bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative efficacies of cilofungin (Ly121019) and amphotericin B against disseminated Candida albicans infection in normal and granulocytopenic mice
Authors: Khardori N , Nguyen H , Stephens L C , Kalvakuntla L , Rosenbaum B , Bodey G P
Published: June 2012

The efficacies of cilofungin (Ly121019), a semisynthetic lipopeptide antifungal agent, and amphotericin B in the treatment of disseminated candidiasis in normal and neutropenic mice were compared. In mice infected with 2 x 10(6) CFU of Candida albicans, treatment with cilofungin in twice-daily doses of 25 or 35 mg/kg of body weight by intraperitoneal injection for 10 days gave survival rates of 83 and 90%. In contrast, there was 97% mortality in infected controls receiving 2 x 10(6) CFU intravenously and 93% survival in mice treated with 1 mg of amphotericin B per kg once a day. Mice rendered granulocytopenic by the administration of cyclophosphamide showed survival rates of 83 and 80% when treated with 25 or 35 mg of cilofungin per kg for 10 days compared with 43% survival rate in mice treated with 1 mg of amphotericin B per kg (P = 0.0030 and P = 0.0080, respectively). Similar results were obtained when the two antifungal agents were administered for a period of 30 days. Administration of 25 or 35 mg of cilofungin per kg twice a day to granulocytopenic mice receiving 10(6) CFU of C. albicans gave survival rates of 93% and 93% compared with 53% survival with amphotericin B. With 15 mg of cilofungin per kg twice a day for 10 days, a survival rate of 43 to 50% was observed in both normal and granulocytopenic mice compared with 56 and 60%, respectively, when this dosage was continued for 30 days. Cilofungin eradicated C. albicans from the kidneys, spleens, and livers of surviving animals. No toxic effects were observed with any of the dosage regimens used. The clearance of C. albicans from the kidneys, spleens, livers, and brains in normal mice was studied following infection with 5 x 10(5) and 1 x 10(5) intravenously. The mice in the treatment groups received 25 mg of cilofungin per kg twice a day for 10 days. In 8 to 12 days, this treatment was able to clear the organisms from the kidneys, spleens, and livers of mice infected with 5 x 10(5) C. albicans. Mice infected with 10(5) C. albicans and treated with cilofungin (25 mg/kg) twice a day for 10 days had no organisms in the kidney, spleen, and liver at days 8, 2, and 8, respectively. There was 1-log-unit reduction in C. albicans counts in brain tissue from mice of one of the treated groups between 2 h and 2 days postinfection, after which the numbers of organisms remained the same until day 12. These data demonstrate the efficacy of cilofungin in the treatment of disseminated C. albicans infections in normal and granulocytopenic mice. The treatment regimen used in this study was able to clear C. albicans from the kidneys, spleen, and liver but not from brain tissue.
In vitro activity of MDL 62,879 (GE2270 A) against aerobic gram-positive and anaerobic bacteria
Authors: King A , Bethune L , Phillips I
Published: June 2012

The in vitro activity of MDL 62,879, a new peptide antibiotic that inhibits protein synthesis through an interaction with elongation factor Tu, against a wide range of recent clinical isolates of common aerobic gram-positive and anaerobic organisms was determined. MDL 62,879 was highly active against staphylococci (MIC for 90% of isolates [MIC90], 0.125 microgram/ml), streptococci (MIC90, 1 microgram/ml), and enterococci (MIC90, 0.03 microgram/ml). All isolates of peptostreptococci and Mobiluncus spp. were susceptible, as were most isolates of clostridia. MDL 62,879 was not active against isolates of fusobacteria or Bacteroides spp., but some isolates of Prevotella spp. and Porphyromonas asaccharolytica were susceptible.
Diarylsulfones, a new chemical class of nonnucleoside antiviral inhibitors of human immunodeficiency virus type 1 reverse transcriptase
Authors: McMahon J B , Gulakowski R J , Weislow O S , Schultz R J , Narayanan V L , Clanton D J , Pedemonte R , Wassmundt F W , Buckheit R W , Decker W D
Published: June 2012

