bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic evaluations of low- and high-dose zidovudine plus high-dose acyclovir in patients with symptomatic human immunodeficiency virus infection
Authors: Tartaglione T A , Collier A C , Opheim K , Gianola F G , Benedetti J , Corey L
Published: June 2012

The pharmacokinetics of zidovudine were evaluated in 41 patients with Centers for Disease Control HIV class IVA infection. The patients were assigned escalating doses of zidovudine (300, 600, or 1,500 mg daily) and were randomized to receive either zidovudine alone or zidovudine with a high dose of acyclovir (4,800 mg per day). Single and multiple intravenous- and oral-dose pharmacokinetic studies were performed on days 1 and 7 and weeks 6 and 12 of therapy. Zidovudine concentrations were analyzed by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by noncompartmental methods. Zidovudine concentrations in serum declined in a biphasic manner, with half-lives ranging from 1 to 2 h, and were independent of acyclovir administration or length of zidovudine therapy. The median time of peak concentrations in serum following oral doses was 0.75 h (range, 0.25 to 3 h). Accumulation of zidovudine in serum was not observed, but the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve increased proportionally with increased zidovudine doses. Mean day 7 oral Cmax values were 0.20 +/- 0.12, 0.55 +/- 0.33, and 1.0 +/- 0.5 micrograms/ml for 17 patients receiving total daily doses of, respectively, 300, 600, and 1,500 mg of zidovudine alone, whereas Cmax values were, respectively, 0.27 +/- 0.18, 0.43 +/- 0.33, and 1.2 +/- 0.80 micrograms/ml for 15 comparably treated recipients of zidovudine plus acyclovir (P was not significant). The median bioavailability of oral zidovudine was 67% (42 to 120%) and did not vary with dosage. Absolute and apparent total body clearances were similar among the patients given the various zidovudine doses regardless of whether there was concomitant acyclovir therapy. Drug-related toxicities were observed more frequently in the subjects who received high doses of zidovudine than they were in those who received median and low doses of zidovudine (P=0.03). Overall, acyclovir did not influence the disposition of zidovudine over a wide range of zidovudine doses. No unusual toxicities could be attributed to the zidovudine and high-dose acyclovir combination during the 12-week observation period.
Induction of a class I beta-lactamase from Citrobacter freundii in Escherichia coli requires active ftsZ but not ftsA or ftsQ products
Authors: Ottolenghi A C , Ayala J A
Published: June 2012

A possible connection between septation/division and induction of cloned ampC beta-lactamase was investigated. When a ftsZ84(Ts) mutant of Escherichia coli carrying ampR-ampC from Citrobacter freundii was grown at the restrictive temperature (42 degrees C), induction of beta-lactamase by cefoxitin was inhibited by about 80%. Inhibition was virtually complete when a ftsZ84(Ts) mutant of different genetic background was tested. Although somewhat delayed, the induction of beta-lactamase in transformed ftsA(Ts) and ftsQ(Ts) mutants was similar to that observed in wild-type transformants. These results imply that FtsZ is involved in the process of beta-lactamase induction.
Comparison of the Tu elongation factors from Staphylococcus aureus and Escherichia coli: possible basis for elfamycin insensitivity
Authors: Hall C C , Watkins J D , Georgopapadakou N H
Published: June 2012

In a previous study (C. C. Hall, J. D. Watkins, and N. H. Georgopapadakou, Antimicrob. Agents Chemother. 33:322-325, 1989), the elongation factor Tu (EF-Tu) from Staphylococcus aureus was found to be insensitive to a series of kirromycin analogs which were inhibitory to the EF-Tu from Escherichia coli. In the present study, the EF-Tu from S. aureus was partially purified and characterized. Its apparent molecular mass was approximately 41,000 Da, and the enzyme copurified with EF-Ts (molecular mass, 34,000 Da). S. aureus EF-Tu differed from its E. coli counterpart in that it bound negligible amounts of [3H]GDP, in addition to being insensitive to pulvomycin and aurodox (50% inhibitory concentrations, approximately 100 and 1,000 microM, respectively, versus 2 and 0.2 microM, respectively, for E. coli). The results are consistent with the formation of a stable EF-Tu.EF-Ts complex that affects the interaction of EF-Tu with guanine nucleotides and inhibitors.
Randomized comparison of cefepime and ceftazidime for treatment of skin, surgical wound, and complicated urinary tract infections in hospitalized subjects
Authors: Gentry L O , Rodriguez-Gomez G
Published: June 2012

We undertook a prospective, randomized open comparison of the broad-spectrum cephalosporins cefepime and ceftazidime in treatment of hospitalized subjects with skin or wound infections and complicated nosocomial urinary tract infections. Cefepime treatment (dosage, 2.0 g intravenously twice daily for 4 to 28 days) was successful in 36 (90%) of 40 infections of the skin and skin structure or wounds and in 16 (84%) of 19 nosocomial urinary tract infections. Ceftazidime treatment, 2.0 g every 8 h, was successful in 34 (96%) of 36 infections of the skin and skin structure and in 15 (88%) of 17 urinary tract infections. Microbiological eradication rates of each agent overall and for Pseudomonas aeruginosa were greater than 90%. In the cefepime group, one death occurred, contributed to by an enterococcal superinfection acquired during study drug therapy, and there were two mild and transient adverse experiences observed. Cefepime was comparable to ceftazidime in treatment of infections of the skin and skin structure requiring hospitalization and of complicated nosocomial urinary tract infections.
Activity of meropenem against antibiotic-resistant or infrequently encountered gram-negative bacilli
Authors: Jorgensen J H , Maher L A , Howell A W
Published: June 2012

