bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro activity of Ro 23-9424, a dual-action cephalosporin, compared with activities of other antibiotics
Authors: Gu J W , Neu H C
Published: June 2012

The in vitro activity of Ro 23-9424, which is desacetyl-cefotaxime linked to fleroxacin, was compared with the activities of cefotaxime, desacetyl-cefotaxime, fleroxacin, ofloxacin, and ciprofloxacin. It inhibited the majority of members of the family Enterobacteriaceae, except for some Serratia marcescens, Citrobacter freundii, and Enterobacter cloacae strains, at less than or equal to 0.25 microgram/ml and had an MIC for 90% of strains tested (MIC90) of 8 micrograms/ml against Pseudomonas aeruginosa. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited at less than or equal to 0.25 microgram/ml. Ninety percent of the staphylococci were inhibited at less than or equal to 4 micrograms/ml, except for some methicillin-resistant Staphylococcus aureus isolates. The MIC90S of Ro 23-9424 for Enterococcus faecalis and Listeria monocytogenes were greater than or equal to 16 micrograms/ml. Ninety percent of Clostridium perfringens isolates were inhibited by less than or equal to 2 micrograms/ml, whereas Bacteroides fragilis had an MIC90 of 32 micrograms/ml. There was a minimal inoculum size effect. The MICs and MBCs were either identical or within a twofold dilution. The MICs of Ro 23-9424 for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Staphylococcus aureus increased 16- to 128-fold after 2 weeks of transfer in the presence of Ro 23-9424, showing that the presence of two agents does not prevent resistance.
Ofloxacin versus co-trimoxazole for prevention of infection in neutropenic patients following cytotoxic chemotherapy
Authors: Liang R H , Yung R W , Chan T K , Chau P Y , Lam W K , So S Y , Todd D
Published: June 2012

The efficacy of ofloxacin in preventing infection in neutropenic patients following cytotoxic chemotherapy was evaluated and was compared with that of co-trimoxazole. A total of 102 patients with hematological malignancies were randomly selected to receive either co-trimoxazole or ofloxacin. All patients were monitored for compliance, occurrence of infection, and drug-related side effects. A surveillance culture of a rectal swab was performed regularly. A total of 25 of the 52 patients (48%) who received co-trimoxazole and 11 of the 50 patients (22%) who received ofloxacin developed fever during the study period (P less than 0.025). Gram-negative bacteremia occurred in nine patients in the co-trimoxazole group (17%) but in only one patient (2%) in the ofloxacin group (P less than 0.05). No patient in either group had documented gram-positive bacterial or Pneumocystis carinii infection. Poor performance status was the only identifiable factor associated with an increased incidence of bacteremia. The surveillance study showed that significantly fewer bacterial strains were resistant to ofloxacin than to co-trimoxazole and that acquisition of resistance to co-trimoxazole was more commonly observed than was acquisition of resistance to ofloxacin. Significantly more patients had skin rashes following co-trimoxazole than ofloxacin treatment (P less than 0.05). Ofloxacin was superior to co-trimoxazole in preventing infection in this population of neutropenic patients.
Pharmacokinetics and inflammatory fluid penetration of cefpodoxime proxetil in volunteers
Authors: O'Neill P , Nye K , Douce G , Andrews J , Wise R
Published: June 2012

The pharmacokinetics of cefpodoxime were determined after a single oral dose of 261 mg of cefpodoxime proxetil, equivalent to 200 mg of cefpodoxime, was given to each of six healthy male volunteers. Concentrations in serum, urine, and cantharidin-induced inflammatory fluid were measured by a microbiological assay. The mean peak level in plasma was 2.1 micrograms/ml, attained at a mean time of 2.9 h. The mean half-life of elimination from serum was 2.2 h. The inflammatory exudate was penetrated moderately rapidly, the mean peak level being 1.7 micrograms/ml at 3.5 h. The mean percent penetration of the inflammatory exudate was 103.7. The mean 24-h urine recovery of cefpodoxime was 32.2%. This study suggests that cefpodoxime proxetil taken once or twice daily will be sufficient to treat urinary or systemic infections caused by susceptible pathogens.
Staphylococcus aureus ventriculitis treated with single-dose intraventricular vancomycin or daptomycin (LY146032): bacterial and antibiotic kinetics in hydrocephalic rabbits
Authors: Haworth C S , Sobieski M W , Scheld W M , Park T S
Published: June 2012

Vancomycin and a new antibiotic, daptomycin (LY146032), were tested in vitro and in vivo against Staphylococcus aureus. In vivo tests were performed with rabbits with kaolin-induced hydrocephalus. Five groups of rabbits were studied: untreated ventriculitis, intraventricular vancomycin only, and ventriculitis treated with intraventricular vancomycin (30 micrograms or 120 micrograms) or daptomycin (7.5 micrograms). Results of this study were as follows. (i) S. aureus demonstrated static growth in cerebrospinal fluid in vitro and in ventriculitis at a maximum titer of 10(5) to 10(6) CFU/ml. (ii) In vitro time kill curves in cerebrospinal fluid matched those in vivo. (iii) Single-dose intraventricular vancomycin did not lower S. aureus concentrations over 8 h, whereas daptomycin did. (iv) Ventriculitis did not significantly alter the clearance of intraventricular vancomycin. (v) Intraventricular half-lives were approximately 2.8 h (maximum) for vancomycin and 4.5 h for daptomycin. (vi) Vancomycin was detectable in the periventricular white matter only in the presence of ventriculitis. Daptomycin was also detectable in the periventricular white matter of rabbits with ventriculitis, but in amounts too small to quantitate. We concluded that daptomycin achieved greater bactericidal activity, more rapid killing kinetics, and a longer half-life in the ventricle than vancomycin did in this model.
Genetic basis of tetracycline resistance in urogenital bacteria
Authors: Roberts M C , Hillier S L
Published: June 2012

