bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolism of carbovir, a potent inhibitor of human immunodeficiency virus type 1, and its effects on cellular metabolism
Authors: Parker W B , Shaddix S C , Bowdon B J , Rose L M , Vince R , Shannon W M , Bennett L L
Published: June 2012

Carbovir (CBV) [the (--)-enantiomer of the carbocyclic analog of 2',3'-dideoxy-2',3'-didehydroguanosine] is a potent inhibitor of human immunodeficiency virus type 1 (HIV) replication in vitro. We have characterized the metabolism of CBV and its effect on cellular metabolism in an effort to better understand its mechanism of action. CBV was primarily metabolized to the 5'-triphosphate of CBV (CBV-TP) to concentrations sufficient to inhibit HIV reverse transcriptase. Infection of CEM cells with HIV did not affect the metabolism of CBV. In CEM cells, there was no evidence of the degradation of CBV by purine nucleoside phosphorylase. The half-life of CBV-TP in CEM cells was 2.5 h, similar to that of the 5'-triphosphate of zidovudine (AZT). However, unlike the levels of the 5'-triphosphate of AZT, CBV-TP levels declined without evidence of a plateau. CBV did not affect the metabolism of AZT, and AZT did not affect the metabolism of CBV. A small amount of CBV was incorporated into DNA in intact CEM cells, and this incorporation was increased by incubation with mycophenolic acid, an inhibitor of IMP dehydrogenase. CBV specifically inhibited the incorporation of nucleic acid precursors into DNA but had no effect on the incorporation of radiolabeled precursors into RNA or protein. CBV did not decrease the level of TTP, dGTP, dCTP, or dATP. These results suggested that the cytotoxicity of CBV was due to the inhibition of DNA synthesis. Further studies are necessary to identify the target(s) responsible for growth inhibition.
Nonparametric approach to population pharmacokinetics in oncology patients receiving aminoglycoside therapy
Authors: Inciardi J F , Batra K K
Published: June 2012

A nonparametric expectation maximization approach to the study of population pharmacokinetics is described for an aminoglycoside antibiotic. The method is used to explore population estimates for gentamicin clearance (liters per hour per creatinine clearance) and volume of distribution (liters per kilogram) in tumor patients. Joint and marginal probability distributions are plotted and further characterized by using standard descriptors such as mean, median, mode, standard deviation, skewness, and kurtosis. Results of additional analyses using hematologic or solid tumor subpopulations agree with those of a recent larger study which found no significant pharmacokinetic differences between these groups. Nonparametric maximum-expectation analyses are convenient and allow exploratory analysis of population estimates directly from routine laboratory information.
Pyrimethamine inhibits renal secretion of creatinine
Authors: Opravil M , Keusch G , Lüthy R
Published: June 2012

The mechanism of increased serum creatinine after administration of pyrimethamine and dapsone was evaluated for six healthy volunteers. Serum parameters, urine sediment, and clearances of creatinine, inulin, and para-aminohippurate were assessed prior to and 28 h after the ingestion of a single, combined dose of 100 mg of pyrimethamine and 200 mg of dapsone. In a second series, the same renal function tests were performed for nine human immunodeficiency virus-infected men before and after 1 month of prophylactic treatment with a weekly dose of 75 mg of pyrimethamine and 200 mg of dapsone to evaluate sustained effects on renal function. Serum creatinine increased within 28 h from 81 +/- 14 to 102 +/- 16 mumol/liter (P = 0.002) in the healthy volunteers. Blood urea nitrogen, beta 2-microglobulin, and urine remained normal. Creatinine clearance decreased from 125 +/- 27 to 91 +/- 26 ml/min (P < 0.02) without changes in inulin clearance. The effect was reversible within 21 days and attributable to pyrimethamine, as determined by administration of each drug alone. The sustained effect of four doses of pyrimethamine and dapsone in human immunodeficiency virus-infected patients consisted of an analogous rise in serum creatinine from 69 +/- 17 to 87 +/- 32 mumol/liter (P < 0.05). Both creatinine and inulin clearances, however, were unchanged, representing a new equilibrium between creatinine production and elimination at a higher level in serum. Pyrimethamine, thus, may reversibly inhibit renal tubular secretion of creatinine without affecting the glomerular filtration rate. This physiologic effect in pyrimethamine-treated patients must be differentiated from possible organ-related nephropathies.
Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu)
Authors: Meshnick S R , Yang Y Z , Lima V , Kuypers F , Kamchonwongpaisan S , Yuthavong Y
Published: June 2012

Artemisinin is an important new antimalarial agent containing a bridged endoperoxide. The in vitro antimalarial activity of an artemisinin derivative, arteether, is antagonized by two iron chelators, pyridoxal benzoylhydrazone and 1,2-dimethyl-3-hydroxypyrid-4-one. Similarly, the acute toxicity of artemisinin in mice is antagonized by another chelator, deferoxamine-hydroxyethylstarch. A combination of artemisinin and hemin oxidizes erythrocyte membrane thiols in vitro, and this oxidation is also inhibited by an iron chelator. Thus, iron plays a role in the mechanisms of action and toxicity of artemisinin. The combination of artemisinin and hemin also decreases erythrocyte deformability. Iron probably catalyzes the generation of free radicals from artemisinin since alpha-tocopherol antagonizes the thiol-oxidizing activity of artemisinin and since a spin-trapped free radical signal can be seen by electron paramagnetic resonance only when artemisinin is incubated in the presence of iron.
Activity of pirlimycin against pathogens from cows with mastitis and recommendations for disk diffusion tests
Authors: Thornsberry C , Marler J K , Watts J L , Yancey R J
Published: June 2012