Meropenem was compared in vitro with imipenem as well as with several other contemporary beta-lactams, ciprofloxacin, and gentamicin against a group of highly antibiotic resistant members of the family Enterobacteriaceae and a collection of oxidase-positive and/or glucose-nonfermentative gram-negative bacilli. In this study, meropenem was more active than imipenem against isolates of Enterobacter, Klebsiella, Morganella, Providencia, Alcaligenes, Aeromonas, and Pasteurella.
Mechanism of action of sparfloxacin against and mechanism of resistance in gram-negative and gram-positive bacteria
Authors: Piddock L J , Zhu M
Published: June 2012

The inhibition of DNA synthesis by sparfloxacin; accumulation of sparfloxacin into members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and staphylococci; induction of recA in Escherichia coli; and the optimum bactericidal concentration (OBC) were measured, and killing kinetics at the OBC were estimated. The OBC and maximum recA-inducing concentration in E. coli were both 1 microgram of sparfloxacin per ml. Accumulation was rapid; two- to threefold more sparfloxacin than ciprofloxacin accumulated in staphylococci and more sparfloxacin accumulated in staphylococci than in gram-negative bacteria. Laboratory mutants with decreased susceptibilities to quinolones alone or multiply resistant were selected from the Enterobacteriaceae and Staphylococcus aureus by using sparfloxacin.
Sulfated polyanions do not inhibit duck hepatitis B virus infection
Authors: Offensperger W B , Offensperger S , Walter E , Blum H E , Gerok W
Published: June 2012

On the basis of the antiviral action of sulfated polyanions in human immunodeficiency virus and other viral infections, we studied the effect of dextran sulfate and heparin on duck hepatitis B virus infection. These agents do not affect viral uptake and replication in liver cells in vitro or in vivo. Sulfated polyanions, therefore, appear to have no potential for the treatment of hepadnavirus infections.
Conjugative transfer genes in staphylococcal isolates from the United States
Authors: Archer G L , Scott J
Published: June 2012

Staphylococcus aureus and coagulase-negative staphylococcal isolates from various geographic areas in the United States were examined by using a conjugative transfer gene DNA probe in dot-blot hybridization assays. Of 175 S. aureus isolates, 47 (27%) hybridized with the probe, while 24 of 208 (11.5%) coagulase-negative staphylococci hybridized. However, among methicillin-resistant S. aureus 52% (45 of 89) were probe positive while only 2% (2 of 86) of methicillin-susceptible S. aureus were probe positive. In contrast, 12.5% (22 of 176) of methicillin-resistant and 6% (2 of 32) of methicillin-susceptible coagulase-negative staphylococci contained transfer genes. All but one of the staphylococci containing transfer genes were resistant to gentamicin; 91.5% of S. aureus and 65% of coagulase-negative staphylococci containing transfer genes transferred gentamicin resistance to a S. aureus recipient. Of the 12 isolates that hybridized with the probe but did not transfer resistance, 10 (6 coagulase-negative staphylococci and 4 S. aureus) carried both gentamicin resistance and conjugative transfer genes on the same plasmid. Of these 10, 6 contained plasmid target fragments of sizes different from that of the probe, suggesting additions or deletions of DNA essential for transfer, while in 4 no such alterations could be detected. In two coagulase-negative staphylococci the entire transfer region was apparently integrated into the chromosome. Thus, staphylococci carrying conjugative transfer genes are widely disseminated in the United States and are usually found in multiresistant isolates on plasmids that also encode gentamicin resistance.
Steady-state pharmacokinetics of ciprofloxacin in plasma from patients with nosocomial pneumonia: penetration of the bronchial mucosa
Authors: Fabre D , Bressolle F , Gomeni R , Arich C , Lemesle F , Beziau H , Galtier M
Published: June 2012

A 30-min intravenous (i.v.) infusion of 200 mg of ciprofloxacin was administered twice daily to 12 patients with nosocomial pneumonia scheduled to undergo diagnostic fiberoptic bronchoscopy. The pharmacokinetics of ciprofloxacin were examined at the presumed steady state after 5 days of treatment. Eleven successive plasma samples were collected in the interval from 0 to 12 h after administration, and bronchial mucosa samples were taken 2 h after administration. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with fluorimetric detection. The results showed that the kinetics in plasma did not differ from those determined previously in healthy volunteers. The mean concentrations in plasma peaked at 4.94 +/- 2.90 mg/liter at the end of infusion. The terminal half-life was 4.95 +/- 2.81 h, and the mean residence time 6.13 +/- 3.17 h. A large volume of distribution was calculated: 2.59 +/- 1.43 liters/kg. Mean total body clearance was 23.3 +/- 10.1 liters/h. The concentrations in bronchial mucosa reached 21.6 +/- 5.63 micrograms/g 2 h after drug intake. The tissue-versus-plasma concentration ratios ranged from 10.1 to 26.3 (mean value, 16.9 +/- 5.43). After 6 to 12 days of i.v. treatment, four patients were switched to oral ciprofloxacin. We propose a model for the simultaneous fit of the concentration-time curves obtained after i.v. infusion and oral dosing. The concentrations in tissue observed in this study were in excess of the MICs for bacteria considered to be susceptible to ciprofloxacin.
Susceptibility of Legionella pneumophila grown extracellularly and in human monocytes to indole-3-propionic acid
Authors: Mandelbaum-Shavit F , Barak V , Saheb-Tamimi K , Grossowicz N
Published: June 2012