The distributions of the nucleotide sequences related to the tetracycline resistance determinants Tet K, Tet L, Tet M, and Tet O were studied by dot blot hybridization with randomly chosen clinical urogenital tract isolates of viridans group streptococci, Streptococcus agalactiae, Enterococcus faecalis, Gardnerella vaginalis, Lactobacillus spp., Fusobacterium nucleatum, Peptostreptococcus spp., and Veillonella parvula. Among the Peptostreptococcus spp., 79% of the isolates hybridized with one (64%) or more (36%) of the probes for Tet K (27%), Tet L (30%), Tet M (75%) and Tet O (13%). Of the viridans group streptococci, 82% of the strains hybridized with one (34%) or more (66%) of the four probes. The distribution of the four determinants in this group was as follows: Tet K, 36%; Tet L, 31%; Tet M, 43%; Tet O, 61%. Twenty-nine percent of the enterococci and forty-six percent of the group B streptococci hybridized with the probes; however, the Tet K, Tet L, and Tet O determinants were found in only a few strains, while the Tet M determinant predominated. A total of 29% of the F. nucleatum isolates, 55% of the G. vaginalis isolates, and 26% of the V. parvula isolates hybridized with the Tet M determinant. In contrast, 43% of the Lactobacillus spp. hybridized with the Tet O determinant. The data indicate that tetracycline resistance determinants are common to many of the microorganisms isolated from the urogenital tract.
Cyclobut-A and cyclobut-G, carbocyclic oxetanocin analogs that inhibit the replication of human immunodeficiency virus in T cells and monocytes and macrophages in vitro
Authors: Hayashi S , Norbeck D W , Rosenbrook W , Fine R L , Matsukura M , Plattner J J , Broder S , Mitsuya H
Published: June 2012

Two newly synthesized carbocyclic oxetanocin analogs, (+/-)-9-[(1 beta,2 alpha,3 beta)-2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine (cyclobut-A) and (+/-)-9-[(1 beta,2 alpha,3 beta)-2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine (cyclobut-G) were tested for activity against the infectivity of human immunodeficiency virus (HIV) in vitro. A number of other carbocyclic oxetanocin analogs failed to exert good antiretroviral effects. Both cyclobut-A and cyclobut-G protected CD4+ ATH8 cells against the infectivity and cytopathic effect of HIV type 1 (HIV-1) and suppressed proviral DNA synthesis in ATH8 cells exposed to HIV-1 in vitro at concentrations of 50 to 100 microM. These compounds also inhibited the in vitro infectivity of another human pathogenic retrovirus, HIV-2. Furthermore, both compounds completely suppressed the replication of a monocytotropic strain of HIV-1 in monocytes and macrophages at concentrations as low as 0.5 microM, as assessed by inhibition of HIV-1 p24 gag protein production. We also found that 2'-deoxyguanosine readily reversed the antiretroviral activity of cyclobut-G in our system, whereas the activity of cyclobut-A was hardly reversed by 2'-deoxyadenosine or 2'-deoxycytidine. We noted, however, that these compounds inhibited the proliferation of peripheral blood mononuclear cells at concentrations of greater than or equal to 100 microM in vitro. Although both cyclobut-A and cyclobut-G appear to have a certain level of in vitro toxicity, our observations may have theoretical and clinical implications in understanding the structure-activity relationships of antiretroviral agents active against HIV.
Paradoxical response of Enterococcus faecalis to the bactericidal activity of penicillin is associated with reduced activity of one autolysin
Authors: Fontana R , Boaretti M , Grossato A , Tonin E A , Lleò M M , Satta G
Published: June 2012

Ten clinical isolates of Enterococcus faecalis were examined for susceptibility to the bactericidal activity of penicillin. Four of these had MBCs of penicillin equal to 2 to 4 x the MIC, and six exhibited a paradoxical response to penicillin, i.e., the bactericidal activity of the antibiotic had a concentration optimum at 2 to 4 x the MIC and decreased significantly at concentrations above this. We found that the paradoxical response to penicillin was an intrinsic and stable property of a strain, but that its phenotypic expression was not homogeneous; only a fraction of the cell population that died at low concentrations was able to survive at high penicillin concentrations. The size of this fraction increased with increasing antibiotic concentration and reached a maximum in the late-log phase of growth. All 10 strains produced a lytic enzyme that was active on Micrococcus luteus heat-killed cells, whereas only some strains lysed E. faecalis heat-killed cells. Strains producing large amounts of the latter enzyme did not show the paradoxical response to penicillin, whereas mutants of these strains that lacked this enzymatic activity paradoxically responded to the antibiotic activity. In addition, from strains that showed paradoxical response to penicillin and produced only the enzyme that was active on M. luteus, it was possible to isolate mutants that were also capable of lysing E. faecalis cells and that were killed with similar efficiency by all concentrations above the MBC. On the basis of these findings, the paradoxical response to penicillin is explained as a property of certain strains of E. faecalis; this property is genetically characterized by alterations in synthesis or activity of one autolysin but phenotypically expressed only by a few cells that are in a particular physiological condition when exposed to high concentrations of antibiotics.
Single-dose oral cefixime versus amoxicillin plus probenecid for the treatment of uncomplicated gonorrhea in men
Authors: Megran D W , Lefebvre K , Willetts V , Bowie W R
Published: June 2012

