E. coli in 181 (95%) of the poultry cultures; 96% of the isolates were resistant to one or more antibiotics, and 87% were multiply resistant. Of the 649 women whose urine was cultured and who had not recently received antibiotic therapy, 69 (10.6%) had positive urine cultures, with E. coli accounting for 67% of the isolates. Of the 46 E. coli isolates, 8 (17.4%) were resistant to one or more antibiotics. All of the antibiograms of the urinary isolates were unique, and only one, a strain with resistance only to streptomycin, matched those of any of the poultry isolates. Of the women tested for bacteriuria, 74 had taken antibiotics within 3 months of culture, and these women were analyzed separately. Among the recent antibiotic users, six (8.1%) had positive urine cultures, all with E. coli. Four of these isolates were resistant to at least one antibiotic; all had patterns that matched at least one of the poultry isolates. Therefore, in a population of female abattoir workers who were not receiving antibiotic therapy, despite a high exposure to resistant microorganisms of animal origin, infections were infrequently caused by organisms with resistance patterns characteristic of the livestock to which the women were heavily exposed.
Pharmacokinetics of ciprofloxacin in cystic fibrosis
Authors: Davis R L , Koup J R , Williams-Warren J , Weber A , Heggen L , Stempel D , Smith A L
Published: June 2012

We studied the pharmacokinetics of ciprofloxacin in 12 adult males with and 12 adult males without cystic fibrosis (CF). In a randomized crossover sequence, the subjects received 200 mg intravenously or 750 mg orally. With intravenous dosing, subjects also received 651 mg of iothalamate, a marker of glomerular filtration, and 700 mg of antipyrine, an indicator of hepatic oxidative drug metabolism. Pharmacokinetic parameters were determined by model independent methods. In the CF subjects, the ciprofloxacin concentration in serum during the first hour after intravenous administration was higher, and the oral absorption rate was slower. Other parameters did not differ between the groups. Mean concentrations in serum 5 min postinfusion were 3.08 and 2.14 micrograms/ml, and mean peak concentrations after oral dosing were 3.24 and 3.34 micrograms/ml in subjects with and without CF, respectively. Mean values for elimination half-life in all subjects were 4.8 and 5.0 h after intravenous and oral administration, respectively. The mean renal clearances in all subjects after intravenous and oral administration were 19.4 and 14.5 liters/h and accounted for 64 and 47% of the total clearance, respectively. These values were significantly greater than renal iothalamate clearance, indicating that tubular secretion contributed to the renal clearance of ciprofloxacin. A total of 69 and 35.4% of the administered ciprofloxacin was recovered from the urine within 48 h after intravenous and oral administration, respectively. The mean bioavailability was 71.2% and did not differ between the groups. We conclude that similar dosing regimens can be used to treat patients with CF and their normal counterparts.
Pharmacokinetics of cefoperazone in ambulatory elderly volunteers compared with young adults
Authors: Meyers B R , Mendelson M H , Deeter R G , Srulevitch-Chin E , Sarni M T , Hirschman S Z
Published: June 2012

Two groups of 10 healthy ambulatory subjects, i.e., a group of 10 persons less than or equal to 30 years of age (mean age, 27.6 years) and a group of 10 persons greater than or equal to 65 years of age (mean age, 70 years), were randomized in a single-trial crossover design to receive 1 and 2 g of cefoperazone with a 1-week washout between doses. The elderly subjects had both decreased estimated creatinine clearances and decreased albumin concentrations in serum. Cefoperazone concentrations in serum of elderly persons were significantly higher at each interval from 30 min to 6 h for the 2-g dose. Compared with that in younger persons, the total clearance in elderly subjects was significantly lower for both the 1- and 2-g doses, the renal clearance was significantly lower for the 2-g dose, and the area under the curve was significantly higher for the 2-g dose in the elderly persons. The half-life at beta phase was higher in the elderly persons at both the 1- and 2-g doses but not significantly so. Changes in total clearance and area under the curve and higher levels in serum in the elderly persons suggest a longer duration of antimicrobial activity in this age group.
Effect of clavulanic acid on susceptibility of Campylobacter jejuni and Campylobacter coli to eight beta-lactam antibiotics
Authors: Gaudreau C L , Lariviere L A , Lauzer J C , Turgeon F F
Published: June 2012