A series of variously substituted diarylsulfones and related derivatives were found to prevent human immunodeficiency virus type 1 (HIV-1) replication and HIV-1-induced cell killing in vitro. One of the more potent derivatives, 2-nitrophenyl phenyl sulfone (NPPS), completely protected human CEM-SS lymphoblastoid cells from the cytopathic effects of HIV-1 in cell culture at 1 to 5 microM concentrations. HIV-1 replication, as assessed by the production of infectious virions, viral p24 antigen, and virion reverse transcriptase (RT), was inhibited by NPPS at similar concentrations. There was no evidence of direct cytotoxicity of the drug at concentrations below 100 microM. A variety of other CD4+ T-cell lines as well as cultures of peripheral blood leukocytes and monocytes were protected from HIV-1-induced cytopathicity and/or viral replication. NPPS also inhibited several distinctly different strains of HIV-1 but was ineffective against three strains of HIV-2. Biochemical studies revealed that NPPS inhibited HIV-1 RT but not HIV-2 RT. NPPS had no direct effect on HIV-1 virions, nor did it block the initial binding of HIV-1 to target cells. Time-limited treatments of cells with NPPS found that NPPS had to be present continuously in culture to provide maximum antiviral protection. In addition, HIV-1 replication in cells in which infection was already fully established or in chronically infected cells was also unaffected by NPPS. We conclude that NPPS acts in a reversible manner as a nonnucleoside HIV-1-specific RT inhibitor. Although markedly different in structure from a larger, structurally diverse group of known HIV-1-specific nonnucleoside RT inhibitors, NPPS shares several of the biological properties that characterize this emerging new pharmacologic class.
Two mechanisms of butenafine action in Candida albicans
Authors: Iwatani W , Arika T , Yamaguchi H
Published: June 2012

The mechanism of action of a new benzylamine antimycotic, butenafine hydrochloride, was studied in Candida albicans by using the thiocarbamate antimycotic tolnaftate as a reference drug. Butenafine completely inhibited the growth of a test strain of C. albicans at 25 micrograms/ml and was cidal at 50 micrograms/ml. Tolnaftate did not show any growth-inhibitory activity up to 100 micrograms/ml. Both butenafine and tolnaftate inhibited squalene epoxidation in C. albicans, with 50% inhibitory concentrations being 0.57 and 0.17 microgram/ml, respectively. Butenafine, but not tolnaftate, induced the release of appreciable amounts of Pi from C. albicans cells at 12.5 micrograms/ml. This effect of butenafine was augmented when the cells were pretreated with tolnaftate. The results suggest that the direct membrane-damaging effect of butenafine may play a major role in its anticandidal activity and that the drug-induced alteration in the cellular sterol composition renders the cell membrane more susceptible to the membrane-damaging effect of this drug.
Comparative efficacies of ofloxacin, cefotaxime, and doxycycline for treatment of experimental epididymitis due to Escherichia coli in rats
Authors: Vieler E , Jantos C , Schmidts H L , Weidner W , Schiefer H G
Published: June 2012

The in vivo efficacy of ofloxacin was compared with those of cefotaxime and doxycycline in a rat model of epididymitis due to Escherichia coli. Treatment was started 24 h after infection and was continued for 7 days. Ofloxacin reduced the numbers of E. coli organisms in the epididymides significantly more than the other therapeutic regimens and cured the infection more frequently. Histopathological changes in the epididymides of ofloxacin-treated animals were significantly less severe than those observed in untreated animals. Doxycycline was less effective than ofloxacin but significantly reduced the titers of organisms in rat epididymides. In contrast, despite excellent in vitro activity, cefotaxime failed to reduce the magnitude of infection. The results of this study suggest that ofloxacin may be a very effective antimicrobial agent for the treatment of epididymitis due to E. coli.
Kinetic interactions of tazobactam with beta-lactamases from all major structural classes
Authors: Bush K , Macalintal C , Rasmussen B A , Lee V J , Yang Y
Published: June 2012