Indole-3-propionic acid (IPA), a phytohormone derivative, is a potent inhibitor of growth of Legionella pneumophila cultivated extracellularly in a chemically defined hypotonic medium and intracellularly in human monocytes. The inhibitory activity turns into bactericidal activity with increasing concentrations. The susceptibility of the microorganism to IPA was more evident in "fast-growing" cultures (under conditions of vigorous shaking) than in static cultures growing under an atmosphere of 5% CO2-95% air, which resulted in a decreased growth rate. The MIC, after incubation with the drug for 48 h and as determined by counting of the CFU, was 1.58 microM for fast-growing cultures and 2.64 microM for those grown under static conditions. The MBCs were 5.28 and 26.43 microM, respectively. Tryptophan (Trp) at 150 microM prevented the inhibition caused by 2.64 microM IPA, increased the MIC about 3-fold, and increased the MBC by 10-fold. The effect of Trp was less remarkable in "slow-growing" cultures. The susceptibility of L. pneumophila proliferating in human monocytes was markedly lower than that when it was cultivated extracellularly in the chemically defined hypotonic medium. The MIC after incubation for 48 h was 5.28 microM, and a decrease in viable count was achieved with 105.70 microM. The lower susceptibility was apparently due (at least partially) to the presence of Trp (24.50 microM) in the RPMI 1640 medium that was used for the monocyte cultures. The effect of IPA was time dependent, and prolonged exposure enhanced the bactericidal activity and turned the inhibitory dose into a bactericidal dose. The present data demonstrate that IPA is a potent anti-L. pneumophila factor, although it has a markedly lower activity against bacteria growing intracellularly compared with its activity against extracellularly proliferating microorganisms.
Mechanisms of clinical resistance to fluoroquinolones in Staphylococcus aureus
Authors: Nakanishi N , Yoshida S , Wakebe H , Inoue M , Yamaguchi T , Mitsuhashi S
Published: June 2012

Mechanisms of Staphylococcus aureus resistance to fluoroquinolones were characterized. Subunit A and B proteins of DNA gyrase were partially purified from fluoroquinolone-susceptible strain SA113 and resistant isolate MS16405, which was 250- to 1,000-fold less susceptible to fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, temafloxacin, and sparfloxacin than SA113 was. The supercoiling activity of the gyrase from SA113 was inhibited by the fluoroquinolones, and the 50% inhibitory concentrations of the drugs correlated well with their MICs. In contrast, the gyrase from MS16405 was insensitive to inhibition of supercoiling by all of the quinolones tested, even at 800 micrograms/ml. Combinations of heterologous gyrase subunits showed that subunit A from MS16405 conferred fluoroquinolone resistance, suggesting that an alteration in gyrase subunit A is a cause of the fluoroquinolone resistance in MS16405. Uptake of hydrophilic fluoroquinolones such as ciprofloxacin and norfloxacin by MS16405 was significantly lower than that by SA113. Furthermore, this difference was abolished by the addition of an energy inhibitor, carbonyl cyanide m-chlorophenylhydrazone, suggesting that an alteration in an energy-dependent process, such as an active efflux of hydrophilic quinolones, may lead to decreased drug uptake and hence to increased resistance to fluoroquinolones in MS16405. These findings suggest that the fluoroquinolone resistance in MS16405 is due mainly to an alteration in subunit A of DNA gyrase and may also be associated with an alteration in the drug uptake process.
Comparison of conventional susceptibility tests with direct detection of penicillin-binding protein 2a in borderline oxacillin-resistant strains of Staphylococcus aureus
Authors: Gerberding J L , Miick C , Liu H H , Chambers H F
Published: June 2012

Six selected strains of Staphylococcus aureus classified as borderline oxacillin-resistant, according to standard disk diffusion and microdilution susceptibility test methods, and seven methicillin-resistant and seven methicillin-susceptible control strains were examined for the presence of penicillin-binding protein 2a (PBP 2a) by fluorography and immunoblotting and for DNA hybridization with a mec-specific probe in a dot blot assay. Oxacillin agar screen tests with and without NaCl supplementation were also performed with all strains. PBP 2a was detected both by fluorography and by immunoblotting in all seven methicillin-resistant control strains and in none of the susceptible controls. PBP 2a was detected in two borderline strains. Results of agar screen tests performed without NaCl supplementation were completely concordant with susceptibility determined by PBP 2a and mec detection methods. Agar screening with NaCl supplementation was less accurate. These findings were confirmed with 20 additional borderline strains. Direct detection methods for the presence of PBP 2a or mec, the gene encoding it, allow accurate and definitive classification of borderline strains. Further efforts to develop a rapid, clinically useful, antibody detection system for PBP 2a are warranted.
Pharmacokinetics and tissue penetration of a single 1,000-milligram, intravenous dose of metronidazole for antibiotic prophylaxis of colorectal surgery
Authors: Martin C , Sastre B , Mallet M N , Bruguerolle B , Brun J P , De Micco P , Gouin F
Published: June 2012

The levels of metronidazole in serum and tissue penetration of metronidazole were studied after prophylactic administration in 11 patients undergoing elective colorectal surgery. A single dose of 1,000 mg given intravenously was administered before surgery. Adequate drug levels in serum (greater than or equal to MIC for 90% of strains tested [MIC90] for Bacteroides fragilis) were found in all patients throughout the procedure. Mean peak (15-min) and last-determined (24-h) metronidazole levels in serum were 28.8 +/- 8 and 4.2 +/- 1.7 mg/liter, respectively. The beta-phase elimination half-life was 9.5 +/- 2.3 h, and the clearance and apparent volume of distribution were 57 +/- 13 ml/min and 0.7 +/- 0.1 liter/kg, respectively. In the colonic wall at surgical anastomosis, tissue metronidazole levels greater than or equal to MIC90 for B. fragilis were found in 91% of patients. In the abdominal wall fat and epiploic fat, tissue metronidazole levels greater than or equal to MIC90 for B. fragilis were found in 40 to 60% of patients at surgical incision and closure. No anaerobic infection occurred during the study.
Inhibition of membrane potential-dependent amino acid transport by daptomycin
Authors: Allen N E , Alborn W E , Hobbs J N
Published: June 2012