The effect of clavulanic acid on the susceptibility of 32 strains of Campylobacter jejuni and Campylobacter coli to eight beta-lactam agents was studied. Almost all strains tested became susceptible to amoxicillin and ticarcillin with 1 microgram of clavulanic acid per ml. This compound had little or no effect on susceptibility to penicillin G, cephalothin, cefamandole, and cefoxitin. Clavulanic acid had a marginal effect on cefotaxime and moxalactam susceptibility.
Rapid herpes simplex virus susceptibility testing using an enzyme-linked immunosorbent assay performed in situ on fixed virus-infected monolayers
Authors: Rabalais G P , Levin M J , Berkowitz F E
Published: June 2012

An enzyme-linked immunosorbent assay was performed directly on fixed, virus-infected cell monolayers to rapidly determine the susceptibility of herpes simplex virus to antiviral drugs. Susceptibility determinations by this method correlated well with those obtained by plaque reduction assay and avoided some of the drawbacks of other methods currently available.
Ciprofloxacin interactions with imipenem and amikacin against multiresistant Pseudomonas aeruginosa
Authors: Giamarellou H , Petrikkos G
Published: June 2012

In vitro interactions of ciprofloxacin with imipenem and amikacin were evaluated by the killing-curve technique against 26 Pseudomonas aeruginosa strains resistant to amikacin and resistant or moderately susceptible to ciprofloxacin and imipenem. Imipenem enhanced killing by ciprofloxacin in tests with 11 strains, whereas amikacin enhanced killing in tests with only 4 strains.
Genetic characterization of a Clostridium difficile erythromycin-clindamycin resistance determinant that is transferable to Staphylococcus aureus
Authors: Hächler H , Berger-Bächi B , Kayser F H
Published: June 2012

The transferable macrolides-lincosamides-streptogramin B (MLS) resistance determinant of clinical isolates of Clostridium difficile, designated ermZ, has been shown to share homology with ermB, which is associated with Staphylococcus aureus transposon Tn551. Homology within Tn551 was confined to less than or equal to 1.3 kilobases, whereas no homology could be demonstrated between Tn551 sequences external to ermB and MLS-resistant C. difficile. Transfer of ermZ from C. difficile to S. aureus was achieved by means of the filter mating technique, suggesting that (conjugative?) intergeneric exchange between clostridia and staphylococci may also occur in nature. S. aureus transcipients were shown to contain additional DNA from C. difficile besides ermZ. This additional DNA appeared to be present in MLS-susceptible C. difficile and might form part of an as yet undemonstrated insertion sequence element associated with ermZ of resistant strains.
In vitro and in vivo antibacterial activities of CS-807, a new oral cephalosporin
Authors: Utsui Y , Inoue M , Mitsuhashi S
Published: June 2012

CS-807 is a new oral prodrug of R-3746, a cephalosporin derivative, with potent in vitro and in vivo antibacterial activity against both gram-positive and gram-negative bacteria. The susceptibility of about 1,200 clinical isolates to R-3746 was determined by the agar dilution method. Ninety percent or more of pathogens such as Staphylococcus aureus, streptococci, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, indole-positive and indole-negative Proteus spp., Providencia rettgeri, and Haemophilus influenzae were inhibited at concentrations ranging less than or equal to 0.01 to 1.56 micrograms/ml. Furthermore, at a concentration of 3.13 micrograms/ml, 50% or more of Staphylococcus epidermidis, Morganella morganii, Citrobacter freundii, and Serratia marcescens strains were also inhibited. Pseudomonas aeruginosa and Xanthomonas maltophilia were resistant to R-3746. The activity of R-3746 was scarcely influenced by several growth conditions. R-3746 was highly resistant to hydrolysis by beta-lactamases derived from various species of bacteria. Killing-curve studies demonstrated bactericidal activity of R-3746 at concentrations above the MIC. R-3746 showed high affinity for penicillin-binding proteins 1, 3, and 4 of Staphylococcus aureus and 1A, 1Bs, and 3 of Escherichia coli. Systemic infections in mice caused by various pathogens, including beta-lactamase-producing strains, responded well to therapy with oral doses of CS-807.
Inhibition of murine hepatitis virus infections by the immunomodulator 2,3,5,6,7,8-hexahydro-2-phenyl-8,8-dimethoxy-imidazo[1,2a]pyridine (PR-879-317A)
Authors: Sidwell R W , Huffman J H , Call E W , Warren R P , Radov L A , Murray R J
Published: June 2012