Tazobactam was shown to be a potent inhibitor of group 1, 2a, 2b, and 2b' beta-lactamases. Extended kinetic studies with class A and C serine beta-lactamases showed that the PC1, TEM-2, and P99 enzymes all were reversibly inhibited prior to inactivation of the enzymes. The CcrA metallo-beta-lactamase was less well inhibited, with a 50% inhibitory concentration at least 3 orders of magnitude less favorable than those for most serine beta-lactamases. The numbers of hydrolytic turnovers of tazobactam before inactivation were 2 for PC1, 125 for TEM-2, 50 for P99, and 4,000 for the CcrA enzyme. In spectral studies, transient intermediates were formed after reaction of tazobactam with the PC1, TEM-2, and CcrA beta-lactamases, corresponding to enzyme-associated intermediates responsible for hydrolysis of tazobactam. Chromophores absorbing at 270 nm (CcrA) and 288 nm (TEM-2 and PC1) were observed for these reaction intermediates. The P99 cephalosporinase formed a stable complex with a UV maximum at 295 nm. Incubation of tazobactam with all of the enzymes resulted in accumulation of a tazobactam reaction product with a short-wavelength absorbance. This product has characteristics similar to those of the major eucaryotic metabolite of tazobactam. Possible reaction mechanisms are presented to explain the findings. In conclusion, both serine-based and metallo-beta-lactamases were irreversibly inactivated by tazobactam following an initial transient inhibition phase.
Changes in adherence of respiratory pathogens to HEp-2 cells induced by subinhibitory concentrations of sparfloxacin, ciprofloxacin, and trimethoprim
Authors: Visser M R , Beumer H , Hoepelman A I , Rozenberg-Arska M , Verhoef J
Published: June 2012

Preincubation with subinhibitory concentrations of sparfloxacin, ciprofloxacin, and trimethoprim decreased the adherence of the respiratory pathogens Klebsiella pneumoniae, Haemophilus influenzae, and Moraxella (Branhamella) catarrhalis to human larynx carcinoma HEp-2 cells. Subinhibitory concentrations of sparfloxacin did not change the adherence of Pseudomonas aeruginosa or Streptococcus pneumoniae 15.62, but adhesion of S. pneumoniae 15.42 was significantly enhanced by subinhibitory antimicrobial concentrations.
Preincubation of Haemophilus influenzae with subinhibitory concentrations of macrolides: influence on human neutrophil chemiluminescence
Authors: Bonnet M , Van der Auwera P
Published: June 2012

Preincubation of Haemophilus influenzae with antibiotics may influence opsonophagocytosis as studied by chemiluminescence. Two strains of H. influenzae (strain 1 [type b] and strain 2 [uncapsulated]) were pretreated with erythromycin, roxithromycin, clarithromycin, and azithromycin for 1 h in Haemophilus test medium (the last 25 min was either without serum or with 10% fresh serum or 10% decomplemented serum). Human neutrophils were stimulated with a pretreated or control inoculum at four different bacterium/neutrophil ratios and tested for luminol chemiluminescence with an LKB luminometer. The results were normalized for bacterium/neutrophil ratio and compared by the two-sided Wilcoxon test. Pretreatment of bacteria with one-half of the MICs of erythromycin, clarithromycin, and roxithromycin produced nonsignificant (P > 0.05) increases in the chemiluminescence response (means of 23% for strain 1 and 4% for strain 2). Pretreatment with azithromycin at one-half of the MIC produced an increase in the chemiluminescence response induced by serum-opsonized strain 1 (320% +/- 36% [mean +/- standard error of the mean]) and strain 2 (107% +/- 20%) (P < 0.05). This increase was concentration dependent: for strain 1, 60% +/- 18% at one-fourth of the MIC to 440% +/- 41% at the MIC; for strain 2, 10% +/- 5% at one-fourth of the MIC to 300% +/- 20% at the MIC. For strain 1, the maximal increase with azithromycin pretreatment (at the MIC) required opsonization with fresh serum. Opsonization with decomplemented serum was associated with a 53% +/- 21% increase; this increase was 28% +/- 3% in the absence of serum. For strain 2, azithromycin reduced the lag phase of the chemiluminescence response induced by the absence of serum but did not alter the chemiluminescence response in the presence of decomplemented serum. A significant contribution of soluble factors in the enhanced response observed with bacteria preincubated with azithromycin was excluded. The increase of the chemiluminescence response with azithromycin pretreatment was probably due to improvement in complement-dependent opsonization for strain 1 and to improvement in both serum-independent and serum-dependent opsonization for strain 2.
In vitro susceptibility of Helicobacter pylori to several antimicrobial combinations
Authors: Pavicić M J , Namavar F , Verboom T , van Winkelhoff A J , De Graaff J
Published: June 2012