Daptomycin inhibits the formation of UDP-N-acetylmuramyl-pentapeptide in Bacillus megaterium by inhibiting active transport of amino acids incorporated into the pentapeptide. The ability of daptomycin to inhibit active transport and peptidoglycan formation may be due to its ability to disrupt the transmembrane electrochemical gradient.
Characterization of unusual tetracycline-resistant gram-positive bacteria
Authors: Roberts M C , Moncla B J , Hillier S L
Published: June 2012

Tetracycline-resistant Tet M-negative isolates of Actinomyces viscosus, Eubacterium lentum, Mobiluncus curtisii, and Mobiluncus mulieris were screened with the Tet K, Tet L, and Tet O DNA probes. Ten (71%) of the resistant Mobiluncus strains hybridized with the Tet O probe, two of the three E. lentum strains hybridized with the Tet K probe, and the A. viscosus isolate hybridized with the Tet L probe.
Quantitation of postantibiotic effect by measuring CO2 generation of bacteria with the BACTEC blood culture system
Authors: Gottfredsson M , Erlendsdottir H , Gudmundsson S
Published: June 2012

The duration of the postantibiotic effect (PAE) determined by bacterial CO2 production measured by using the BACTEC NR 730 blood culture system was compared with PAEs determined by standard viability counting. PAEs for Staphylococcus aureus after exposure to dicloxacillin, vancomycin, rifampin, gentamicin, and ciprofloxacin and for Escherichia coli after exposure to ampicillin, gentamicin, and ciprofloxacin were quantitated by the two methods, and an excellent correlation (r = 0.93) was demonstrated. The difference in the PAE durations determined by the two methods was 0.1 +/- 0.4 (mean +/- standard deviation) h. Thus, the BACTEC CO2 generation method provides a simple, alternate way of determining the PAE in vitro.
Comparison of methods for in vitro testing of susceptibility of porcine Mycoplasma species to antimicrobial agents
Authors: Ter Laak E A , Pijpers A , Noordergraaf J H , Schoevers E C , Verheijden J H
Published: June 2012

The MICs of 18 antimicrobial agents used against strains of three porcine Mycoplasma species were determined by a serial broth dilution method. Twenty field strains of M. hyorhinis, ten field strains of M. hyopneumoniae, six field strains of M. flocculare, and the type strains of these species were tested. Twelve field strains and the type strain of M. hyorhinis were also tested by an agar dilution method. Tests were read at various time points. When the broth dilution method was used, the final MIC had to be read 2 days after color changes had stopped. MICs of tetracycline, oxytetracycline, doxycycline, and minocycline were low for the three Mycoplasma species tested. MICs of chlortetracycline were 8 to 16 times higher than MICs of the other tetracyclines. Spiramycin, tylosin, kitasamycin, spectinomycin, tiamulin, lincomycin, and clindamycin were effective against all strains of M. hyorhinis and M. hyopneumoniae. The quinolones were highly effective against M. hyopneumoniae but less effective against M. hyorhinis. The susceptibility patterns for M. hyopneumoniae and M. flocculare were similar.
Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis
Authors: Isono F , Inukai M
Published: June 2012

Mureidomycin A (MRD), a novel peptidylnucleoside antibiotic with antipseudomonal activity, inhibited not only peptidoglycan synthesis but also lipid-intermediate formation from UDP-N-acetylmuramyl (MurNAc)-pentapeptide and UDP-N-acetylglucosamine in an in vitro peptidoglycan-synthesizing system, using ether-treated cells of Pseudomonas aeruginosa. Both types of inhibition by MRD disappeared when UDP-MurNAc-pentapeptide was preincubated with ether-treated cells. Moreover, MRD completely inhibited lipid-intermediate I (undecaprenyl-p-p-MurNAc-pentapeptide) formation at a concentration below the MIC. From these results, it was concluded that the real target of MRD's action was translocase, which catalyzes lipid-intermediate I formation from UDP-MurNAc-pentapeptide and a lipid carrier.
Penicillin-resistant isolates of Neisseria lactamica produce altered forms of penicillin-binding protein 2 that arose by interspecies horizontal gene transfer
Authors: Lujan R , Zhang Q Y , Sáez Nieto J A , Jones D M , Spratt B G
Published: June 2012

Isolates of Neisseria lactamica that have increased resistance to penicillin have emerged in recent years. Resistance to penicillin was shown to be due to the production of altered forms of penicillin-binding protein 2 (PBP 2) that have reduced affinity for the antibiotic. The sequences of the PBP 2 genes (penA) from two penicillin-resistant isolates were almost identical (less than or equal to 1% sequence divergence) to that of a penicillin-susceptible isolate, except in a 175-bp region where the resistant and susceptible isolates differed by 27%. The nucleotide sequences of these divergent regions were identical (or almost identical) to the sequence of the corresponding region of the penA gene of N. flavescens NCTC 8263. Altered forms of PBP 2 with decreased affinity for penicillin in the two penicillin-resistant isolates of N. lactamica appear, therefore, to have arisen by the replacement of part of the N. lactamica penA gene with the corresponding region from the penA gene of N. flavescens.
BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine
Authors: Richman D , Rosenthal A S , Skoog M , Eckner R J , Chou T C , Sabo J P , Merluzzi V J
Published: June 2012