PR-879-317A (2,3,5,6,7,8-hexahydro-2-phenyl-8,8-dimethoxy-imidazo [1,2a]pyridine) has been found to be a T-cell-selective immunomodulating agent. In the current studies, a series of experiments was designed to determine the potential antiviral activity of this compound in mice infected with murine hepatitis virus. In a comparative antiviral experiment, the activity seen was superior to that of levamisole, a known immunorestorative agent. This activity was characterized by an increase in the 21-day survival frequency, a decrease in hepatic discoloration, a decrease in the amount of infectious virus recoverable from the liver, and normalization of serum glutamic oxalacetate and pyruvate transaminase levels. A comparison of treatment routes indicated the relative efficacies as intraperitoneal greater than per os greater than intramuscular greater than or equal to subcutaneous. Alteration of the treatment schedule markedly affected the antiviral effect; prophylactic or therapeutic treatments once or twice daily for 3 days were usually effective. Single treatments begun 4 h before or 24 h after virus inoculation were highly efficacious. Three treatments administered on alternate days, beginning 48 h before virus inoculation, proved moderately effective. Thrice-daily treatments were ineffective, as were treatments with durations of greater than 3 days. The optimal dosage varied according to the treatment route and dosage schedule. When assessed for direct antiviral activity in vitro, PR-879-317A failed to demonstrate any significant activity against murine hepatitis virus. The positive in vivo activity noted might therefore be the result of immune modulation rather than a direct antiviral effect.
Penicillin tolerance in Streptococcus faecium ATCC 9790
Authors: Said I , Fletcher H , Volpe A , Daneo-Moore L
Published: June 2012

Tolerant strains of Streptococcus faecium had higher levels of muramidase 2 and lower levels of trypsinactivable muramidase 1 than did susceptible strains. Susceptible strains lysed faster than did tolerant strains in buffer and at some antibiotic concentrations. The addition of Triton X-100 produced equal lysis rates for susceptible and tolerant cultures.
In vitro activity of ceftriaxone, cefetamet (Ro 15-8074), ceftetrame (Ro 19-5247; T-2588), and fleroxacin (Ro 23-6240; AM-833) versus Neisseria gonorrhoeae and Haemophilus ducreyi
Authors: Le Saux N M , Slaney L A , Plummer F A , Ronald A R , Brunham R C
Published: June 2012

We examined 300 strains of Neisseria gonorrhoeae and 100 strains of Haemophilus ducreyi to determine their in vitro susceptibility to two new cephalosporins, cefetamet (Ro 15-8074) and ceftetrame (Ro 19-5247; T-2588), and a new fluroquinolone, fleroxacin (Ro 23-6240; AM-833). Their activity was compared with that of ceftriaxone, penicillin, spectinomycin, tetracycline, and erythromycin. Cefetamet, ceftetrame, and fleroxacin had excellent in vitro activity against both groups of microorganisms. beta-Lactamase production did not significantly affect the MICs of these agents. The Mtr phenotype of N. gonorrhoeae raised the MICs two- to fourfold, but the MICs remained within the range of achievable levels in serum. These newer compounds have a distinct advantage over existing therapeutic agents in that they can be administered orally. Clinical trials are warranted to assess their usefulness in the therapy of gonorrhea and chancroid.
Pharmacokinetics and therapeutic efficacy of gentamicin in an experimental pleural empyema rabbit model
Authors: Shohet I , Yellin A , Meyerovitch J , Rubinstein E
Published: June 2012