Pirlimycin is an analog of clindamycin that will be recommended for therapy of bovine mastitis. It has good activity against staphylococci and streptococci, the major pathogens for bovine mastitis. Five hundred and thirty bacterial isolates recovered from cows with mastitis were studied to confirm the spectrum of activity and to develop recommendations for susceptibility testing. Pirlimycin is not active against isolates of Enterobacteriaceae, it varies in its activity against enterococci, and it is active against veterinary isolates of streptococci (MIC for 50% of strains tested, < or = 0.03 to 0.06 microgram/ml) and staphylococci (MIC for 50% of strains tested, 0.25 to 1.0 microgram/ml). On the basis of levels of drug attained in the milk with recommended dosing schedules, we chose MIC breakpoints of < or = 2 micrograms/ml for susceptibility and > or = 4 micrograms/ml for resistance. We also recommended a disk diffusion test using a disk containing 2 micrograms/ml and breakpoints of < or = 12 mm for resistance and > or = 13 mm for susceptibility.
blaI and blaR1 regulate beta-lactamase and PBP 2a production in methicillin-resistant Staphylococcus aureus
Authors: Hackbarth C J , Chambers H F
Published: June 2012

For Staphylococcus aureus, it is hypothesized that two genes located upstream of the beta-lactamase gene, blaZ, are required for the inducible expression of beta-lactamase. blaR1 is predicted to encode a signal-transducing membrane protein, and blaI is predicted to encode a repressor protein. These same two genes may also regulate the production of penicillin-binding protein 2a (PBP 2a), a protein essential for expression of methicillin resistance. To confirm that these two genes encode products that can control both beta-lactamase and PBP 2a production, blaI, blaR1, and blaZ with a 150-nucleotide deletion at the 3' end were subcloned from a 30-kb staphylococcal beta-lactamase plasmid and three beta-lactamase-negative strains of methicillin-resistant S. aureus were transformed with the recombinant plasmid containing that insert. The production of PBP 2a and a nonfunctional beta-lactamase was detected by fluorography and by immunoblots with polyclonal antisera directed against each of the proteins. Whereas the parent strains did not produce beta-lactamase and constitutively produced PBP 2a, PBP 2a and a truncated beta-lactamase were now inducible in the transformants. Therefore, two plasmid-derived genes regulate the production of both PBP 2a and beta-lactamase.
In vitro postantibiotic effects following multiple exposures of cefotaxime, ciprofloxacin, and gentamicin against Escherichia coli in pooled human cerebrospinal fluid and Mueller-Hinton broth
Authors: Karlowsky J A , Zhanel G G , Davidson R J , Zieroth S R , Hoban D J
Published: June 2012

Multiple exposures with cefotaxime in either Mueller-Hinton broth or cerebrospinal fluid had no effect on killing or the duration of postantibiotic effect (PAE) in Escherichia coli strains tested. However, upon multiple exposures in Mueller-Hinton broth, ciprofloxacin and gentamicin PAEs significantly decreased with a concomitant reduction in bacterial killing. A reduction in bacterial killing following multiple ciprofloxacin and gentamicin exposures was also seen with cerebrospinal fluid; however, the PAE was maintained.
Activities of the triazole D0870 in vitro and against murine blastomycosis
Authors: Clemons K V , Hanson L H , Stevens D A
Published: June 2012

The novel triazole D0870 was tested for in vitro activity, as well as in vivo in a murine model of pulmonary blastomycosis. In vitro, D0870 had inhibitory and fungicidal activity against Blastomyces dermatitidis (MIC = 0.048 microgram/ml; minimal fungicidal concentration = 0.097 microgram/ml). In vivo, D0870 was approximately 100-fold more active than fluconazole on the basis of milligrams per kilogram of body weight given once daily (QD) against blastomycosis. D0870 doses of both 1 or 10 mg/kg given QD and 10 or 100 mg/kg given every other day prolonged survival (P < 0.001) over fluconazole (100 mg/kg given QD). A D0870 dosage of 1 mg/kg QD was equivalent to fluconazole given at 100 mg/kg in reduction of lung burdens of B. dermatitidis, and D0870 administered at 10 mg/kg QD and 10 or 100 mg/kg every other day caused greater reduction (P < 0.001). However, D0870 at 100 mg/kg given QD was lethally toxic, whereas fluconazole at 100 mg/kg was not. These results indicate that D0870 is an effective therapy for murine blastomycosis and should be further tested.
Penetration of cefprozil into tonsillar and adenoidal tissues
Authors: Shyu W C , Reilly J , Campbell D A , Wilber R B , Barbhaiya R H
Published: June 2012

Penetration of cefprozil into tonsillar and/or adenoidal tissues was investigated for patients undergoing tonsillectomy and/or adenoidectomy. A total of 29 patients ranging in age from 2 to 14 years participated in the study. The tonsils and/or the adenoids were removed at times ranging from 0.33 to 3.17 h after oral administration of a dose of either 7.5 or 20 mg/kg of body weight. A blood sample was also collected as soon as the tissue sample was removed. Plasma, tonsil, and adenoid samples were analyzed for cis and trans isomers of cefprozil by high-performance liquid chromatographic assays. The concentrations of the cis isomer of cefprozil in plasma ranged from 0.60 to 9.87 micrograms/ml at the 7.5-mg/kg dose level and from 1.04 to 20.40 micrograms/ml at the 20-mg/kg dose level. The corresponding concentrations of the cis isomer in tonsil tissue ranged from 0.48 to 2.42 micrograms/g and from 1.00 to 4.29 micrograms/g, respectively. The corresponding concentrations of the cis isomer in adenoid tissue ranged from 0.40 to 4.20 micrograms/g and from 1.74 to 4.94 micrograms/g, respectively. The concentrations of the trans isomer were about 1/10 of those observed for the cis isomer. The median ratios of the cefprozil concentration in tonsillar tissue to that in plasma were 0.37 and 0.47 for patients receiving a 7.5- or a 20-mg/kg oral dose of cefprozil, respectively. The corresponding median ratios for the adenoidal tissue were 0.46 and 0.82, respectively. The cefprozil concentrations in either the tonsillar or the adenoidal tissue at both dose levels over 3.17 h after dosing are much higher than the MICs for common pathogens which cause pharyngitis or tonsillitis.
In vitro activity of azithromycin against bacterial enteric pathogens
Authors: Gordillo M E , Singh K V , Murray B E
Published: June 2012