A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The lead compound, BI-RG-587, had a 50% inhibitory concentration of 84 nM against HIV-1 reverse transcriptase activity. This compound reduced plaque formation of HIV-1 in HeLa cells expressing the CD4 receptor by 50% at 15 nM. BI-RG-587 at comparable concentrations inhibited the production of p24 antigen following the acute infection of CEM T-lymphoblastoid cells or primary human monocyte-derived macrophages with HIV-1. No inhibitory effects against HIV-2 or against three picornaviruses were detected. Zidovudine (3'-azido-3'-deoxythymidine [AZT])-susceptible and AZT-resistant isolates of HIV-1 were equally susceptible to BI-RG-587. AZT and BI-RG-587 exhibited synergistic inhibition of HIV-1BRU at all concentrations examined.
Significance of the methyl group on the oxazine ring of ofloxacin derivatives in the inhibition of bacterial and mammalian type II topoisomerases
Authors: Hoshino K , Sato K , Akahane K , Yoshida A , Hayakawa I , Sato M , Une T , Osada Y
Published: June 2012

A study was made of the correlation between the in vitro inhibitory effects of several quinolones, including four ofloxacin derivatives, on bacterial DNA gyrase from Escherichia coli KL-16 and on topoisomerase II from fetal calf thymus. No correlation was observed between the inhibitions of DNA gyrase activity and topoisomerase II activity. On the other hand, the inhibitory effects of these quinolones against topoisomerase II were closely correlated with their inhibition of cell growth. Furthermore, among the oxazine derivatives tested, the derivative with a methyl group at position 3 in an S configuration showed the highest activity against DNA gyrase and derivatives without a methyl group on the oxazine ring were more potent against topoisomerase II than those with a methyl group. Among these derivatives, DR-3355, the S isomer of ofloxacin, showed the highest activity against DNA gyrase and low activity against topoisomerase II. These results indicate that the methyl group on the oxazine ring plays an important role in the inhibitory activities of ofloxacin derivatives for these enzymes.
Prolonged malaria prophylaxis with chloroquine and proguanil (chloroguanide) in a nonimmune resident population of an endemic area with a high prevalence of chloroquine resistance
Authors: Gozal D , Hengy C , Fadat G
Published: June 2012

One hundred thirty nonimmune subjects living in Yaoundé, Cameroon, completed an 18-month prospective study on the efficacy and safety of weekly chloroquine and daily proguanil (chloroguanide) (Ch-P) in malaria prevention. A total of 9 of 78 Ch-P-treated subjects and 26 of 52 subjects who received no prophylaxis contracted Plasmodium falciparum infection during this period (P less than 0.00005). These two groups were comparable for demographic parameters and degree of exposure. Clinical manifestations were of similar severities in the two groups, but parasite counts were significantly higher in the subjects who received no prophylaxis (P less than 0.00005). Side effects of prophylaxis were frequent (31%), minor, and related to chloroquine, and they usually resolved within 4 to 6 weeks. Prolonged administration of Ch-P is safe and effectively prevents P. falciparum malaria in an endemic area with a high prevalence of chloroquine resistance.
Bioavailability and pharmacokinetics of ofloxacin in healthy volunteers
Authors: Yuk J H , Nightingale C H , Quintiliani R , Sweeney K R
Published: June 2012

The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied in an open-label, randomized, two-way crossover study. Ofloxacin (400 mg) was administered either as a 1-h infusion or as an oral tablet. The mean peak concentration after intravenous infusion was 4.30 +/- 0.69 microgram/ml, and that after oral administration was 3.14 +/- 0.53 microgram/ml, occurring 1.74 +/- 0.57 h after dosing. The bioavailability (F) of the oral dosage form of ofloxacin was virtually identical to that of the intravenous form (F = 105% +/- 7%). This complete bioavailability of ofloxacin is supportive of the use of the oral dosage form for the treatment of infections in hospitalized patients either as a replacement for intravenous ofloxacin therapy or in streamlining therapy from the intravenous to the oral route.
Efficacy of a loading dose of oral chloroquine in a 36-hour treatment schedule for uncomplicated plasmodium falciparum malaria
Authors: Pussard E , Lepers J P , Clavier F , Raharimalala L , Le Bras J , Frisk-Holmberg M , Bergqvist Y , Verdier F
Published: June 2012

The efficacy of a loading dose of 20 mg of chloroquine per kg of body weight per os given at intervals during the first day was evaluated in 27 patients in Madagascar with Plasmodium falciparum malaria. The conventional regimen of 25 mg/kg over 3 days (schedule 1) was thus compared with a regimen of 30 mg/kg over 2 days (schedule 2; one dose of 10 mg/kg followed by two doses of 5 mg/kg at 6-h intervals on the first day and two doses of 5 mg/kg at 12-h intervals on the second day) in terms of their clinical and parasitological efficacies, tolerance, and drug concentration-time curves. At 24 h schedule 2 gave higher chloroquine levels in blood, which induced a more rapid decrease in parasitemia. The time required for a 50% decrease in the initial parasitemia was shorter in patients on schedule 2 (14.3 +/- 1.6 h) than it was in patients on schedule 1 (35.5 +/- 5.4 h; P less than 0.01). Moreover, negative blood smears were obtained more rapidly with schedule 2 (50.8 +/- 3.7 h) than with schedule 1 (72 +/- 8.7 h). As predicted by the drug concentration-time curve, no high, potentially toxic peak drug concentration appeared and no adverse effects were observed with the loading dose regimen (schedule 2). These findings support the idea that a loading dose of 20 mg/kg given at intervals during the first 12 h is well tolerated and can be used to obtain a more rapid decrease in parasitemia and to shorten the treatment time of uncomplicated chloroquine-susceptible falciparum malaria in the field.
In vitro and in vivo antibacterial activities of E-4497, a new 3-amine-3-methyl-azetidinyl tricyclic fluoroquinolone
Authors: Gargallo-Viola D , Esteve M , Llovera S , Roca X , Guinea J
Published: June 2012