In this randomized study, a single 800-mg oral dose of cefixime cured 96 of 97 men with uncomplicated gonococcal urethritis, compared with 44 cures of 46 men who received standard therapy with amoxicillin (3 g) plus probenecid (1 g). Both regimens were ineffective against coexistent infection with Chlamydia trachomatis and Ureaplasma urealyticum. Cefixime was well tolerated, and all side effects were mild and self-limited.
Vancomycin resistance is encoded on a pheromone response plasmid in Enterococcus faecium 228
Authors: Handwerger S , Pucci M J , Kolokathis A
Published: June 2012

In Enterococcus faecium 228, vancomycin resistance is encoded on a 55-kilobase conjugative plasmid, pHKK100. This plasmid was transferred with high frequency into susceptible strains of Enterococcus faecalis and conferred responses to pheromones produced by E. faecalis and Streptococcus sanguis. pHKK100 is the first plasmid described that mediates both vancomycin resistance and pheromone response.
Bactericidal activities of various antimicrobial agents against human and animal isolates of Mycobacterium paratuberculosis
Authors: Chiodini R J
Published: June 2012

The MICs and MBCs of various antimicrobial agents for strains of Mycobacterium paratuberculosis isolated from animal and human sources were evaluated. The MICs and MBCs of rifabutin, ciprofloxacin, ethambutol, clofazimine, streptomycin, cefazolin, and amikacin were found to be well below therapeutic levels in serum and tissue.
Effect of renal impairment on distribution of ofloxacin
Authors: Sanchez Navarro A , Martinez Lanao J , Sanchez Recio M M , Domínguez-Gil Hurlé A , Tabernero Romo J M , Gomez Sanchez J C , Terreiro Delgado M M
Published: June 2012

A study was made of the plasma and distribution kinetics of ofloxacin administered at a dosage of 400 mg orally to a group of healthy volunteers and a group of patients with renal impairment. Blood and blister fluid samples were taken at programmed times from all individuals included in the study. The analytical techniques for the determination of ofloxacin in both fluids were a plate diffusion method and a high-performance liquid chromatographic technique. The fitting of the experimental data to the kinetic model used was done with the help of the AUTOAN 2 and NONLIN 84 computer programs. In the groups of healthy volunteers, the elimination half-life mean values were found to be 5.1 and 5.9 h in plasma and blister fluid, respectively. The maximum concentration reached in plasma (3.9 micrograms/ml) proved to be slightly higher than that in interstitial tissue fluid (2.8 micrograms/ml). In the patients with renal impairment, the maximum concentrations in both plasma and blister fluid were significantly increased, in the order of 5 to 8 micrograms/ml in the former and 3 to 4 micrograms/ml in interstitial tissue fluid. The parameters seen to undergo an increase as a result of the renal impairment were the area under the curve of the plasma-time levels, the area under the curve of the blister fluid-time levels, and the elimination half-life in plasma and blister fluid. The degree of absorption and the access capacity of the drug to interstitial tissue fluid remained constant.
Activities and mechanisms of action of halogen-substituted flavanoids against poliovirus type 2 infection in vitro
Authors: Conti C , Genovese D , Santoro R , Stein M L , Orsi N , Fiore L
Published: June 2012

The effects of some halogen-substituted flavanoids (dichloroflavan, halogenated isoflavans, and isoflavenes) on poliovirus type 2 infection was examined. Only two isoflavenes exhibited a significant inhibitory activity on the virus-induced cytopathic effect and plaque formation. In a single cycle of viral replication, both compounds reduced the viral yield by approximately 90%. The presence of the isoflavenes from the beginning of infection or during the adsorption period only prevented the shutoff of host translation and viral RNA and protein synthesis, suggesting that the drugs blocked an early step of viral replication. Indeed, both isoflavenes were not virucidal, did not protect virus infectivity from heat inactivation, and had no measurable effect on the binding of virus to cells, viral penetration, and uncoating of the viral RNA. In contrast, both compounds significantly reduced the infectivity of free viral RNA. The possibility that compounds interfere with poliovirus replication at a very early stage of translation of the input RNA is discussed.
Affinities of SM-7338 for penicillin-binding proteins and its release from these proteins in Staphylococcus aureus
Authors: Sumita Y , Fukasawa M , Okuda T
Published: June 2012