Synergy between metronidazole and its hydroxymetabolite and between each compound and amoxicillin or tetracycline-HCl was determined against Helicobacter pylori. Metronidazole plus its hydroxymetabolite and either compound combined with amoxicillin showed synergism against all 10 strains of H. pylori tested. Metronidazole plus tetracycline-HCl or the hydroxymetabolite plus tetracycline-HCl acted synergistically against seven and six strains, respectively, acted additively against three strains, and had no additional effect against one strain. These results may help to explain the in vivo efficacies of metronidazole combinations in the treatment of H. pylori-associated gastritis.
Plasmid-mediated AmpC-type beta-lactamase isolated from Klebsiella pneumoniae confers resistance to broad-spectrum beta-lactams, including moxalactam
Authors: Horii T , Arakawa Y , Ohta M , Ichiyama S , Wacharotayankun R , Kato N
Published: June 2012

Klebsiella pneumoniae NU2936 was isolated from a patient and was found to produce a plasmid-encoded beta-lactamase (MOX-1) which conferred resistance to broad spectrum beta-lactams, including moxalactam, flomoxef, ceftizoxime, cefotaxime, and ceftazidime. Resistance could be transferred from K. pneumoniae NU2936 to Escherichia coli CSH2 by conjugation with a transfer frequency of 5 x 10(-7). The structural gene of MOX-1 (blaMOX-1) was cloned and expressed in E. coli HB101. The MIC of moxalactam for E. coli HB101 producing MOX-1 was > 512 micrograms/ml. The apparent molecular mass and pI of this enzyme were calculated to be 38 kDa and 8.9, respectively. Hg2+ and Cu2+ failed to block enzyme activity, and the presence of EDTA in the reaction buffer did not reduce the enzyme activity. However, clavulanate and cloxacillin, serine beta-lactamase inhibitors, inhibited the enzyme activity competitively (Kis = 5.60 and 0.35 microM, respectively). The kinetic study of MOX-1 suggested that it effectively hydrolyzed broad-spectrum beta-lactams. A hybridization study confirmed that blaMOX-1 is encoded on a large resident plasmid (pRMOX1; 180 kb) of strain NU2936. By deletion analysis, the functional region was localized within a 1.2-kb region of the plasmid. By amino acid sequencing, 18 of 33 amino acid residues at the N terminus of MOX-1 were found to be identical to those of Pseudomonas aeruginosa AmpC. These findings suggest that MOX-1 is a plasmid-mediated AmpC-type beta-lactamase that provides enteric bacteria resistance to broad-spectrum beta-lactams, including moxalactam.
Nucleotide and deduced protein sequences of the class D tetracycline resistance determinant: relationship to other antimicrobial transport proteins
Authors: Varela M F , Griffith J K
Published: June 2012

The nucleotide sequence of the plasmid pRA1 gene encoding the TetA(D) tetracycline/H+ antiporter was determined. The deduced amino acid sequence was compared with those of other antimicrobial and antiseptic transporters. The deduced product of tetA(D) is a 41.1-kDa protein consisting of 394 amino acids comprising 12 membrane-spanning domains. Three classes of amino acid motifs found in TetA(D) are highly conserved in other transporters, implying that they participate in structures necessary for substrate recognition, binding, or translocation. A common mechanism of transport is suggested, with subtle sequence variations accounting for varied substrate specificities, modes of transport, and directions of transport.
Comparative antimycobacterial activities of the newly synthesized quinolone AM-1155, sparfloxacin, and ofloxacin
Authors: Tomioka H , Saito H , Sato K
Published: June 2012

AM-1155 is a newly synthesized 6-fluoro-8-methoxy quinolone. We assessed its in vitro antimycobacterial activity using sparfloxacin (SPFX) and ofloxacin (OFLX) as comparison drugs. The MICs of these agents for various mycobacterial strains were determined by the agar dilution method with 7H11 medium. AM-1155 had lower MICs for 50 and 90% of tested strains of Mycobacterium kansasii, M. marinum, and M. fortuitum-M. chelonae complex than SPFX and OFLX, and the values for M. tuberculosis, M. scrofulaceum, and the M. avium-M. intracellulare complex were similar to those of SPFX and considerably lower than those of OFLX. In addition, the antimicrobial activity of AM-1155 against M. tuberculosis and M. intracellulare phagocytosed into murine peritoneal macrophages was compared with that of OFLX. AM-1155 (1 microgram/ml) inhibited the intracellular growth of both M. tuberculosis and M. intracellulare, whereas OFLX at the same concentration failed to show any such effect. Moreover, AM-1155 (10 micrograms/ml) exhibited a steady bactericidal action against M. tuberculosis, whereas OFLX at the same concentration had only a weak effect. AM-1155 (10 micrograms/ml) also inhibited the growth of M. intracellulare more effectively than OFLX.
Pharmacokinetics of 18F-labeled fluconazole in healthy human subjects by positron emission tomography
Authors: Fischman A J , Alpert N M , Livni E , Ray S , Sinclair I , Callahan R J , Correia J A , Webb D , Strauss H W , Rubin R H
Published: June 2012