The pharmacokinetics and therapeutic efficacy of gentamicin were investigated in an experimental pleural empyema rabbit model. Pleural effusion was induced by the intrapleural administration of turpentine, and empyema was induced by direct inoculation of the effusion with Klebsiella pneumoniae. Pleural empyema compared with effusion was characterized by lower pH, oxygen tension (PaO2), and glucose levels and higher leukocyte count, lactic acid concentration, and PaCO2. After a single administration, gentamicin was first detectable in the pleural fluid at 60 min, whereas peak levels in empyema were observed at 180 min. Gentamicin persisted in the empyema longer than in blood. Animals treated with gentamicin only had 60% bacterial cure on day 7; those treated with gentamicin in an oxygen chamber had 100% cure on day 5 (P = 0.004). Low oxygen tension diminished the antibacterial efficacy of gentamicin in this model. An increase in oxygen tension improved the therapeutic results without alteration of the pharmacokinetics of gentamicin.
Enhanced therapeutic efficacy of poly(ICLC) and ribavirin combinations against Rift Valley fever virus infection in mice
Authors: Kende M , Lupton H W , Rill W L , Levy H B , Canonico P G
Published: June 2012

The therapeutic efficacy of polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine and carboxymethyl cellulose [poly(ICLC)] given alone or in combination with ribavirin was evaluated in Swiss Webster mice infected with Rift Valley fever virus. Four or more 20-micrograms doses of poly(ICLC) given at various intervals beginning 24 h after infection protected all mice against death. On the other hand, a treatment regimen consisting of only three doses of poly(ICLC) given 24 h postinfection resulted in a 50% survival rate. When initiated 48 h postinfection, an extended treatment regimen with the same dose was required to yield 40% survivors. Lower doses (5 micrograms) of poly(ICLC) per mouse were only marginally effective even when six injections were given between days 1 and 9 postinfection. The combined administration of ribavirin and poly(ICLC) initiated as late as 48 h postinfection was effective even when treatment consisted of doses that were ineffective when either drug was used alone.
Activity of LY146032 in vitro and in experimental enterococcal pyelonephritis
Authors: Miniter P M , Patterson T F , Johnson M A , Andriole V T
Published: June 2012

The efficacy of LY146032 (LY), a new lipopeptide antibiotic, was compared with that of vancomycin, ciprofloxacin, ceftriaxone, imipenem, and gentamicin and combinations of LY-ceftriaxone, LY-imipenem, and LY-gentamicin against 15 strains of Streptococcus (Enterococcus) faecalis by microtiter dilution and checkerboard techniques. LY was effective within a very narrow range of drug concentrations (from 0.125 to 2.0 micrograms/ml) and was more active than other agents tested against S. faecalis. Enhanced inhibition of S. faecalis was seen more frequently with combinations of either penicillin or ampicillin and an aminoglycoside than with combinations of LY and gentamicin, imipenem, or ceftriaxone. The in vivo efficacy of LY was compared with that of vancomycin and ampicillin alone and combinations of vancomycin-gentamicin, ampicillin-gentamicin, and LY-gentamicin in a rat model of chronic enterococcal pyelonephritis. At a dose of 10 mg/kg given twice daily, LY reduced the number of organisms per kidney significantly compared with that in infected untreated controls within 48 h after the initiation of therapy. At 20 mg/kg given once a day, LY was less effective but reduced colony counts significantly after 4 days of therapy, and its activity was comparable to that of vancomycin or vancomycin-gentamicin given twice daily. LY may be a promising agent for the treatment of enterococcal infections.
Response of Streptococcus pyogenes to therapy with amoxicillin or amoxicillin-clavulanic acid in a mouse model of mixed infection caused by Staphylococcus aureus and Streptococcus pyogenes
Authors: Boon R J , Beale A S
Published: June 2012