SM-7338, a carbapenem antibiotic, had high affinities for penicillin-binding proteins (PBPs) 1, 2, and 4 of Staphylococcus aureus but not for PBP 3 when a competition assay with [14C]benzylpenicillin was used. However, binding of [14C]SM-7338 was saturated for PBP 3 at a concentration of 1 microgram/ml. These results were due to the rapid release of SM-7338 from PBP 3-SM-7338 complexes with a half-life of 2 min.
Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase
Authors: Fantin B , Pangon B , Potel G , Caron F , Vallée E , Vallois J M , Mohler J , Buré A , Philippon A , Carbon C
Published: June 2012

We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.
Efficacy and safety of mercuric oxide in the treatment of bacterial blepharitis
Authors: Hyndiuk R A , Burd E M , Hartz A
Published: June 2012

A double-masked, placebo-controlled, randomized study was done to assess the safety and clinical and quantitative microbiologic efficacy of 1% mercuric oxide (yellow) ophthalmic ointment in the treatment of eyelid infections, i.e., bacterial blepharitis. A total of 39 patients with bacterial counts and clinical signs indicative of eyelid infection were treated twice daily for 7 days. Clinical biomicroscopic examination and quantitative microbiologic cultures were done just prior to initiation of treatment and again on days 3 and 7. Statistical analysis revealed a significant improvement in the clinical signs, bacterial count, cure rate, and improvement rate for subjects taking the active medication, compared with those taking the placebo on days 3 and 7. In addition, the medication was well tolerated.
Beta-lactamase production in members of the family Enterobacteriaceae and resistance to beta-lactam-enzyme inhibitor combinations
Authors: Thomson K S , Weber D A , Sanders C C , Sanders W E
Published: June 2012

Recent reports that members of the family Enterobacteriaceae that produce high levels of certain beta-lactamases are often resistant to ticarcillin-clavulanate prompted this study to assess the relationship between type and amount of enzyme produced and susceptibility to ticarcillin-clavulanate, piperacillin-tazobactam, and cefoperazone-sulbactam. Agar dilution MICs were determined by using 73 strains of Enterobacteriaceae that produced a single beta-lactamase that had been characterized and quantified and a beta-lactamase-negative control strain of Escherichia coli. For E. coli and Klebsiella pneumoniae, MICs of each combination increased as levels of TEM, SHV-1, or class IV enzymes increased. However, the percentage of strains that were resistant was highest for ticarcillin-clavulanate (32%), with only 18 and 6% resistant to piperacillin-tazobactam and cefoperazone-sulbactam, respectively. Strains producing PSE-1, regardless of level, were resistant or moderately susceptible to ticarcillin-clavulanate but were susceptible to piperacillin-tazobactam and cefoperazone-sulbactam. HMS-1 and OHIO-1 beta-lactamases were associated with resistance to ticarcillin-clavulanate and piperacillin-tazobactam, respectively. High levels of class IV enzymes in Klebsiella oxytoca were associated with resistance to all three combinations. These results indicate that the level and type of beta-lactamase produced by members of the family Enterobacteriaceae are important determinants of susceptibility to beta-lactam-inhibitor combinations, especially ticarcillin-clavulanate.
Use of Saccharomyces cerevisiae expressing beta-galactosidase to screen for antimycotic agents directed against yeast cell wall biosynthesis and possible application to pathogenic fungi
Authors: Zaworski P G , Gill G S
Published: June 2012

Saccharomyces cerevisiae expressing beta-galactosidase was used to develop a screen for compounds active against formation of the yeast cell wall. The screen detailed here is based on the release of beta-galactosidase from cells which had received an osmotic shock.
Increased aminoglycoside dosage requirements in hematologic malignancy
Authors: Zeitany R G , El Saghir N S , Santhosh-Kumar C R , Sigmon M A
Published: June 2012

Aminoglycoside pharmacokinetic parameters were studied prospectively in 27 patients with an underlying hematologic malignancy and fever associated with neutropenia and in 18 control patients. Pharmacokinetic parameters and dosages were determined by linear regression analysis of a one-compartment model by the method of Sawchuk et al. (R. J. Sawchuk, D. E. Zaske, R. J. Cippolle, W. A. Wargin, and R. G. Strate, Clin. Pharmacol. Ther. 21:362-369, 1976). Significant differences between the study and control groups were found for aminoglycoside volume of distribution (0.40 +/- 0.1 versus 0.27 +/- 0.05 liter/kg [mean +/- standard deviation], respectively; P less than 0.0001), clearance (116.6 +/- 48.9 versus 68.6 +/- 26.7 ml/min, respectively; P less than 0.0001), half-life (2.27 +/- 0.66 versus 3.5 +/- 1.8 h, respectively; P less than 0.0001), and elimination rate constant (0.33 +/- 0.11 versus 0.24 +/- 0.09 h-1, respectively; P less than 0.001). The percentage of bone marrow blast cells (at the time of diagnosis) in patients with acute leukemia significantly correlated with increased aminoglycoside clearance (R2 = 36.98%; P = 0.0001). Patients with stage IV lymphomas (Hodgkins disease and non-Hodgkins lymphoma) had a significantly increased clearance compared with patients with lower stages of lymphomas (105.1 +/- 18.5 versus 84.1 +/- 14.9 ml/min; P = 0.014). Fever, leukocyte count, or chemotherapy, among other clinical and laboratory parameters that were studied, had no significant correlation or effect on aminoglycoside disposition. The average dose of amikacin required to maintain peak concentrations in serum above 20 micrograms/ml in patients with a hematologic malignancy was 27.5 +/- 8.43 mg/kg per day. Pharmacokinetic parameters and dosages for the control patients were comparable to general literature standards. we conclude that the dosages recommended by the manufacturers or those derived from nomograms underestimate the aminoglycoside volume of distribution and clearance in patients with a hematologic malignancy and result in suboptimal peak aminoglycoside concentrations in serum. We recommend that in febrile neutropenic patients with an underlying hematologic malignancy, amikacin be initiated at 7.5 to 10 mg/kg per dose every 8 h (2 to 2.5 mg/kg per dose every 8 h for gentamicin) and adjusted within 24 h based on individual pharmacokinetic analysis.
Preliminary study of the pharmacokinetics of oral amifloxacin in elderly subjects
Authors: Stroshane R M , Silverman M H , Sauerschell R , Brown R R , Boddy A W , Cook J A
Published: June 2012