The in vitro and in vivo antibacterial activities of a new tricyclic fluoroquinolone, E-4497 [S(-)-9-fluoro-3-methyl-10-(3-amine-3-methyl-azetidin-1-yl)-7-oxo- 2,3-dihydro- 7H-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid], were evaluated in comparison with those of DR-3355 [S-(-)-ofloxacin], norfloxacin, and ciprofloxacin. E-4497 was more potent than norfloxacin and as potent as or more potent than DR-3355 and ciprofloxacin against Staphylococcus spp., Streptococcus spp., and Enterococcus faecalis. With the exception of Providencia spp., E-4497 inhibited 90% of the Enterobacteriaceae at less than or equal to 0.25 micrograms/ml. Against enteric bacteria, E-4497 was similar in potency to norfloxacin but less potent than DR-3355 and ciprofloxacin. For Pseudomonas aeruginosa, the MICs of E-4497, DR-3355, norfloxacin, and ciprofloxacin for 90% of strains were 2, 2, 4, and 0.5 micrograms/ml, respectively. Against Clostridium perfringens and Bacteroides fragilis, E-4497 (MICs for 90% of strains, 2 and 8 micrograms/ml, respectively) was two- to fourfold more active than norfloxacin and ciprofloxacin. E-4497 activity decreased moderately in the presence of 10 mM Mg2+. Urine at pH 5.5 caused a significant decrease in activity compared with urine at pH 7.2. However, the presence of serum either had no effect or increased the activity of E-4497. In general, E-4497 was bactericidal at the MIC. In systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa in mice, the protective effect of E-4497 was generally greater than that of norfloxacin and comparable to those of DR-3355 and ciprofloxacin.
Randomized study of vancomycin versus teicoplanin for the treatment of gram-positive bacterial infections in immunocompromised hosts
Authors: Van der Auwera P , Aoun M , Meunier F
Published: June 2012

Seventy-four immunocompromised patients with severe infection due to gram-positive organisms were randomized to receive either vancomycin or teicoplanin. Extensive cancer was present in 71 patients, of whom 47 died within a month. The types of infections were 46 bacteremias (39 associated with central catheters), 24 skin and soft tissue infections (3 with bacteremia), and 7 others (mainly bronchopneumonia). The most frequent pathogen was Staphylococcus epidermidis, followed by Staphylococcus aureus. Microbiological eradication was obtained in 23 of 35 evaluable patients treated with vancomycin (65.7%) and 28 of 36 patients treated with teicoplanin (77.8%) (P = 0.4). Clinical cure and improvement were obtained in 26 of 35 patients (74.3%) and 27 of 36 patients (75.0%), respectively. No significant side effects were observed with teicoplanin, in contrast to reversible increases in serum creatinine (three patients) and skin rashes (four patients) with vancomycin. Superinfection was observed in five patients treated with vancomycin and two patients treated with teicoplanin. No relation was found between peak concentration in serum (at steady state) or bactericidal titers and outcome.
Effect of SDZ MRL 953 on the survival of mice with advanced sepsis that cannot be cured by antibiotics alone
Authors: Lam C , Schütze E , Liehl E , Stütz P
Published: June 2012

Stimulation of nonspecific immunity as an additional modality for therapy of sepsis that cannot be cured by antibiotics alone was investigated. SDZ MRL 953, a novel monosaccharidic lipid A analog as a prototype immunostimulant, and cefotaxime or gentamicin were administered to normal or myelosuppressed mice in a state of advanced sepsis caused by Escherichia coli or Staphylococcus aureus. In this novel model, antibiotic therapy was initiated when the infected mice appeared moribund. At this stage, neither pretreatment with the immunostimulant nor therapy with high doses of cefotaxime or gentamicin was effective in protecting the animals from fatal sepsis. However, pretreatment with a single dose of SDZ MRL 953 1 day prior to microbial inoculation dramatically improved the curative effects of the antibiotics. Hence, long-term survival was significantly enhanced with increasing doses of the immunostimulant in the combined therapy. Peritoneal macrophages from SDZ MRL 953-pretreated animals were primed for enhanced production of microbicidal reactive oxygen metabolites in vitro. In conclusion, the results of the present study indicate that SDZ MRL 953 is a potential candidate for use in a clinical setting as an adjunct to antimicrobial therapy for infections that cannot be treated successfully with appropriate antibiotics alone.
Increase in susceptibility of Pseudomonas aeruginosa to carbapenem antibiotics in low-amino-acid media
Authors: Fukuoka T , Masuda N , Takenouchi T , Sekine N , Iijima M , Ohya S
Published: June 2012

The in vitro susceptibility of Pseudomonas aeruginosa PAO1 to carbapenem antibiotics, such as CS-533, was influenced by various concentrations of basic amino acids, i.e., L-lysine, L-histidine, and L-arginine, in agar media. P. aeruginosa PAO1 showed higher susceptibility to carbapenems in minimal medium than it did in rich media such as Mueller-Hinton II agar. The susceptibility was decreased by the addition of a basic amino acid to the minimal medium, whereas it was influenced less by other amino acids. The susceptibility of PAO1 to cephalosporins, piperacillin, quinolones, and gentamicin was not influenced by the addition of a basic amino acid to the minimal medium. A significant change in susceptibility to carbapenems by the addition of a basic amino acid was not observed with D2 protein-deficient mutants of PAO1. Clinical isolates of P. aeruginosa also showed an increase in susceptibility in minimal medium. L-Lysine in minimal medium did not have any influence on the production of D2 protein, beta-lactamases, or penicillin-binding proteins of PAO1 or on the chemical degradation of CS-533. These results strongly indicate that the increase in susceptibility of P. aeruginosa to carbapenems relates to less competition with basic amino acids for permeation through the D2 protein channel of P. aeruginosa.
In vitro synergy studies with Clostridium difficile
Authors: Bacon A E , McGrath S , Fekety R , Holloway W J
Published: June 2012