The response of Streptococcus pyogenes to amoxicillin or amoxicillin-clavulanic acid (Augmentin; Beecham Group) therapy of a mixed streptococcal-staphylococcal infection was studied in a surgical wound in mice. A superficial wound was produced on the backs of anesthetized mice, and a suture infected with S. pyogenes, Staphylococcus aureus, or a mixed inoculum of both organisms was inserted. Oral therapy was started 4 h after infection and continued for 3 days. Both amoxicillin and amoxicillin-clavulanic acid were effective in eliminating the streptococci from the pure wound infection. In contrast, amoxicillin failed to eliminate the streptococci from a mixed infection in which a beta-lactamase-producing strain of S. aureus was also present, wound counts reaching 10(7) streptococci per wound by 80 h, whereas amoxicillin-clavulanic acid reduced the count to less than 33 streptococci per wound by 24 h. Numbers of S. aureus were also reduced by amoxicillin-clavulanic acid therapy, controlling the infection, whereas amoxicillin was ineffective. Also of significance was the fact that successful therapy was achieved with blood and tissue concentrations of amoxicillin and clavulanic acid of the same order as those measured in humans. These results show that amoxicillin therapy failed to eliminate S. pyogenes from a wound infection in the presence of a beta-lactamase-producing strain of S. aureus and suggest the potential of amoxicillin-clavulanic acid in the treatment of mixed bacterial skin infections involving beta-lactamase-producing organisms.
Susceptibility testing of macrolide antibiotics against Haemophilus influenzae and correlation of in vitro results with in vivo efficacy in a mouse septicemia model
Authors: Fernandes P B , Hardy D , Bailer R , McDonald E , Pintar J , Ramer N , Swanson R , Gade E
Published: June 2012

There is poor correlation between the MICs and zone sizes obtained for erythromycin against Haemophilus influenzae. The effect of two media, Mueller-Hinton medium supplemented with 3% lysed horse blood and 10 micrograms of NAD per ml (MHA + LYHB) and Mueller-Hinton agar supplemented with 1% bovine hemoglobin and 1% IsoVitaleX (MHA + HGB), on the MICs and zone sizes of erythromycin against H. influenzae was determined. The effect of three different methods for inoculum preparation on the susceptibility of H. influenzae was also determined. The MICs were independent of the method of inoculum preparation, but the zone sizes were smaller if the inoculum was carefully adjusted to contain approximately 10(8) CFU/ml. MICs were higher and zone sizes were smaller when MHA + HGB was used instead of MHA + LYHB. Good correlation was found when MHA + LYHB was used for determining the MIC and MHA + HGB was used for determining susceptibility by the disk method. When the inoculum was adjusted to match a McFarland 0.5 standard, the viable counts had to be approximately 10(8) CFU/ml for good correlation between MICs and zone sizes. A-56268, a new macrolide antibiotic, was tested against H. influenzae, and its MICs and tentative breakpoints against this organism were determined. The MICs obtained by various methods were correlated with in vivo efficacy by using a mouse septicemia model. MICs obtained on MHA + HGB or MHA + LYHB incubated without a 5% CO2 atmosphere showed the best correlation with in vivo efficacy.
Pharmacokinetics of teicoplanin in renal failure
Authors: Falcoz C , Ferry N , Pozet N , Cuisinaud G , Zech P Y , Sassard J
Published: June 2012

By using a highly specific chromatographic technique, the effect of renal failure on the pharmacokinetics of the six main components of teicoplanin, taken individually or as a whole, was assessed for over 120 h after administration of a 3-mg/kg intravenous dose to healthy volunteers (group 1, n = 6) and to noninfected patients with moderate (group 2, n = 6) or severe (group 3, n = 7) renal failure. In subjects with normal renal function, total teicoplanin was mainly excreted in urine and its concentrations in plasma could be adequately fitted to a three-compartment model. Renal failure did not affect the model or the distribution of teicoplanin but strongly decreased its renal clearance (9.3, 3.2, and 0.6 ml/h per kg, respectively, for the three groups of subjects), in close relationship with the creatinine clearance (r = 0.973, n = 18, P less than 0.001). The cumulative urinary excretion of unchanged total teicoplanin was decreased (50, 21, and 5% of the given dose for groups 1 to 3) and the terminal half-life was enhanced (62, 96, and 111 h for groups 1 to 3) by renal impairment. The relative behavior of the six major components was only slightly affected by renal failure. Consequently, the dosage regimen adjustment could be based on the total teicoplanin concentration, and simulations with the mean estimated pharmacokinetic parameters suggest that the 6-mg/kg daily dose, known to be effective in patients with normal renal function, could be given every 2 and 3 days in patients with moderate and severe renal insufficiency, respectively.
Pulmonary disposition of roxithromycin (RU 28965), a new macrolide antibiotic
Authors: Chastre J , Brun P , Fourtillan J B , Soler P , Basset G , Manuel C , Trouillet J L , Gibert C
Published: June 2012