The distribution of fluconazole in tissue of human volunteers was determined by positron emission tomographic scanning over a 2-h period following the infusion of a tracer dose of 18F-fluconazole (5 to 7 mCi) plus 400 mg of unlabeled drug (the standard daily dose of fluconazole). Previous studies have validated this approach for animals. From serial positron emission tomographic imaging and blood sampling, pharmacokinetics of fluconazole in tissue were determined. There was significant distribution of the radiolabeled drug in all organs studied, with nearly constant levels achieved by 1 h. Plateau concentrations of fluconazole in key organs (micrograms per gram) included the following: whole brain, 4.92 +/- 0.17; heart, 6.98 +/- 0.20; lung, 7.81 +/- 0.46; liver, 12.94 +/- 0.24; spleen, 22.96 +/- 2.5; kidney, 11.23 +/- 0.61; prostate, 8.24 +/- 0.58; and blood, 3.76 +/- 0.30. Since levels of fluconazole of > 6 micrograms/g are needed to treat infection with most strains of Candida and levels of > 10 micrograms/g are needed for Cryptococcus neoformans, Coccidioides immitis, and Histoplasma capsulatum, the following predictions can be made. The current standard dose of 400 mg/day should be more than adequate in the treatment of urinary tract and hepatosplenic candidiasis but problematic in the treatment of candidal osteomyelitis, even with the higher levels that develop after multiple doses. Similarly, higher doses should be considered, particularly in immunocompromised patients, with infection with C. neoformans, H. capsulatum, and C. immitis that involves the central nervous and musculoskeletal systems.
A novel dihydrofolate reductase cassette inserted in an integron borne on a Tn21-like element
Authors: Heikkilä E , Skurnik M , Sundström L , Huovinen P
Published: June 2012

In this study, a 498-bp dhfrXII gene coding for trimethoprim resistance was found inserted in a cassette-like manner in the recombinationally active locus, the integron, borne on a transposon Tn21-like element. The dhfrXII cassette is distinct from those cassettes earlier observed in integrons and was found here upstream of two similarly inserted cassettes. The second one carried the new unidentified orfF, which is 85% identical to the orfD cassette in R46. The third cassette contained the aadA2 gene mediating spectinomycin resistance. The plasmid carrying this Tn21-like element was originally isolated from a trimethoprim-resistant urinary tract pathogen, Escherichia coli, from Turku City Hospital, Turku, Finland. By colony hybridization and polymerase chain reaction, this group of three cassettes, including dhfrXII, was detected in four additional E. coli strains of similar origin and in four Shigella strains isolated in Finland but originating from Asia. The dihydrofolate reductase produced from dhfrXII showed an unusual drug resistance in that 50% of the enzymatic activity remained at a trimethoprim concentration of 1 mM.
Enhancement of drug susceptibility in Plasmodium falciparum in vitro and Plasmodium berghei in vivo by mixed-function oxidase inhibitors
Authors: Ndifor A M , Howells R E , Bray P G , Ngu J L , Ward S A
Published: June 2012