Amifloxacin pharmacokinetics after a single oral dose in healthy elderly subjects were determined. Five males and five females aged 65 to 79 years and having creatinine clearances of 39.3 to 87.2 ml/h per kg of body weight were given a 200-mg amifloxacin caplet following an overnight fast. Mean (standard deviation) pharmacokinetic parameters for amifloxacin were as follows: maximum observed concentration in plasma, 1.13 (0.48) and 1.95 (0.52) micrograms/ml; half-life, 5.37 (0.96) and 4.47 (0.87) h; total plasma clearance (unadjusted for fraction absorbed), 259 (53) and 199 (55) ml/h per kg; renal clearance, 113 (20) and 86 (26) ml/h per kg; Varea/F (Varea is volume of distribution; F is fraction absorbed), 2.05 (0.75) and 1.28 (0.39) liter/kg; and amifloxacin excreted in the urine, 42.5% (14.5%) and 42.8% (10.6%) for males and females, respectively. There were no statistically significant differences in pharmacokinetic parameters between sexes that could not be attributed to differences in body weight. Except for a modest 23% reduction in renal clearance and the suggestion of reduced bioavailability, mean values of pharmacokinetic parameters for elderly male subjects were similar to those previously determined for younger male volunteers. Therefore, a modification in amifloxacin dosage regimen based solely on age may not be necessary.
Enhancement of drug susceptibility of Mycobacterium avium by inhibitors of cell envelope synthesis
Authors: Rastogi N , Goh K S , David H L
Published: June 2012

Treatment of infections caused by Mycobacterium avium complex bacteria still remains a challenge since these organisms are resistant to a majority of antituberculous drugs. M. avium is very often linked with acquired immune deficiency syndrome-associated opportunistic infections. We earlier suggested that one of the strategies for circumventing multiple-drug resistance might be the enhancement of M. avium drug susceptibility by inhibiting the synthesis of the outermost layer of its envelope, which appears to act as an exclusionary barrier for drugs. In this investigation, we have examined this strategy by simultaneously using drugs and the following inhibitors of the M. avium cell envelope: m-fluoro-phenylalanine (an inhibitor of mycoside-C biosynthesis), DL-norleucine (an inhibitor of transmethylation reactions), ethambutol (an inhibitor of arabinogalactan synthesis), EDTA (a divalent-ion chelator), and colistin (an inducer of membrane flux of divalent cations). All the drugs were used in concentrations which were low enough for a possible medical application to be foreseen. This approach, tested on seven strains of the M. avium complex, showed that both m-fluoro-phenylalanine and ethambutol were interesting candidates because they caused significant enhancement of M. avium drug susceptibility.
Potentiation of susceptibility to aminoglycosides by salicylate in Escherichia coli
Authors: Aumercier M , Murray D M , Rosner J L
Published: June 2012

Susceptibility of Escherichia coli to kanamycin and seven other aminoglycosides has been found to be strongly potentiated by salicylate. At pH 7.5, in the presence of 15 mM salicylate and 0.5 micrograms of kanamycin per ml, the efficiency of plating of the bacteria was 2 x 10(-5), whereas there was no significant killing in the presence of kanamycin or salicylate alone. With 0.75 micrograms of kanamycin per ml, the addition of 2.5 mM salicylate was sufficient to reduce the efficiency of plating by more than 10(4)-fold. Synergistic effects were found also at pHs 6.5 and 8.5. To determine whether the action of salicylate resulted from its behavior as a weak acid or its salicyl structure, similar experiments were carried out with acetate and salicyl alcohol. Acetate, a membrane-permeating weak acid, showed a synergistic effect on kanamycin susceptibility at pH 6.5 that was comparable to the effect seen with salicylate at pH 6.5. However, acetate had no synergistic effect with kanamycin at pH 7.5 or 8.5. This is consistent with the ability of acetate to increase the membrane potential of cells and the dependence of susceptibility to kanamycin and other aminoglycosides on the membrane potential. Salicyl alcohol, which has a hydroxyl group in the place of the carboxyl group that is present in salicylate, was an effective synergist with kanamycin. It was equally effective at pHs 6.5 and 7.5 and somewhat more effective at pH 8.5. These results support the hypothesis that two effects are involved in the synergy between aminoglycosides and salicylate: a weak acid effect, possibly to increase the membrane potential, and an uncharacterized effect related to the salicyl structure.
Efficacy of teicoplanin in two dosage regimens for experimental endocarditis caused by a beta-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin
Authors: Yao J D , Thauvin-Eliopoulos C , Eliopoulos G M , Moellering R C
Published: June 2012