The penetration of roxithromycin (RU 28965), an ether oxime derivative of erythromycin, into the cells and fluid lining the epithelial surface of the lower respiratory tract was studied by performing fiber-optic bronchoscopy with bronchoalveolar lavage on eight patients who had received roxithromycin at 300 mg perorally every 12 h for 5 days. The apparent volume of epithelial lining fluid recovered by bronchoalveolar lavage was determined by using urea as an endogenous marker. There was a significant relationship (r = 0.75; P less than 0.02) between roxithromycin levels in plasma and epithelial lining fluid, with a correlation whose slope suggested that the level of drug penetration into the lining fluid was 0.2. Concentrations of the antibiotic in cells recovered by bronchoalveolar lavage (21 +/- 10 micrograms/ml) were 2 and 10 times higher than in plasma (11.4 +/- 5.7 micrograms/ml) and epithelial lining fluid (2.0 +/- 1.7 micrograms/ml), respectively. Thus, when administered perorally in humans, roxithromycin is markedly accumulated by resident alveolar macrophages in concentrations largely exceeding the MBCs of the drug for most facultative intracellular pathogens including Legionella pneumophila, despite low concentrations in the epithelial lining fluid.
Pharmacokinetics and tolerance of desciclovir, a prodrug of acyclovir, in healthy human volunteers
Authors: Petty B G , Whitley R J , Liao S , Krasny H C , Rocco L E , Davis L G , Lietman P S
Published: June 2012

Because of the incomplete absorption of acyclovir (ACV) when given orally in humans, efforts have been made to develop a prodrug of ACV that would be better absorbed from the gastrointestinal tract and then converted in vivo to ACV. One such compound, desciclovir (DCV), is converted to acyclovir in vivo by xanthine oxidase. We gave each of 13 healthy volunteers 250 mg (about 3.25 mg/kg of body weight) of DCV orally thrice daily for 10 days, collected serial plasma and urine specimens, and measured DCV and ACV concentrations. The absorption of DCV was at least 75%, and almost two-thirds of the administered oral dose was recovered in the urine as ACV. Peak ACV levels in plasma were about 5 micrograms/ml and were reached in less than 1 h. The levels of ACV achieved in plasma were of the same magnitude as those reported for subjects given intravenous ACV at a dose of 2.5 mg/kg and approximately 10-fold higher than levels attained after administration of 200 mg of oral ACV every 4 h as measured in previous studies. The half-life of DCV was 0.85 +/- 0.16 h, compared with 2.6 +/- 0.5 h for ACV, indicating rapid conversion of DCV to ACV. There was no substantial increase in ACV levels in plasma on day 11 compared with day 2. No serious or consistent adverse effects were noted. In particular, the creatinine level in serum did not significantly rise in any subject and remained within the normal range in all.
Autoradiographic study of tobramycin uptake by proximal and distal tubules of normal and pyelonephritic rats
Authors: Bergeron M G , Marois Y , Kuehn C , Silverblatt F J
Published: June 2012

Multiple factors may modify the pharmacokinetics of aminoglycosides and affect their nephrotoxic potential. In the present study, the influence of Escherichia coli pyelonephritis on the renal handling of [3H]tobramycin was investigated. The accumulation of [3H]tobramycin in proximal and distal tubules in both normal and infected rats was compared. Following induction of pyelonephritis, disturbed intrarenal localization of the drug was noted. Grain counts were affected in both proximal and distal tubules. Decreased labeling was observed at all time intervals in the proximal tubules. Electron microscopy showed that radioactivity was associated mostly with lysosomes in both normal and infected rats 1 and 24 h following the injection of the drug. We could detect significantly higher amounts of drug in the distal tubules of the pyelonephritic kidney than the normal levels at 10 min and 24 h postinjection. The drug did not seem to be associated with any particular organelle and was evenly distributed within the distal tubular cells. The present study shows that the transport of tobramycin within the infected nephron is disturbed. These data might shed some light on the influence of infection on the intrarenal pharmacology of aminoglycosides.
Role of beta-lactamase in expression of resistance by methicillin-resistant Staphylococcus aureus
Authors: Boyce J M , Medeiros A A
Published: June 2012