A number of compounds, as exemplified by verapamil and desipramine, have been shown to enhance the susceptibility of resistant malaria parasites to chloroquine. The mechanism by which these agents reverse resistance is still controversial but is though to involve alterations in drug transport causing an increase in steady-state drug concentrations. We have proposed that an alternative resistance mechanism may involve the metabolic deactivation of the drug in some resistant parasites via cytochrome P-450 mixed-function oxidases. If the hypothesis is true, it should be possible to alter drug susceptibility in malaria parasites by the use of agents known to inhibit or induce cytochrome P-450 activities. We have assessed the ability of known inhibitors of cytochrome P-450 enzymes (cimetidine, metyrapone, and alpha-naphthoflavone) to enhance chloroquine susceptibility in Plasmodium falciparum culture-adapted and wild-type isolates in vitro and P. berghei in vivo. In all three systems, the inhibitor cimetidine enhanced parasite susceptibility to chloroquine, and this increase in susceptibility was unrelated to changes in chloroquine steady-state concentrations in vitro or to alterations in host pharmacokinetics in vivo. Additionally, the cytochrome P-450 inducer phenobarbital produced slight decreases in P. falciparum drug susceptibility in vitro. We have compared the ability of the cytochrome P-450 inhibitors cimetidine and metyrapone to enhance drug susceptibility with that of verapamil by using wild-type malaria isolates obtained from Cameroon. Verapamil completely reversed resistance, i.e., to below the cutoff point of 70 nM, in all the resistant isolates. Cimetidine enhanced chloroquine susceptibility in 60% of the isolates and reduced 50% inhibitory concentrations by at least 43% in all the resistant isolates. The compounds tested had little or no effect on the 50% inhibitory concentrations for the susceptible isolates. The data support a possible role for detoxification in chloroquine resistance, and even in the absence of such a process we have observed apparent chemosensitization by agents whose common biological feature is the inhibition of cytochrome P-450 enzymes. Additionally, sensitization has been observed in wild-type isolates of P. falciparum obtained form immune residents of an area of endemicity as well as culture-adapted parasites.
Ganciclovir sensitivity of cytomegalovirus at diagnosis and during treatment of cytomegalovirus pneumonia in marrow transplant recipients
Authors: Slavin M A , Bindra R R , Gleaves C A , Pettinger M B , Bowden R A
Published: June 2012

Cytomegalovirus (CMV) often persists in the lungs of marrow transplant patients with CMV pneumonia, despite ganciclovir (GCV) treatment. To determine whether GCV resistance contributes to viral persistence, the susceptibilities of CMV isolates from diagnostic bronchoalveolar lavage samples and CMV isolates obtained during treatment or from autopsy lung tissue from 12 patients were compared by DNA hybridization. Resistance (50% effective dose, > 12 microM) was detected in an isolate from only one patient who had also received several courses of GCV. GCV resistance did not explain the persistence of CMV in the lung.
Pharmacokinetic interaction between rifampin and zidovudine
Authors: Burger D M , Meenhorst P L , Koks C H , Beijnen J H
Published: June 2012

A potential pharmacokinetic interaction between rifampin (Rimactan, Rifadin) and zidovudine (AZT, Retrovir) was investigated in the population of human immunodeficiency virus-infected patients at our hospital. The results from four patients who were on long-term (> or = 6 months) combination therapy with zidovudine and rifampin are presented. In all cases of combined use of zidovudine and rifampin, a lower area under the plasma concentration-time curve (AUC) and, consequently, a higher apparent clearance of zidovudine were found, compared with a reference population of zidovudine users. Patients had a low to normal maximum concentration of zidovudine in plasma. Elimination half-lives were normal in all but one patient. Zidovudine glucuronide concentrations were determined in three patients and three control subjects. The patients all had relatively higher peak plasma concentrations and higher AUCs of zidovudine glucuronide than the control subjects. In one patient, zidovudine and zidovudine glucuronide were also measured 2.5 months after discontinuation of rifampin. The AUC of zidovudine increased by a factor of 2. These data are in agreement with an enzyme-inducing effect of rifampin on the glucuronidation of zidovudine. They indicate that long-term combination therapy of rifampin and zidovudine leads to increased clearance of zidovudine, which may have therapeutic consequences.
Shedding of Clostridium difficile, fecal beta-lactamase activity, and gastrointestinal symptoms in 51 volunteers treated with oral cefixime
Authors: Chachaty E , Bourneix C , Renard S , Bonnay M , Andremont A
Published: June 2012

Microbial changes including the shedding of Clostridium difficile, fecal beta-lactamase activity, and gastrointestinal symptoms were assessed in 51 healthy volunteers given 200 mg of cefixime twice daily for 8 days. The number of organisms of the family Enterobacteriaceae (means +/- standard deviations) dropped from 6.9 +/- 1.1 to 3.9 +/- 1.8 log CFU/g of feces (P < 0.01), whereas counts of enterococci rose from 7.0 +/- 1.5 to 9.0 +/- 1.0 log CFU/g of feces (P < 0.01). Both counts returned to their initial levels 50 days after the cessation of treatment. Cefixime did not significantly modify the frequency of fecal excretion of Pseudomonas aeruginosa, Staphylococcus spp., yeasts, or members of the Enterobacteriaceae resistant to ceftazidime or ampicillin. The proportion of subjects shedding C. difficile rose from 6% before treatment to 57% (P < 0.01) at the end of treatment but returned to 8% 50 days thereafter. No case of pseudomembranous colitis was observed. Stool changes occurred in 13 volunteers during treatment (25%) and in 2 others more than 10 days after the end of treatment (4%). These changes were not significantly associated with the shedding of toxigenic strains of C. difficile or with the presence of toxin A in feces. By contrast, during treatment, stool changes occurred in 8 of the 18 volunteers (44%) who had antibiotic activity in their feces but in only 5 of the 33 (15%) for whom no such activity was found (P < 0.05). The absence of antibiotic activity in the feces was itself linked with the presence of beta-lactamase activity in the feces. Since we had found earlier that fecal beta-lactamase activity afforded protection against alteration in stool consistency during treatments with oral cephalosporins, the present study confirmed our previous preliminary results in this respect.
4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro
Authors: Woods J M , Bethell R C , Coates J A , Healy N , Hiscox S A , Pearson B A , Ryan D M , Ticehurst J , Tilling J , Walcott S M
Published: June 2012