Optimal therapy for the treatment of infections caused by strains of enterococci demonstrating high-level resistance to gentamicin and other aminoglycosides has not been established. The present study examined the efficacy of teicoplanin, a glycopeptide antibiotic active against gram-positive bacterial infections in various animal models, in the treatment of experimental endocarditis due to a beta-lactamase-producing strain of Enterococcus faecalis with high-level resistance to gentamicin. Vancomycin was used as a comparative antibiotic. In the first set of experiments, both antimicrobial agents were administered by continuous intravenous infusion for 5 days at dosages which yielded comparable mean levels in serum (plus or minus the standard deviation) of 14.6 +/- 4.3 micrograms/ml for teicoplanin and 14.3 +/- 2.2 micrograms/ml for vancomycin. These regimens proved similarly effective in sterilizing cardiac vegetations (38 versus 50% of treated animals, respectively; P greater than 0.05). Mean (plus or minus the standard deviation) residual bacterial titers within vegetations were reduced to 3.2 +/- 1.2 log10 CFU/g and 3.4 +/- 1.7 log10 CFU/g, respectively. In separate experiments, the potential of teicoplanin to cure endocarditis was assessed, using two dosage regimens: (i) 30 mg/kg per day (mean level in serum, 13 micrograms/ml) for 10 days or (ii) 150 mg/kg per day (mean level in serum, 84 micrograms/ml) for 5 days. Surviving animals were sacrificed 10 days after the discontinuation of therapy. Both teicoplanin regimens were more effective than the comparative vancomycin (150 mg/kg per day) regimen: 92 versus 43% cured (P =0.025) in the standard-dose group, and 82 versus 37% cured (P = 0.015) in the high-dose group. Results in this rat model of enterococcal endocarditis show that teicoplanin may prove useful in the treatment of serious infections due to high level-gentamicin-resistant enterococci in humans.
Prolonged endotoxemia enhances the renal injuries induced by gentamicin in rats
Authors: Auclair P , Tardif D , Beauchamp D , Gourde P , Bergeron M G
Published: June 2012

The aim of this study was to evaluate the role of chronic endotoxemia in the nephrotoxicity of gentamicin (GM). Saline or Escherichia coli lipopolysaccharide (LPS) was administered to conscious rats by continuous intravenous perfusion (1 mg/kg per day for 7 days) from a subcutaneously implanted osmotic pump. Twenty-four hours after surgery (day zero), treatment with saline or GM (15 mg/kg; intraperitoneally, twice a day) was started for 5 days. Levels of LPS in plasma measured by Limulus amoebocyte lysate activity decreased significantly from days 1 through 8. At days 5 and 8, the cortical concentrations of GM were higher in the LPS-perfused and GM-treated group (LPS plus GM) than they were in the saline-perfused and GM-treated group (saline plus GM) (P less than 0.05). Blood urea nitrogen and serum creatinine remained at normal levels throughout the experiment. A significant increase of cortical tubular cell regeneration was observed in the LPS plus GM animals as compared with regeneration observed in the other groups (saline plus saline, LPS plus saline, and saline plus GM), as measured by [3H]thymidine incorporation into DNA. Moreover, histopathological nephrotoxicity scores showed a synergistic toxic effect between LPS and GM. These results demonstrate that chronic perfusion of low doses of LPS potentiates the nephrotoxicity of GM.
Treatment of murine pulmonary blastomycosis with SCH 39304, a new triazole antifungal agent
Authors: Sugar A M , Picard M , Noble L
Published: June 2012

SCH 39304, a broad-spectrum azole derivative, was evaluated in an experimental mouse model of blastomycosis pneumonia. Five days after being inoculated with Blastomyces dermatitidis, infected mice were treated with either oral SCH 39304, fluconazole, or intraperitoneal amphotericin B. A dose response protective effect was observed with SCH 39304 at 5 to 100 mg/kg of body weight per day, with 5 mg of SCH 39304 per kg per day providing activity similar to that of 100 mg of fluconazole per kg per day. Colony counts of yeasts in the lungs of mice sacrificed while on therapy with SCH 39304 were consistently below those of controls, and several lungs were sterile. We conclude that SCH 39304 is effective in murine blastomycosis treatment and deserves to be evaluated in the treatment of human blastomycosis.
In vitro activities of vancomycin and teicoplanin against coagulase-negative staphylococci isolated from neutropenic patients
Authors: Maugein J , Pellegrin J L , Brossard G , Fourche J , Leng B , Reiffers J
Published: June 2012