Of 27 unique clinical isolates of methicillin-resistant Staphylococcus aureus, only 4 were homogeneously resistant, and all 4 produced little or no beta-lactamase. Among heterogeneously resistant strains, those most resistant to beta-lactam antibiotics produced the most beta-lactamase. Similar genes may regulate production of the low-affinity penicillin-binding protein and beta-lactamase.
In vitro activity of cefmetazole, cefotetan, amoxicillin-clavulanic acid, and other antimicrobial agents against anaerobic bacteria from endometrial cultures of women with pelvic infections
Authors: Ohm-Smith M J , Sweet R L
Published: June 2012

The MICs of the new antimicrobial agents cefmetazole, cefotetan, and amoxicillin-clauvulanic acid were compared with the MICs of other antimicrobial agents against anaerobic bacteria from endometrial cultures from women with pelvic inflammatory disease or endometritis. The activity of cefmetazole was similar to that of cefoxitin and generally greater than that of cefotetan. Amoxicillin-clavulanic acid was generally more active than all cephamycins tested.
Mapping of trimethoprim resistance genes from epidemiologically related plasmids
Authors: Campbell I G , Mee B J
Published: June 2012

Trimethoprim resistance dihydrofolate reductase genes from plasmids known to be exchanging between human and animal populations were mapped. The dihydrofolate reductase gene has been highly conserved in all plasmids, but differences in the flanking regions provide evidence that the most recent exchange of plasmids between the two ecosystems has been from animals to humans.
Azole antifungal agents: emphasis on new triazoles
Authors: Saag M S , Dismukes W E
Published: June 2012

Many advances have been made in antifungal therapy over the last three decades. Itraconazole and fluconazole, two investigational triazole agents, are the most recent additions to the list of antifungal drugs. This review has focused primarily on their mechanisms of action, favorable pharmacologic properties, and spectra of activity against a broad range of systemic pathogens. Itraconazole and fluconazole show much promise as orally active agents, with less potential for toxicity than the currently available azoles. Fluconazole and, to a lesser degree, itraconazole are especially promising therapies for cryptococcal meningitis. In addition, fluconazole may prove to be highly effective in urinary tract infections caused by Candida species and other fungi. Ongoing and future clinical trials will more clearly define the specific roles of itraconazole and fluconazole in the treatment of systemic mycoses.
Radiometric method for pyrazinamide susceptibility testing of Mycobacterium tuberculosis in egg-yolk-enriched BACTEC 12A medium
Authors: Woodley C L , Smithwick R W
Published: June 2012

A radiometric method for testing the susceptibility of Mycobacterium tuberculosis to pyrazinamide in egg-yolk-enriched 12A medium (pH 5.5) is described. We obtained 100% agreement between the 7H10 agar method with 25 microgram of pyrazinamide per ml and the modified radiometric method with a drug concentration of 50 microgram/ml in tests of 90 clinical isolates.
Increase in permeability of Escherichia coli outer membrane by local anesthetics and penetration of antibiotics
Authors: Labedan B
Published: June 2012

The MICs of several antibiotics (both hydrophobic and hydrophilic) which penetrate very poorly into intact Escherichia coli cells were found to be 2- to 10-fold decreased in the presence of low doses of various local anesthetics (procaine, dibucaine, tetracaine, chlorpromazine, and quinine). The concentrations of anesthetics necessary for this effect have no adverse effect on cell growth and are markedly lower than those concentrations used clinically.
Penetration of cefpiramide and cefazolin into peritoneal capsular fluid in rabbits
Authors: Matsui H , Okuda T
Published: June 2012