The sialidase (neuraminidase) inhibitor 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-guanidino-Neu5Ac2en) has been examined for the ability to inhibit the growth of a wide range of influenza A and B viruses in vitro in comparison with amantadine, rimantadine, and ribavirin. 4-Guanidino-Neu5Ac2en inhibited plaque formation by laboratory-passaged strains of influenza A and B viruses, with 50% inhibitory concentrations ranging from 0.005 to 0.014 microM. A wider range of values (0.02 to 16 microM) was obtained with more recent clinical isolates, but in all cases 4-guanidino-Neu5Ac2en inhibited influenza A and B virus replication at lower concentrations than amantadine, rimantadine, or ribavirin. Inhibition by 4-guanidino-Neu5Ac2en was not obviously affected by the passage history of the viruses or by resistance to amantadine or rimantadine. 4-Guanidino-Neu5Ac2en was a very potent inhibitor of the sialidases of all the influenza viruses examined, with 50% inhibitory concentrations ranging from 0.00064 to 0.0079 microM. No cytotoxicity was observed with 4-guanidino-Neu5Ac2en at up to 10 mM. 4-Guanidino-Neu5Ac2en therefore represents a new potent and selective inhibitor of influenza A and B virus sialidase activity and replication in vitro.
Gentamicin administered during gestation alters glomerular basement membrane development
Authors: Smaoui H , Mallie J P , Schaeverbeke M , Robert A , Schaeverbeke J
Published: June 2012

Gentamicin during gestation alters glomerular basement membrane development. A drug-induced nephrotoxicity was described for neonates after gentamicin was given intraperitoneally to pregnant Wistar rats; glomerular alterations and changes in permselectivity were important. We investigated the ultrastructure of the glomerular basement membrane (GBM), the arrangement of anionic sites, and the urinary proteins at two ages, with 1-day- and 12-month-old control and prenatally exposed animals. For neonates, the pattern of glomerular differentiation was similar, anionic sites were made of heparan sulfate proteoglycans, and the GBM had the same total thickness in both groups. After transplacental gentamicin exposure, the lamina densa was larger; the laminae rarae were thinner; the density of anionic sites was increased; the levels of hydroxyproline, sulfate, and hexuronic acid in the kidney were increased; and the immunoelectrophoresis of urinary proteins was abnormal. For adults, prenatal exposure to gentamicin led to altered juxta-medullary glomeruli with a larger GBM and abundant anionic sites, especially in the lamina densa, and to a protein excretion different from that of controls. Thus, gentamicin administered during pregnancy leads to permanent alterations of the GBM with modifications of both the layers and the anionic sites, possibly because of a perturbed protein metabolism. These altered glomeruli are at risk during life and could be the starting point for a kidney disease.
Passage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges
Authors: Nau R , Prange H W , Muth P , Mahr G , Menck S , Kolenda H , Sörgel F
Published: June 2012