This study reports the in vitro activities of vancomycin and teicoplanin against 185 coagulase-negative staphylococcal strains isolated from 80 neutropenic patients who received different antibiotic treatments. All strains were susceptible to vancomycin: MICs for 50 and 90% of strains tested were 2 and 4 mg/liter, respectively. Teicoplanin was less active, and MICs displayed a wider range. For only teicoplanin was there a correlation between resistance and previous treatment. At the 4- and 32-mg/liter breakpoint levels, only 20% of the strains isolated from patients without glycopeptide treatment were intermediate or resistant, whereas 49.2% of the strains from patients who had received vancomycin or teicoplanin or both were intermediate or resistant.
Serum sickness-like illness associated with ciprofloxacin
Authors: Slama T G
Published: June 2012

Serum sickness is a systemic hypersensitivity reaction initially reported in children receiving horse serum. Drugs such as penicillins, cephalosporins, and sulfonamides are now noted to be the most common etiologic agents of serum sickness-like reactions. This case report describes a serum sickness-like reaction temporally related to ciprofloxacin, a previously unreported adverse effect of this drug or any of the other quinolones.
Sucralfate significantly reduces ciprofloxacin concentrations in serum
Authors: Garrelts J C , Godley P J , Peterie J D , Gerlach E H , Yakshe C C
Published: June 2012

The effect of sucralfate on the bioavailability of ciprofloxacin was evaluated in eight healthy subjects utilizing a randomized, crossover design. The area under the concentration-time curve from 0 to 12 h was reduced from 8.8 to 1.1 micrograms.h/ml by sucralfate (P less than 0.005). Similarly, the maximum concentration of ciprofloxacin in serum was reduced from 2.0 to 0.2 micrograms/ml (P less than 0.005). We conclude that concurrent ingestion of sucralfate significantly reduces the concentrations in serum produced by a 500-mg dose of ciprofloxacin. On the basis of these findings, ciprofloxacin and sucralfate should not be administered concurrently.
Penetration of ciprofloxacin into human pleural fluid
Authors: Jacobs F , Marchal M , de Francquen P , Kains J P , Gangji D , Thys J P
Published: June 2012

The concentrations of ciprofloxacin (1.5 mg/kg of body weight) in serum and in uninfected pleural exudates were studied after one and three intravenous injections had been given at 8-h intervals. The drug was assayed in serum and in pleural fluid by high-performance liquid chromatography. The peak concentrations in pleural fluid 1.5 h after one and three injections were (mean +/- standard error of the mean) 0.52 +/- 0.09 and 0.77 +/- 0.15 mg/liter, respectively; the corresponding 8-h concentrations were 0.19 +/- 0.05 and 0.39 +/- 0.10 mg/liter. At 1 and 8 h, the ratios of mean concentrations in pleural fluid to mean concentrations in serum were 112 and 158%, respectively, after one injection and 77 and 122% after three injections. This study suggested that there is a satisfactory pleural penetration of ciprofloxacin after intravenous injection.
Double-blind, randomized, controlled clinical trial of norfloxacin for cholera
Authors: Bhattacharya S K , Bhattacharya M K , Dutta P , Dutta D , De S P , Sikdar S N , Maitra A , Dutta A , Pal S C
Published: June 2012

In a double-blind, randomized clinical trial with 78 adults with acute watery diarrhea and severe dehydration, 37 subjects were positive for Vibrio cholerae. In conjunction with rehydration therapy, 13 patients received norfloxacin, 12 received trimethoprim-sulfamethoxazole (TMP-SMX), and 12 received a placebo. Norfloxacin was superior to TMP-SMX and to the placebo in reducing stool output, duration of diarrhea, fluid requirements, and vibrio excretion. TMP-SMX was no better than the placebo.
Effects of aztreonam on fecal flora and on vitamin K metabolism
Authors: Sakata H , Kakehashi H , Fujita K , Yoshioka H
Published: June 2012

The effects of aztreonam on fecal flora and on descarboxy prothrombin (PIVKA-II) in plasma and gamma-carboxyglutamic acid (Gla) in urine as an index of vitamin K metabolism were studied in seven children (age range, 2 months to 2 years) with urinary tract infections. Daily doses of aztreonam were 60 to 80 mg/kg. Stool specimens were obtained before the treatment, on days 3 to 5 of aztreonam use, and from 3 to 5 days after the cessation of treatment. The counts of enterobacteria decreased (P less than 0.01) and those of streptococci increased (P less than 0.05) during aztreonam treatment. The anaerobic organisms, especially bifidobacteria and bacteroides, showed no marked change. PIVKA-II and Gla were investigated before and during the treatment with aztreonam. PIVKA-II was not detected in seven patients before or during aztreonam use. There were no significant differences in the levels of Gla in urine before or during the treatment.
Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses
Authors: Barbhaiya R H , Forgue S T , Gleason C R , Knupp C A , Pittman K A , Weidler D J , Martin R R
Published: June 2012

In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime.
Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding
Authors: Levy M , Egersegi P , Strong A , Tessoro A , Spino M , Bannatyne R , Fear D , Posnick J C , Koren G
Published: June 2012