Penetration of cefpiramide and cefazolin into a specific extravascular fluid was measured with rabbits bearing capsules in the peritoneal cavity. A general feature of slow accumulation and elimination of drugs from extravascular sites having low surface area/volume ratios has also been observed in this study. The capsular concentration-time profiles were well expressed by the following equation: C(CF) = A(CF)[e-kel(CF)(t-to)-e-kp(CF)(t-to)], where C(CF), A(CF), kp(CF), kel(CF), and to indicate capsular concentration at time t, constant for the dimension of concentration, capsule penetration rate constant, capsule elimination rate constant, and lag time before penetration occurs, respectively. The kp(CF), kel(CF), and to were 0.139 h-1, 0.059 h-1, and 0.45 h, respectively, for cefpiramide, and 0.448 h-1, 0.0145 h-1, and 0.14 h, respectively, for cefazolin. A(CF) was 22.7 micrograms/ml for cefpiramide and 4.53 micrograms/ml for cefazolin, being parallel to the area under the plasma concentration-time curve for free drug from to to infinity (20.1 micrograms.h/ml for cefpiramide and 3.43 micrograms.h/ml for cefazolin). In conclusion, it is suggested that as well as kp(CF) and kel(CF), the area under the plasma concentration-time curve for free drug from to to infinity may play an important role regarding the circulating reservoir of drugs in determining capsular concentration-time profiles in experimental models for particular extravascular sites of infection, like abscesses into which drugs cannot easily penetrate.
In vitro culture system to determine MICs and MBCs of antimicrobial agents against Treponema pallidum subsp. pallidum (Nichols strain)
Authors: Norris S J , Edmondson D G
Published: June 2012

A new procedure for determining the susceptibility of Treponema pallidum subsp. pallidum to antimicrobial agents was developed, utilizing a tissue culture system which promotes the in vitro multiplication of this organism. In the absence of antibiotics, T. pallidum (Nichols virulent strain) multiplied an average of 10-fold when incubated for 7 days in the presence of Sf1Ep cottontail rabbit epithelial cell cultures. Varied concentrations of penicillin G, tetracycline, erythromycin, and spectinomycin were added to triplicate cultures to determine their effects on treponemal multiplication, motility, and virulence. The MIC of each antibiotic was defined as the lowest concentration which prevented treponemal multiplication, whereas the MBC was defined as the lowest concentration which abrogated the ability of the cultured treponemes to multiply and cause lesions in rabbits. The in vitro culture technique provided highly reproducible MICs and (in parentheses) MBCs of each of the antibiotics tested: aqueous penicillin G, 0.0005 (0.0025) microgram/ml; tetracycline, 0.2 (0.5) microgram/ml; erythromycin, 0.005 (0.005) microgram/ml; and spectinomycin, 0.5 (0.5) microgram/ml. The significance of these results in light of the in vivo activities and the previous in vitro evaluations of these antibiotics is discussed. The T. pallidum in vitro cultivation system shows promise as a method for studying the interaction between T. pallidum and antimicrobial agents and for screening new antibiotics for syphilis therapy.
Tigemonam, an oral monobactam
Authors: Chin N X , Neu H C
Published: June 2012

Tigemonam is an orally administered monobactam. At less than or equal to 1 microgram/ml it inhibited the majority of strains of Escherichia coli, Klebsiella spp., Enterobacter aerogenes, Citrobacter diversus, Proteus spp., Providencia spp., Aeromonas hydrophila, Salmonella spp., Shigella spp., Serratia marcescens, and Yersinia enterocolitica. At less than or equal to 0.25 microgram/ml it inhibited Haemophilus spp., Neisseria spp., and Branhamella catarrhalis. It did not inhibit Pseudomonas spp. or Acinetobacter spp. Tigemonam was more active than cephalexin and amoxicillin-clavulanate and inhibited many members of the family Enterobacteriaceae resistant to trimethoprim-sulfamethoxazole and gentamicin. Some Enterobacter cloacae and Citrobacter freundii strains resistant to aminothiazole iminomethoxy cephalosporins and aztreonam were resistant to tigemonam. The MIC for 90% of hemolytic streptococci of groups A, B, and C and for Streptococcus pneumoniae was 16 micrograms/ml, but the MIC for 90% of enterococci, Listeria spp., Bacteroides spp., and viridans group streptococci was greater than 64 micrograms/ml. Tigemonam was not hydrolyzed by the common plasmid beta-lactamases such as TEM-1 and SHV-1 or by the chromosomal beta-lactamases of Enterobacter, Morganella, Pseudomonas, and Bacteroides spp. Tigemonam inhibited beta-lactamases of E. cloacae and Pseudomonas aeruginosa but did not induce beta-lactamases. The growth medium had a minimal effect on the in vitro activity of tigemonam, and there was a close agreement between the MICs and MBCs.