The in vitro activity of azithromycin against enteric bacterial pathogens was determined by agar dilution. Azithromycin was highly active against Campylobacter spp. (MIC for 90% of strains tested [MIC90] = 0.125 micrograms/ml) and against enterotoxigenic, enterohemorrhagic, enteroinvasive, and enteropathogenic Escherichia coli (MIC90 = 2 micrograms/ml), Shigella spp. (MIC90 = 1 micrograms/ml), and Salmonella spp. (MIC90 = 4 micrograms/ml), including Salmonella typhi (MIC90 = 1 microgram/ml). On the basis of the in vitro activity of the drug against these organisms, clinical studies of azithromycin in enteric diseases should be considered; the high intracellular concentrations achieved by azithromycin may be particularly relevant for organisms like S. typhi, Campylobacter spp., and Shigella spp. which typically invade cells as part of their infectious process.
In vitro activity of FK037, a new parenteral cephalosporin, against anaerobic bacteria
Authors: Kato N , Kato H , Tanaka Y , Bando K , Watanabe K , Ueno K
Published: June 2012

The activity of FK037, a new parenteral cephalosporin, was compared with those of cefpirome, ceftazidime, and flomoxef against 322 recent clinical isolates of anaerobic bacteria. A fastidious facultative anaerobe, Gardnerella vaginalis, was also studied. FK037 inhibited 90% of isolates of Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Clostridium perfringens, Mobiluncus spp., G. vaginalis, and Porphyromonas gingivalis at < or = 0.78 micrograms/ml. The MICs of FK037 for 50 and 90% of Bacteroides fragilis isolates were 25 and > 200 micrograms/ml, respectively; the activity of FK037 was comparable to those of cefpirome and ceftazidime but lower than that of flomoxef. The activity of FK037 against Fusobacterium nucleatum, Fusobacterium varium, and Bilophila wadsworthia decreased when inoculum size was increased from 10(6) to 10(8) CFU/ml. Little influence of inoculum size on the activity of FK037 was observed for other isolates tested. Medium pH affected the activity of FK037 against F. varium (MICs at pHs 5 and 7, 3.13 and 100 micrograms/ml, respectively) and Bacteroides gracilis (MICs at pHs 5 and 7, 12.5 and 1.56 micrograms/ml, respectively) but not against other organisms tested. FK037 was less resistant than flomoxef to hydrolysis by beta-lactamase group 2e derived from B. fragilis GAI 0558 and GAI 10150.
Efficacy of intramuscular amopyroquin for treatment of Plasmodium falciparum malaria in the Gabon Republic
Authors: Gaudebout C , Pussard E , Clavier F , Gueret D , Le Bras J , Brandicourt O , Verdier F
Published: June 2012

The efficacy of a 12-mg/kg (of body weight) intramuscular amopyroquin (ApQ) regimen (two successive 6-mg/kg injections at a 24-h interval), previously established from kinetic studies on healthy volunteers and multicenter studies on patients with malaria, was investigated in 152 patients (children and adults) in Gabon with Plasmodium falciparum malaria. All children in the present study (ages, 1 to 14 years) showed higher degrees of parasitemia and temperatures and lower hematocrit values than did adults at the time of admission. No major side effects in the patients were observed. On day 7, all patients were apyretic; clearance of parasites was obtained in 143 of 152 patients (94%); a low level of parasitemia was observed in nine patients, all of whom were children (6%). In vitro chemosusceptibility tests carried out on P. falciparum isolates from patients demonstrated 51% of resistance to chloroquine (Cq). A correlation was found between the in vitro chemosusceptibilities to Cq and ApQ, but no relationship between the in vitro activity and the in vivo efficacy of ApQ could be found. Concentrations of ApQ in blood assayed by high-performance liquid chromatography on day 2 did not differ significantly between the groups in whom therapy was a success or a failure, although the mean ApQ concentration in blood for the group that failed therapy was 31% lower. Concentrations greater than 100 nmol of self-prescribed Cq and amodiaquine per liter, which were assayed simultaneously with ApQ, were observed in 78 patients (51%). They did not correlate with degrees of parasitemia compared with ApQ alone, which did. Successful treatment by day 7 was obtained in 69 of 74 patients (93%) who had no other 4-aminoquinolines in their blood. The results of the present study show that an ApQ regimen of 12 mg/kg over 2 days may be an alternative for the treatment of Cq-resistant malaria, at least in adult patients, in the field.
In vivo efficacies of quinolones and clindamycin for treatment of infections with Bacteroides fragilis and/or Escherichia coli in mice: correlation with in vitro susceptibilities
Authors: Brook I
Published: June 2012