Agar dilution anaerobic susceptibility studies using rifampin, vancomycin, metronidazole, and bacitracin individually and in combination were performed with Clostridium difficile. Fifty-five strains of C. difficile were studied. Eighty-five percent of strains tested (29 of 34) were synergistically inhibited by the combination of bacitracin and rifampin (fractional inhibitory concentration, less than or equal to 0.50).
Characterization of a gyrB mutation responsible for low-level nalidixic acid resistance in Neisseria gonorrhoeae
Authors: Stein D C , Danaher R J , Cook T M
Published: June 2012

Nalidixic acid-resistant derivatives of Neisseria gonorrhoeae WR302 were identified and categorized into two classes on the basis of their susceptibilities to this antimicrobial agent. The MIC of nalidixic acid for the derivative strain MUG116 was fourfold greater than that for its isogenic parental strain WR302 (2 versus 0.5 micrograms/ml, respectively). MUG324 was significantly more resistant to nalidixic acid (greater than 64 micrograms/ml). The MICs of other antimicrobial agents known to interact with either the gyrA or gyrB gene products were determined. Although the nalidixic acid MIC for MUG116 increased, no significant increases in the MICs of other agents that interact with the gyrA gene product were seen. The MICs of all agents that interact with the gyrA gene product were significantly increased for MUG324. The gene that imparts low-level nalidixic acid resistance was cloned from strain MUG116. The DNA sequence of this gene was determined, and by comparing the deduced amino acid sequence with sequences of proteins in data bases, this protein was found to be approximately 70% homologous with the gyrB gene product of Escherichia coli.
Effect of topical antimicrobial treatment on aerobic bacteria in the stratum corneum of human skin
Authors: Hendley J O , Ashe K M
Published: June 2012

The efficacy of antimicrobial agents applied topically to the skin surface in eradicating coagulase-negative staphylococci (CNS) residing in the stratum corneum underlying the surface was examined. Glabrous skin was sampled with a 26-cm2 contact plate containing Trypticase soy agar. Five antiseptic solutions and four antimicrobial ointments were evaluated. The antiseptic solutions (10% povidone-iodine, 2% aqueous iodine, 2% tincture of iodine, 70% ethanol, and 0.5% chlorhexidine-ethanol) were applied for 15 s with a gauze sponge. The antimicrobial ointments (iodophor, silver sulfadiazine, mupirocin, and a triple-antibiotic ointment containing neomycin, polymyxin, and bacitracin) were applied and covered for 6 h with gauze. After treatment, the surface was sampled, 15 to 25 keratinized layers were subsequently removed by sequential stripping with cellophane tape, and the stratum corneum was sampled. All agents were effective in eradicating CNS from the surface (80 of 88 trials). However, only 2% iodine (17 of 20 trials), iodophor (8 of 12), mupirocin (6 of 10), and the triple-antibiotic ointment (9 of 11) eradicated CNS from the stratum corneum reliably (greater than or equal to 50% of trials). The stratum corneum was repopulated with resident flora within 24 h of treatment with 2% iodine (4 of 4 trials), iodophor (6 of 7), or mupirocin (5 of 6), but repopulation occurred in only 1 of 7 trials with the triple-antibiotic ointment. Topical treatment of skin with antimicrobial agents usually eradicates CNS from the skin surface but may not eradicate CNS from the stratum corneum. Only the triple-antibiotic ointment eradicated CNS from the stratum corneum and prevented repopulation with resident flora.
Lack of interaction between lomefloxacin and caffeine in normal volunteers
Authors: Healy D P , Schoenle J R , Stotka J , Polk R E
Published: June 2012

Sixteen healthy, nonsmoking adult males participated in a randomized, double-blind, placebo-controlled, two-way crossover study to evaluate the influence of chronic lomefloxacin administration on the disposition of caffeine and its major metabolite, paraxanthine, at steady-state conditions. Lomefloxacin (400 mg) or placebo was administered orally once daily for 5 days to xanthine-free volunteers after an overnight fast. Caffeine (200 mg orally) was administered simultaneously with lomefloxacin on days 3 through 5. After a 2-day washout period, subjects were crossed over to the alternate 5-day regimen with caffeine, which was again given on the final 3 days. Blood samples for caffeine, paraxanthine, and lomefloxacin concentration determinations were serially collected for 48 h following the last dose of each regimen. All compounds were analyzed by high-performance liquid chromatography. For the placebo versus lomefloxacin-containing treatments, maximum caffeine concentrations in plasma (4.35 +/- 0.63 versus 4.07 +/- 0.56 micrograms/ml), areas under the concentration-time curve from time zero to 24 h at steady state (30.3 +/- 6.9 versus 29.7 +/- 6.6 micrograms.h/ml), and elimination half-lives of caffeine (4.8 +/- 1.1 versus 4.8 +/- 1.2 h) were not significantly different. In addition, there were no significant changes in the disposition parameters of paraxanthine as a result of lomefloxacin administration. The frequencies of central nervous system-related effects for the two treatments were not statistically different. We conclude that lomefloxacin has no significant effect on the disposition of caffeine in young healthy volunteers.
Cloning, sequencing, and use as a molecular probe of a gene encoding an aminoglycoside 6'-N-acetyltransferase of broad substrate profile
Authors: Terán F J , Suárez J E , Mendoza M C
Published: June 2012