To determine the magnitude of cloxacillin loss during surgical procedures involving significant blood loss and high fluid replacement, we compared the pharmacokinetics of cloxacillin in children during craniomaxillofacial surgery with the disposition of the drug in healthy young adult volunteers with intact circulation. Blood loss during craniofacial operations may exceed blood volume, in some cases by as much as three times. Hemodynamic replacement with electrolyte solutions and blood products, which do not contain the drug, further dilute cloxacillin concentrations. In the patients that we studied, mean drug loss was estimated at 71%. Cloxacillin concentrations in serum fell below the lower range of the MIC for Staphylococcus aureus during significant portions of the surgical procedures. Thus, the traditional dosing of cloxacillin during prolonged operations with massive blood loss is inadequate. A more frequent dosing interval or priming of all replacement fluids with the drug may be required to maintain therapeutic levels. Our findings suggest that massive blood loss is likely to have a dramatic effect on the level of any drug with a small distribution volume. If such a drug is essential to the patient's well-being (e.g., antibiotics, antiarrhythmics, and anticonvulsants), it must be replaced promptly.
Application of a Bayesian method to monitor and adjust vancomycin dosage regimens
Authors: Hurst A K , Yoshinaga M A , Mitani G H , Foo K A , Jelliffe R W , Harrison E C
Published: June 2012

A Bayesian method for monitoring vancomycin concentrations and adjusting regimens in patients with unstable renal function by using a two-compartment population model was evaluated with a personal computer. The population model was derived from data from 12 cardiac outpatients who received single doses of vancomycin. The performance of the method was then tested in 27 acutely ill patients who received multiple doses of vancomycin. Significant renal impairment was observed in 15 patients. Renal function changed in 15 patients. The vancomycin concentrations in the patients with changing renal function were not at steady state during the observation times. Two concentrations in serum (peak and then trough, or trough and then peak) were fitted along with the population model to individualize the parameter values for each patient. All the subsequent concentrations in serum for each patient were then predicted by using the parameter values for each patient. Future concentrations of 118 serum samples were predicted. The mean absolute prediction error was 3.6 +/- 4.5 micrograms/ml, and the mean prediction error was -0.7 +/- 5.3 micrograms/ml. These results confirm that a two-compartment pharmacokinetic model can be sufficiently individualized with the knowledge of just two concentrations of drug in patient serum; it is possible to predict closely subsequent concentrations in serum, and dosing regimens for individual patients can be well adjusted to achieve the chosen therapeutic goals.
Nucleoside metabolism in herpes simplex virus-infected cells following treatment with interferon and acyclovir, a possible mechanism of synergistic antiviral activity
Authors: O'Brien W J , Coe E C , Taylor J L
Published: June 2012

Alpha interferon (IFN-alpha) and nucleoside analogs have been shown to have synergistic antiherpesvirus activity in cultured cells. The mechanisms responsible for this synergistic activity are not known, but we hypothesize that IFN-alpha-induced alterations of nucleoside metabolism in virus-infected cells may play an important role. Infection of cells with herpes simplex virus type 1 (HSV-1) led to an increase in uptake of thymidine into cells. Treatment of infected cells with recombinant IFN-alpha for 24 h prior to infection resulted in a significant reduction in the uptake of exogenous thymidine but did not reduce the apparent incorporation of exogenous thymidine into DNA. The amount of exogenous thymidine phosphorylated relative to the amount taken up was the same in IFN-alpha-treated and control cultures. IFN-alpha treatment of HSV-1-infected cells also resulted in a reduction in the pool sizes of endogenous deoxyribonucleoside-5'-triphosphates relative to those of untreated HSV-1-infected cultures. Although IFN-alpha affected the metabolism of natural nucleosides in HSV-1-infected cells, it did not significantly reduce the uptake of the antiviral guanosine analog acyclovir into HSV-1-infected cells or the amount of acyclovir-5'-triphosphate accumulated. Therefore, in IFN-alpha-treated cells the concentration of a natural nucleoside, thymidine, was reduced, as were the pools of all deoxyribonucleoside-5'-triphosphates. No decrease in acyclovir or acyclovir-5'-triphosphate concentration was observed, however, when acyclovir-treated cells were exposed to IFN-alpha. These data suggest that IFN-alpha-induced alterations in nucleoside metabolism may be one mechanism whereby IFN-alpha and acyclovir express synergistic antiherpes-virus activity.
Differential susceptibility to DL-alpha-difluoromethylornithine in clinical isolates of Trypanosoma brucei rhodesiense
Authors: Bacchi C J , Nathan H C , Livingston T , Valladares G , Saric M , Sayer P D , Njogu A R , Clarkson A B
Published: June 2012

DL-alpha-Difluoromethylornithine is an enzyme-activated inhibitor of ornithine decarboxylase and an antagonist of polyamine metabolism that has been successful in clinical trials against West African sleeping sickness caused by Trypanosoma brucei gambiense. Its potential for use against the more virulent East African form of the disease, caused by T. brucei rhodesiense, is not certain. We examined 14 East African clinical isolates from the Kenya Trypanosomiasis Research Institute strain bank plus 2 established isolates for susceptibility to DL-alpha-difluoromethylornithine and to standard trypanocides. Seven of 16 strains were partially or totally refractory to DL-alpha-difluoromethylornithine in our test system. Four strains were also refractory to arsenical drugs, and five were refractory to diamidines. The results indicate that other novel agents or combinations of established agents may be needed for chemotherapy of East African disease.