Therapy with ofloxacin, ciprofloxacin, and lomefloxacin (alone or in combination with clindamycin) and therapy with sparfloxacin, clinafloxacin, and temafloxacin alone were given to mice with subcutaneous abscesses. The abscesses were caused by two Bacteroides fragilis isolates, one of which was susceptible and one of which was resistant to ofloxacin, ciprofloxacin, and lomefloxacin, alone or in combination with Escherichia coli. The abscesses were examined 5 days after inoculation. Numbers of B. fragilis organisms reached log10 10.2 to 11.8 per abscess, and numbers of E. coli organisms reached log10 10.6 to 11.8 per abscess. All of the quinolones reduced the number of susceptible B. fragilis isolates (log10 3.6 to 6.9) and E. coli isolates (log10 5.7 to 6.8). However, ciprofloxacin and lomefloxacin failed to reduce the number of resistant B. fragilis organisms in single-organism or mixed infections. The addition of clindamycin to either ofloxacin, ciprofloxacin, or lomefloxacin reduced the numbers of both susceptible and resistant B. fragilis organisms (log10 3.8 to 7.8). In contrast, sparfloxacin, clinafloxacin, and temafloxacin were effective as single therapy in eradicating B. fragilis resistant to ofloxacin, ciprofloxacin, and lomefloxacin. These in vivo data confirm the in vitro activity of these quinolones and suggest that although ofloxacin, ciprofloxacin, and lomefloxacin are occasionally effective as single agents in eradicating mixed infection by susceptible strains of B. fragilis and E. coli, addition of an agent with activity against anaerobic organisms will ensure their efficacy. Quinolones with good efficacy against B. fragilis may be effective as single-agent therapy of mixed infections.
Oral rifampin plus ofloxacin for treatment of Staphylococcus-infected orthopedic implants
Authors: Drancourt M , Stein A , Argenson J N , Zannier A , Curvale G , Raoult D
Published: June 2012

We examined the effectiveness and safety of the combination of rifampin plus ofloxacin given orally for treating prosthetic orthopedic implants infected with staphylococci. The prospective cohort study was conducted in a referral public hospital with ambulatory care services between 1985 and 1991. Consecutive patients from whom Staphylococcus organisms susceptible to the study drugs were isolated from their orthopedic implants and who had no contraindication to the treatment were eligible for the study. All patients were treated orally with rifampin, 900 mg/day, plus ofloxacin, 600 mg/day. Patients with hip prosthesis infection were treated for 6 months, with removal of any unstable prostheses after 5 months of treatment; patients with knee prosthesis infection were treated for 9 months, with removal of the prosthesis after 6 months of treatment; and patients with infected bone plates were treated for 6 months, with removal of the plate after 3 months of treatment, if necessary. Monthly clinical evaluations were conducted until the completion of the treatment and follow-up or telephone interviews were conducted at 6, 12, 24, 36, 48, and 60 months thereafter. Treatment failures were documented by clinical evaluation, sampling of the infected site for culture and antibiotic activity measurement, and fistulography, if possible. Cure was defined as the absence of clinical, biological, and radiological evidence of infection 6 months after the completion of treatment, treatment failure was defined as the absence of cure, and relapse was defined as the reappearance of infection caused by the same Staphylococcus isolate that caused the original infection, regardless of the timing of this secondary infection. Among 51 patients included in the study and evaluable for safety, 4 patients had side effects and were not evaluable for treatment effectiveness; the overall success rate was 74% among 47 patients, with a success rate of 81% for the hip prosthesis group, 69% for the knee prosthesis group, and 69% for the osteosynthesis device group. Eight treatment failures were relaxed to the isolation of a resistant bacterium. The combination of rifampin administered orally plus ofloxacin is a suitable alternative to the conventional long-term intravenous therapy for treatment of orthopedic implants infected with staphylococci.
Ciprofloxacin-induced, low-level resistance to structurally unrelated antibiotics in Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus
Authors: Fung-Tomc J , Kolek B , Bonner D P
Published: June 2012

The effects of ciprofloxacin on the rates of development of low-level resistance to other antibiotics were determined in vitro. Three methicillin-resistant Staphylococcus aureus and two Pseudomonas aeruginosa clinical strains were grown overnight in Mueller-Hinton broth with or without subinhibitory concentrations (1/2, 1/4, and 1/8 MICs) of ciprofloxacin or an aminoglycoside and then quantitatively plated onto medium containing 4 or 8 times the MICs of various antibiotics. The spontaneous mutational frequencies were determined and compared with those of cells not exposed to ciprofloxacin. Exposure of methicillin-resistant S. aureus strains to ciprofloxacin resulted in a > 100-fold increase in the isolation of variants with decreased susceptibilities to ciprofloxacin, tetracycline, imipenem, fusidic acid, and gentamicin, but not vancomycin. Likewise, a > 100-fold increase in the isolation of variants with decreased susceptibilities to ciprofloxacin and imipenem (35-fold) in P. aeruginosa A21213 was observed, and a > 100-fold increase in the isolation of variants with decreased susceptibilities to ciprofloxacin, amikacin, and cefepime in P. aeruginosa A22379 was observed. On the other hand, exposure of these strains to an aminoglycoside did not influence the development of resistance to nonaminoglycoside drugs. These results indicate that exposure to subinhibitory levels of ciprofloxacin can promote the development of low-level resistance to antibiotics with different modes of action.
In vitro protein binding of cefonicid and cefuroxime in adult and neonatal sera
Authors: Benson J M , Boudinot F D , Pennell A T , Cunningham F E , DiPiro J T
Published: June 2012