A gene coding for an aminoglycoside 6'-N-acetyltransferase that was able to modify amikacin was cloned from a plasmid isolated from a clinical strain of Enterobacter cloacae. Sequencing of a 955-bp segment which mediates the modifying activity revealed a single open reading frame of 432 nucleotides that predicted a polypeptide of 144 amino acid residues with a molecular weight of 16,021. Putative ribosomal binding sites and -10 and -35 sequences were located at the 5' end of the gene. The size of the polypeptide was confirmed through minicell analysis of the expression products of plasmids containing the sequence. The use of the gene as a molecular probe revealed its specificity toward strains harboring genes coding for related enzymes. This probe is therefore useful for epidemiological studies.
Effect of abnormal levels of serum components on antibiotic activity
Authors: Plotkin B J , Wright M , Lima A , Gruenberg L
Published: June 2012

Antibiotic activity in serum from a model for type II diabetes was similar to that in normal sera or media containing cholesterol but lacking glucose, insulin, or both. The ratio of effects of broth plus obese-rat serum to effects of broth plus lean-rat serum supplemented with cholesterol approached or equaled 1.
Synergistic killing of vancomycin-resistant enterococci of classes A, B, and C by combinations of vancomycin, penicillin, and gentamicin
Authors: Shlaes D M , Etter L , Gutmann L
Published: June 2012

Using both high and low inocula for time-kill curves, we examined the antibiotic killing of clinical isolates of glycopeptide-resistant enterococci (Enterococcus faecium, E. faecalis, and E. gallinarum) belonging to phenotypic resistance classes A, B, and C. None were resistant to high levels (greater than 500 mg/liter) of gentamicin. Vancomycin-penicillin-gentamicin resulted in 2 or more logs of killing above that of the most effective two-antibiotic combination for all strains except two of three E. gallinarum (VanC) strains and a constitutive mutant of a VanB strain. This strategy may be useful clinically.
Mercuric reductase activity and evidence of broad-spectrum mercury resistance among clinical isolates of rapidly growing mycobacteria
Authors: Steingrube V A , Wallace R J , Steele L C , Pang Y J
Published: June 2012

Resistance to mercury was evaluated in 356 rapidly growing mycobacteria belonging to eight taxonomic groups. Resistance to inorganic Hg2+ ranged from 0% among the unnamed third biovariant complex of Mycobacterium fortuitum to 83% among M. chelonae-like organisms. With cell extracts and 203Hg(NO3)2 as the substrate, mercuric reductase (HgRe) activity was demonstrable in six of eight taxonomic groups. HgRe activity was inducible and required NADPH or NADH and a thiol donor for optimai activity. Species with HgRe activity were also resistant to organomercurial compounds, including phenylmercuric acetate. Attempts at intraspecies and intragenus transfer of HgRe activity by conjugation or transformation were unsuccessful. Mercury resistance is common in rapidly growing mycobacteria and appears to function via the same inducible enzyme systems already defined in other bacterial species. This system offers potential as a strain marker for epidemiologic investigations and for studying genetic systems in rapidly growing mycobacteria.
Comparative efficacies of ciprofloxacin, amoxicillin, amoxicillin-clavulanic acid, and cefaclor against experimental Streptococcus pneumoniae respiratory infections in mice
Authors: Gisby J , Wightman B J , Beale A S
Published: June 2012

Experimental respiratory infections were established in mice by intranasal inoculation of Streptococcus pneumoniae. Inoculation of 10(7) CFU of either S. pneumoniae 1629 or S. pneumoniae 7 produced a fatal pneumonia in nontreated mice 2 to 3 days after infection. Oral therapy was commenced 1 h after infection and was continued three times a day for 2 days. The doses used in mice produced peak concentrations in serum and lung tissue similar to those measured in humans. Ciprofloxacin failed to eliminate either strain of pneumococcus from mouse lungs at any of the doses tested (40, 80, or 160 mg/kg of body weight) by the end of therapy (33 h). Mice that received ciprofloxacin at 160 mg/kg were clear of S. pneumoniae 7 5 days later, whereas persistence and regrowth of S. pneumoniae 1629 resulted in the death of 20% of animals treated with ciprofloxacin. Therapy with cefaclor (20 mg/kg) produced an effect similar to that of ciprofloxacin. In contrast, amoxicillin (10 and 20 mg/kg) and amoxicillin-clavulanic acid (10/5 and 20/10 mg/kg) were significantly (P less than 0.05) more effective in eliminating both strains of S. pneumoniae from the lungs by the end of therapy and, by 168 h, had prevented mortality in 80 to 100% of treated animals. The efficacy of ciprofloxacin against these experimental pneumococcal respiratory infections was poor, despite good penetration into lung tissue, and is a reflection of the low in vitro activity of the quinolone against S. pneumoniae, one of the most common pathogens in community-acquired pneumonia.
Interface-area-to-volume ratio of interstitial fluid in humans determined by pharmacokinetic analysis of netilmicin in small and large skin blisters
Authors: Blaser J , Rieder H L , Lüthy R
Published: June 2012

Human pharmacokinetics of netilmicin during multiple dosing were studied in serum and in the fluid of skin blisters with two different ratios of interface area to fluid volume. The kinetics in the blisters followed the serum concentration-time curve with a delay but with a similar elimination half-life of 2.4 h. The kinetics in the 40-microliters blisters followed closely the theoretically calculated concentrations of the peripheral compartment of a two-compartment model. In contrast, the concentrations in the 120-microliter blisters increased less rapidly, lower peaks were achieved, and concentrations decreased with a significantly longer delay. A very similar area-specific flow or clearance rate of 1.6 microliters.h-1.mm-2 was calculated for the interface area between the serum compartment and either the small or large blisters. The observed rapid mass transfer between serum and blister fluid suggests similar oscillations of concentrations in serum and in small interstitial fluid compartments.