The levels of in vitro protein binding of cefonicid and cefuroxime in human adult and neonatal sera were compared. Binding parameters for each drug were determined within the concentration range of 25 to 3,000 micrograms/ml. Cefonicid exhibited concentration-dependent protein binding in both types of sera, with more extensive binding in adult serum at all concentrations. Two classes of binding sites were found: a high-affinity, saturable site and a low-affinity, nonspecific site. Cefuroxime also showed two-class, concentration-dependent protein binding in adult serum, but binding in neonatal serum was to a single class and was independent of drug concentration. Parameters for class 1 binding sites for cefonicid indicated one binding site per albumin molecule in both adult and neonatal sera, with association constants of 7.0 x 10(4) and 1.3 x 10(4) M-1, respectively. These parameters were also derived for cefuroxime in adult serum and were 0.15 and 7.1 x 10(4) M-1, respectively. In neonatal serum, the combined value (number of binding sites per molecule x equilibrium association constant) was similar to combined values calculated for class 2 binding sites for cefuroxime in adult serum and for cefonicid in neonatal serum (287 versus 195 and 261 M-1, respectively). Cephalosporins have been shown to compete with bilirubin for albumin binding sites. Lower levels of protein binding of cefuroxime in the therapeutic range may mean a lower potential for drug displacement of bilirubin in neonates, on the basis of these results. It may be prudent to select less highly protein-bound agents when treating neonatal infections.
A rapid method for screening antimicrobial agents for activities against a strain of Mycobacterium tuberculosis expressing firefly luciferase
Authors: Cooksey R C , Crawford J T , Jacobs W R , Shinnick T M
Published: June 2012

We developed a rapid method to screen the efficacy of antimicrobial agents against Mycobacterium tuberculosis. A restriction fragment carrying a promoterless firefly luciferase gene was cloned into a 4,488-bp shuttle vector, pMV261, and luciferase was expressed under the control of a mycobacterial heat shock promoter. The resulting plasmid, pLUC10, was introduced by electroporation into the avirulent strain M. tuberculosis H37Ra. Luciferase assays of sonic lysates of Triton X-100-treated cells of M. tuberculosis H37Ra(pLUC10) yielded bioluminescence in excess of 1,000 relative light units/approximately 10(9) tubercle bacilli, compared with 0.0025 for the same number of parental cells. A 48-h microdilution antimicrobial agent-screening assay using this strain was developed.
Ceftazidime resistance in Hafnia alvei
Authors: Thomson K S , Sanders C C , Washington J A
Published: June 2012

Two morphotypes of Hafnia alvei differed in their susceptibilities to beta-lactam antibiotics. Both produced an inducible Bush group 1 beta-lactamase. Hyperinducibility of this enzyme was associated with reduced susceptibility in one morphotype.
Role of cephalosporinase in carbapenem resistance of clinical isolates of Pseudomonas aeruginosa
Authors: Zhou X Y , Kitzis M D , Gutmann L
Published: June 2012

With numerous imipenem-resistant clinical isolates of Pseudomonas aeruginosa as well as in vitro-selected resistant mutants, we have demonstrated, by a simple method with a powerful cephalosporinase inhibitor, BRL42715, the contribution of chromosomal cephalosporinase in resistance to imipenem in this species.
Antibiotic susceptibilities of Afipia felis in axenic medium and in cells
Authors: Maurin M , Lepocher H , Mallet D , Raoult D
Published: June 2012

Afipia felis, one of the putative agents of cat scratch disease (CSD), is a facultative intracellular bacterium. Although CSD is considered not to be susceptible to antibiotic therapy, sporadic case reports indicated that aminoglycosides may be effective. We determined the in vitro antibiotic susceptibilities of three A. felis strains in axenic medium and in a cell model. In axenic medium, A. felis was susceptible to imipenem, aminoglycosides, and rifampin when using either the broth dilution technique or the agar technique. When grown in HeLa cells, A. felis was susceptible to amikacin and tobramycin but was resistant to the other compounds tested. Despite its intracellular location, A. felis can apparently be reached by aminoglycosides. Thus, the in vitro data presented here are in accord with the clinical data obtained in patients suffering CSD.
Facilitation of penicillin haptenation to serum proteins
Authors: DiPiro J T , Adkinson N F , Hamilton R G
Published: June 2012

Traditionally, penicillin binding to serum proteins was believed to be a passive chemical process; however, it appears to be facilitated by serum factors. The objectives of this in vitro investigation were to examine facilitated penicillin haptenation, to study the kinetics of haptenation, and to determine the nature of haptenation-facilitating factors. The model involved addition of [3H]benzylpenicillin to serum or albumin solutions (at pH 7.3 to 7.4) and incubation at 37 degrees C for up to 72 h. The extent of penicillin binding to proteins in serum was found to be four- to fivefold higher than with solutions having comparable concentrations of purified albumin, total protein, or total immunoglobulin. Ultrafiltration of serum reduced penicillin binding to serum proteins substantially. An ultrafiltrable haptenation-facilitating factor(s) was found to be less than 0.5 kDa but was not calcium or magnesium. Finally, the extent of penicillin binding was related to albumin purity, as binding substantially increased with albumin purity. These findings suggest that there is a factor(s) in serum that facilitates covalent binding of penicillin to serum proteins. The factor(s) can be removed and then restored to increase penicillin binding to albumin. It appears that at least one component of the facilitation factor is less than 0.5 kDa, which suggests that it is not a peptide and that it is some simple serum component other than calcium or magnesium.
Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers
Authors: Flor S C , Rogge M C , Chow A T
Published: June 2012

The bioequivalence of oral and intravenous ofloxacin was investigated after the administration of multiple doses of 400 mg every 12 h to 20 healthy male volunteers in a randomized, crossover, open-label study. Ofloxacin concentrations in plasma were evaluated after 4 days of oral or intravenous (1-h infusion) dosing with a 3-day wash-out period between regimens. As expected, delivery to the systemic circulation took slightly longer after the oral dosing (time to maximum concentration of drug in serum of 1.7 h) relative to the 1-h intravenous infusion, but the systemic availabilities of ofloxacin by the two routes of administration were equivalent (area under the concentration-time curve from 0 to 12 h ratio of 95%). Since previous studies have not demonstrated any change in the bioavailability of ofloxacin in infectious disease patients, this study supports the interchangeability of these dosing regimens.
pol mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo
Authors: Eron J J , Chow Y K , Caliendo A M , Videler J , Devore K M , Cooley T P , Liebman H A , Kaplan J C , Hirsch M S , D'Aquila R T
Published: June 2012

Specific mutations in the human immunodeficiency virus type 1 (HIV-1) pol gene that cause zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) and didanosine (2',3'-dideoxyinosine; ddI) resistance were studied. The 50% inhibitory concentrations (IC50s) of nucleosides for cloned viruses containing these mutations were compared with the IC50s of the corresponding triphosphate analogs for mutant recombinant-expressed reverse transcriptases (RTs). Changes in ddATP inhibition of RNA-dependent DNA polymerase activity fully accounted for the ddI resistance of the virus caused by a Leu-74-->Val substitution in RT, including an augmentation by the AZT-selected substitutions Thr-215-->Tyr and Lys-219-->Gln in RT. In contrast, the AZT-selected substitutions studied did not cause as great a change in the IC50 of AZT-triphosphate (AZT-TP) for polymerase as they did in the IC50 of AZT for mutant virus. In addition, the mutation at codon 74 suppressed AZT resistance in the virus caused by the mutations at codons 215 and 219 but did not suppress the AZT-TP resistance of enzyme containing these same mutations in RT. The mutation at codon 74 was found in clinical isolates whether or not the patient had received AZT prior to starting ddI therapy. AZT resistance coexisted with ddI resistance following acquisition of Leu-74-->Val in three clinical isolates, indicating that the suppressive effect of Val-74 on the AZT resistance of the virus does not occur in all genetic contexts. When this suppression of AZT resistance was seen in the virus, Val-74 did not appear to cause mutually exclusive changes in AZT-TP and ddATP binding to RT in vitro. The results of the in vitro experiments and characterization of clinical isolates suggest that there are differences in the functional effects of these AZT and ddI resistance mutations.
Biliary excretion of cefixime: assessment in patients provided with T-tube drainage
Authors: Westphal J F , Jehl F , Schloegel M , Monteil H , Brogard J M
Published: June 2012

The biliary excretion profile of cefixime was studied in 10 patients provided with T-tube drainage of the common bile duct after cholecystectomy. Following a single 200-mg oral dose, the peak concentration of cefixime in bile reached 56.9 +/- 70 mg/liter, approximately 20 times as high as the peak concentration in serum, 2.3 +/- 0.85 mg/liter. Cefixime levels in bile proved relatively sustained, since a concentration of 4.3 +/- 3.7 mg/liter was still found 20 h after dosing. The cumulative amount of cefixime recovered in the 24-h bile drainage averaged 10.0 +/- 12.3 mg, which is 5% of the administered dose and positions this beta-lactam antibiotic among the most highly bile-excreted cephalosporins. The presented results show that a single 200-mg oral dose of cefixime provided drug levels in bile consistently higher than the MICs for the most frequently recovered members of the family Enterobacteriaceae in biliary tract infections and maintained these levels for over 20 h after dosing. Accordingly, this cephalosporin deserves further clinical trials to assess its usefulness in both prophylaxis and treatment of biliary tract infections.
Suramin prevents duck hepatitis B virus infection in vivo
Authors: Offensperger W B , Offensperger S , Walter E , Blum H E , Gerok W
Published: June 2012

The effect of suramin on duck hepatitis B virus (DHBV) infection was investigated in vivo. Suramin pretreatment of Pekin ducklings completely prevented DHBV infection. In contrast, suramin given at the time of or after inoculation with DHBV did not inhibit viral infection, replication, or gene expression. These data indicate that suramin effectively blocks the early stages of DHBV infection in vivo.
Use of rifabutin in treatment of systemic Mycobacterium paratuberculosis infection in mice
Authors: Chiodini R J , Kreeger J M , Thayer W R
Published: June 2012

BALB/c mice were infected intraperitoneally with Mycobacterium paratuberculosis and, after allowing the infection to progress for 30 days, were treated with rifabutin at 0, 12.5, 25, and 50 mg/kg of body weight. Rifabutin was administered in drinking water under conditions of water deprivation, whereby the entire daily dose was delivered within a 1-h period. Animals were killed at biweekly intervals from time zero of treatment to 180 days. Spleens and livers from each animal were examined by quantitative bacteriologic culture and histopathology. Restricted water availability was found to be a viable alternative to daily gavage for single-dose bolus administration. Infection, as assessed by bacterial counts, was reduced only in animals that received 50 mg of rifabutin per kg. In these animals, bacterial counts in the liver and spleen were reduced from 7.2 x 10(5) +/- 4.1 x 10(4) and 6.5 x 10(5) +/- 4.1 x 10(4) to 3.0 x 10(3) +/- 1.8 x 10(2) and 3.1 x 10(3) +/- 2.2 x 10(2), respectively, over the 6-month treatment period. Rifabutin may be an appropriate chemotherapeutic drug for long-term treatment of M. paratuberculosis infection and should be considered in any multidrug regimen.
Controlled trial to evaluate protection of high-risk infants against respiratory syncytial virus disease by using standard intravenous immune globulin
Authors: Meissner H C , Fulton D R , Groothuis J R , Geggel R L , Marx G R , Hemming V G , Hougen T , Snydman D R
Published: June 2012

We performed a randomized, controlled trial of intravenous immune globulin (respiratory syncytial virus [RSV] neutralizing [Nt] antibody titer of 1:950 in 5% solution) to evaluate protection against RSV-induced disease over two respiratory virus seasons. Forty-nine children (mean age at enrollment, 4.5 months) with severe congenital heart disease or bronchopulmonary dysplasia were randomized as follows. Twenty-four patients were followed as controls and received no immune globulin. Twenty-five patients received monthly infusions of immune globulin at a dose of 500 mg/kg of body weight. There was a similar distribution between groups of patients with heart disease and bronchopulmonary dysplasia. There were 12 culture-proven RSV infections, 6 in the prophylaxis group and 6 in the control group. There was a trend toward less severe RSV illness in immune globulin recipients, as measured by length of hospitalization. Four of the six immune globulin recipients were hospitalized for a total of 35 days (mean, 8.8 +/- 5.0 days) because of RSV illness, in contrast to 51 hospital days (mean, 12.8 +/- 7.6 days) among RSV-infected controls. We conclude that monthly infusions of standard immune globulin containing RSV Nt antibodies may be safely administered to high-risk children, but that standard intravenous immune globulin does not contain sufficient RSV Nt antibody titer to fully protect against severe RSV illness.
Clarithromycin, minocycline, and rifabutin treatments before and after infection of C57BL/6 mice with Mycobacterium avium
Authors: Lazard T , Perronne C , Grosset J , Vilde J L , Pocidalo J J
Published: June 2012

C57BL/6 mice were pretreated with rifabutin or clarithromycin alone or combined with minocycline 3 days before intravenous challenge (day 0) with Mycobacterium avium. Treatment was continued until sacrifice at days 1, 8, 15, and 21. Rifabutin or clarithromycin decreased the level of infection in both the lungs and the spleen. Rifabutin was as effective as clarithromycin in the lungs but was less [corrected] effective in the spleen. The clarithromycin-minocycline combination was as effective as clarithromycin alone.
Activity of cationically substituted bis-benzimidazoles against experimental Pneumocystis carinii pneumonia
Authors: Tidwell R R , Jones S K , Naiman N A , Berger L C , Brake W B , Dykstra C C , Hall J E
Published: June 2012

On the basis of a previously observed correlation between the antimicrobial activity and DNA binding strength of dicationic molecules, a series of 10 dicationically substituted bis-benzimidazoles were tested for activity in the rat model of Pneumocystis carinii pneumonia. One of the compounds, 1,4-bis[5-(2-imidazolinyl)-2-benzimidazolyl]butane, was found to be more potent and less toxic than pentamidine.
Microbial conversion of avermectins by Saccharopolyspora erythraea: glycosylation at C-4' and C-4''
Authors: Schulman M , Doherty P , Arison B
Published: June 2012

Avermectins and ivermectins are glycosylated at C-4'' and C-4' by both growing and resting cells of Saccharopolyspora erythraea. The reaction is catalyzed by a glycosyltransferase which is constitutive. The enzyme uses UDP-glucose as the glycosyl donor and avermectin or ivermectin mono- and disaccharides as acceptors. Avermectin and ivermectin aglycones and erythromycin A are not substrates for the enzyme.
Anti-Mycobacterium avium activity of quinolones: in vitro activities
Authors: Klopman G , Wang S , Jacobs M R , Bajaksouzian S , Edmonds K , Ellner J J
Published: June 2012

The MICs of 88 quinolones against 14 selected reference and clinical strains of Mycobacterium avium-M. intracellular complex were determined. Agents tested included ciprofloxacin, sparfloxacin (PD 131501), and 86 other experimental quinolones. Test strains were selected to represent various susceptibilities to ciprofloxacin and other drug resistance profiles. MICs were determined by the microdilution method in 7HSF broth, with incubation for 14 days at 35 degrees C. The results showed 25 of the quinolones to be active against the strains, with MICs for 90% of the strains (MIC90s) of 2 to 32 micrograms/ml. Ten of these compounds had activities equivalent to or greater than that of ciprofloxacin. The most active compound was PD 125354, with an MIC50 of 0.5 micrograms/ml and an MIC90 of 2 micrograms/ml; comparable values for ciprofloxacin were 4 and 8 micrograms/ml, respectively. The next most active compounds, with MIC90s of 4 micrograms/ml, were sparfloxacin (PD 131501), PD 123982, PD 135144, and PD 119421. MIC90s of PD 131575, PD 126889, PD 122642, PD 139586, and PD 143289 were 8 micrograms/ml. Further evaluation of the most active agents is warranted, as is assessment of structure-activity relationships of active and inactive agents to elucidate the active portions of the compounds and to lead to the development of compounds with enhanced activity.
Age and therapeutic outcome of experimental Pseudomonas aeruginosa keratitis treated with ciprofloxacin, prednisolone, and flurbiprofen
Authors: Hobden J A , Hill J M , Engel L S , O'Callaghan R J
Published: June 2012

This study was conducted to determine whether the age of the host influences the pathogenesis and therapeutic outcome of drug-treated Pseudomonas aeruginosa keratitis. Young (3- to 5-month-old) and old (1.5- to 3-year-old) rabbits were intrastromally infected with P. aeruginosa ATCC 27853. Sixteen hours later, rabbits in both age subpopulations were divided into three groups and treated topically as follows: group 1, phosphate-buffered saline; group 2, 0.3% ciprofloxacin; and group 3, 0.3% ciprofloxacin, 1.0% prednisolone, and 0.03% flurbiprofen. Drops were given every 15 min for 1 h and then every 30 min for 9 h. At 27 h postinfection, ocular pathology was graded with a slit lamp examination (SLE) scoring system. Aqueous humor was collected for ciprofloxacin quantitation, and corneas were harvested for bacterial enumeration and estimation of polymorphonuclear leukocytes. Young rabbits had more severe inflammation and pathology than old rabbits. At 27 h postinfection, SLE scores and polymorphonuclear leukocyte numbers were significantly higher for young rabbits than old rabbits (P < 0.02), regardless of treatment. Prednisolone and flurbiprofen significantly reduced SLE scores in both age groups (P < 0.03) without affecting the antimicrobial efficacy of ciprofloxacin.
Liposome-encapsulated gentamicin treatment of Mycobacterium avium-Mycobacterium intracellulare complex bacteremia in AIDS patients
Authors: Nightingale S D , Saletan S L , Swenson C E , Lawrence A J , Watson D A , Pilkiewicz F G , Silverman E G , Cal S X
Published: June 2012

TLC G-65, a liposome-encapsulated gentamicin, was given intravenously twice weekly for 4 weeks to AIDS patients with Mycobacterium avium-M. intracellulare complex (MAC) bacteremia at 1.7 mg of gentamicin per kg of body weight per infusion (4 patients), 3.4 mg/kg (10 patients), and 5.1 mg/kg (7 patients). MAC colony counts in blood fell by 75% or more in all three groups (P < 0.005). Drug resistance did not emerge during the study period. Transient renal insufficiency developed in one patient; no other adverse effects were detected. Liposome-encapsulated gentamicin is a potential therapy for MAC infections in AIDS patients.
Accumulation of a newly developed fluoroquinolone, OPC-17116, by human polymorphonuclear leukocytes
Authors: Taira K , Koga H , Kohno S
Published: June 2012

The accumulation of OPC-17116 by human polymorphonuclear leukocytes was studied by comparison with three other new quinolones, ofloxacin, levofloxacin, and DR-3354. The intracellular/extracellular concentration ratio was the highest for OPC-17116, being 66.2, followed by 9.8 for levofloxacin, 7.6 for ofloxacin, and 5.8 for DR-3354. Furthermore, it was suggested that the accumulation of these new quinolones was partially related to their active transport system. The elution of OPC-17116 and ofloxacin from cells was rapid, but the elution of OPC-17116 decreased at a high extracellular pH and increased at a low extracellular pH. The accumulation of OPC-17116 as well as that of the other new quinolones was satisfactorily high, thus indicating that they are expected to be useful for the treatment of various kinds of infections, particularly infections caused by cytozoic bacteria.
Identification of highly potent and selective inhibitors of Toxoplasma gondii dihydrofolate reductase
Authors: Chio L C , Queener S F
Published: June 2012

Toxoplasma gondii RH was obtained in high yield from culture in RPMI medium on a line of Chinese hamster ovary cells lacking dihydrofolate reductase activity (ATCC 3952 dhfr-; American Type Culture Collection). Dihydrofolate reductase preparations from harvested organisms had specific activities of 22.9 +/- 2.1 nmol/min/mg. The 50% inhibitory concentrations against reference compounds were 0.014 microM for methotrexate, 0.24 microM for pyrimethamine, 2.7 microM for trimethoprim, and 0.010 microM for trimetrexate. The Km value for NADPH was 11 microM and followed Michaelis-Menten kinetics; the Km for dihydrofolate was ca. 11 microM, but substrate inhibition appeared to occur at high substrate concentrations. Dihydrofolate reductase from T. gondii was used to screen 130 compounds from the National Cancer Institute repository. Thirteen compounds were > 100-fold more potent than pyrimethamine toward T. gondii dihydrofolate reductase; six compounds with various potencies were 8 to 46 times as selective as pyrimethamine for the protozoal form of the enzyme over the mammalian form. Four trimetrexate analogs were more potent than trimetrexate, and two were significantly more selective. Representative compounds were also tested in a culture model of T. gondii employing uracil incorporation as an index of growth. One pyrimethamine analog was as effective as pyrimethamine in inhibiting T. gondii in culture (50% inhibitory concentration, 0.45 microM). Three other compounds were also effective at micromolar concentrations.
In vitro evaluation of the activities of azithromycin alone and combined with pyrimethamine against Toxoplasma gondii
Authors: Cantin L , Chamberland S
Published: June 2012

By using an in vitro microassay to assess drug interaction, azithromycin combined to pyrimethamine was found more active than pyrimethamine alone against Toxoplasma gondii, and additivity between those drugs was demonstrated. Our results show that the combination of azithromycin and pyrimethamine may lead to a more rapid control of T. gondii.
Resistance of Pseudomonas pseudomallei growing as a biofilm on silastic discs to ceftazidime and co-trimoxazole
Authors: Vorachit M , Lam K , Jayanetra P , Costerton J W
Published: June 2012

We have examined the resistance of Pseudomonas pseudomallei biofilm cells to ceftazidime and cotrimoxazole. A large number of these biofilm cells remained viable at 12 and at 24 h, except in the biofilm treated with 200 times the MIC of ceftazidime. The inherent resistance of P. pseudomallei biofilms to conventional antibiotics may explain the lack of success in the treatment of the chronic manifestations of this bacterial infection.
Detection and characterization of mupirocin resistance in Staphylococcus aureus
Authors: Janssen D A , Zarins L T , Schaberg D R , Bradley S F , Terpenning M S , Kauffman C A
Published: June 2012

Fourteen mupirocin-resistant Staphylococcus aureus strains were isolated over 18 months; 12 exhibited low-level resistance, while two showed high-level resistance. Highly mupirocin-resistant strains contained a large plasmid which transferred mupirocin resistance to other S. aureus strains and to Staphylococcus epidermidis. This plasmid and pAM899-1, a self-transferable gentamicin resistance plasmid, have molecular and biologic similarities.
Novel, plasmid-encoded, TEM-derived extended-spectrum beta-lactamase in Klebsiella pneumoniae conferring higher resistance to aztreonam than to extended-spectrum cephalosporins
Authors: Arlet G , Rouveau M , Fournier G , Lagrange P H , Philippon A
Published: June 2012

A clinical isolate of Klebsiella pneumoniae was more resistant to aztreonam than to cefotaxime and ceftazidime. It produced a clavulanate-susceptible beta-lactamase with an isoelectric point of 6.3 which readily hydrolyzed penicillins, cefotaxime, and ceftazidime, but which hydrolyzed aztreonam poorly. The enzyme was encoded by a gene on a 15-kb plasmid; the gene hybridized with an intragenic DNA probe of blaTEM.