Cefotaxime and ceftriaxone have proven to be effective in pyogenic infections of the central nervous system. Since in some bacterial central nervous system infections the blood-cerebrospinal fluid (CSF) barrier is either minimally impaired or recovers in the course of the illness, we studied the penetration of both antibiotics in the absence of inflamed meninges. Patients who had undergone external ventriculostomies for noninflammatory occlusive hydrocephalus received either cefotaxime (2 g/30 min) or ceftriaxone (2 g/30 min) to treat extracerebral infections. Serum and CSF were drawn repeatedly after the first dose. With ceftriaxone, they were also drawn after the last dose. The concentrations of cefotaxime, its metabolite desacetylcefotaxime, and ceftriaxone were determined by high-performance liquid chromatography with UV detection. Maximum concentrations of cefotaxime in CSF were reached 0.5 to 8 h (median = 3 h; n = 6) after the end of the infusion and ranged from 0.14 to 1.81 mg/liter (median = 0.44 mg/liter; n = 6). Maximum levels of ceftriaxone in CSF ranging from 0.18 to 1.04 mg/liter (median = 0.43 mg/liter; n = 5) were seen 1 to 16 h (median = 12 h; n = 5) after the infusion. The elimination half-life of cefotaxime in CSF was 5.0 to 26.9 h (median = 9.3 h; n = 5), and that of ceftriaxone was 15.7 to 18.4 h (median = 16.8 h; n = 3). It is concluded that after a single dose of 2 g, maximal concentrations of cefotaxime and ceftriaxone in CSF do not differ substantially. The long elimination half-lives guarantee uniform concentrations in CSF. These concentrations reliably inhibit highly susceptible bacteria but cannot be relied on to inhibit staphylococci and penicillin G-resistant Streptococcus pneumoniae.
Use of cephalosporins for prophylaxis and therapy of polymicrobial infection in mice
Authors: Brook I
Published: June 2012

Cefoxitin, cefotetan, and cefmetazole were compared in 10-day therapy of intra-abdominal and subcutaneous infections caused by three organisms: Bacteroides fragilis and Bacteroides thetaiotaomicron combined with either Escherichia coli or Staphylococcus aureus. Intra-abdominal infection was caused by B. fragilis plus B. thetaiotaomicron plus E. coli. Therapy was initiated immediately before inoculation or was delayed for 8 h. Mortality was 14 of 30 (47%) for saline-treated mice, and all survivors developed abscesses. Immediate therapy reduced mortality and the percentage of mice with abscesses (in survivors), respectively, to 17 and 20% with cefoxitin, 0 and 13% with cefotetan, and 0 and 17% with cefmetazole, and the numbers of all bacteria were reduced by all the cephalosporins. Delayed therapy reduced mortality and abscess formation, respectively, to 20 and 8% of mice with cefoxitin, 10 and 93% with cefotetan, and 7 and 96% with cefmetazole. B. thetaiotaomicron survived in all abscesses treated with cefotetan and cefmetazole. Subcutaneous abscesses were caused by each organism alone or in combinations of one aerobe (S. aureus or E. coli) and one or two Bacteroides species. Early therapy reduced the numbers of all bacteria independent of their in vitro susceptibility. All agents reduced the number of each Bacteroides species with either E. coli or S. aureus. However, when therapy was delayed, cefotetan and cefmetazole were less effective than cefoxitin against B. thetaiotaomicron. Cefotetan was the most active agent against E. coli, and cefmetazole was the most effective against S. aureus. These data illustrate the efficacy of all tested cephalosporins in the prophylaxis of polymicrobial infections.
Ciprofloxacin susceptibility testing by MIC and disk elution of drug-resistant Mycobacterium tuberculosis and Mycobacterium avium complex
Authors: LaBombardi V J , Cataldo-Caputzal L
Published: June 2012

The ability to provide susceptibility data for certain species of mycobacteria can be clinically useful. In this study, the disk elution method for susceptibility testing was adapted for testing ciprofloxacin against mycobacterial isolates. Of the 75 Mycobacterium tuberculosis isolates tested, including 23 multiply drug-resistant isolates, 96% were susceptible to ciprofloxacin at a breakpoint concentration of 2 micrograms/ml.
Randomized trial comparing ceftriaxone with cefonicid for treatment of spontaneous bacterial peritonitis in cirrhotic patients
Authors: Gómez-Jiménez J , Ribera E , Gasser I , Artaza M A , Del Valle O , Pahissa A , Martínez-Vázquez J M
Published: June 2012

We compared cefonicid (2 g every 12 h) and ceftriaxone (2 g every 24 h) for their efficacy and safety in treating spontaneous bacterial peritonitis in cirrhotic patients in an open randomized clinical trial (30 patients in each group). Clinical, laboratory, and bacteriologic characteristics were similar in both groups. Ceftriaxone-susceptible strains were isolated on 44 occasions (94%), and cefonicid-susceptible strains were isolated on 43 occasions (91.5%). The antibiotic concentration in ascitic fluid/MIC ratio for ceftriaxone was > 100 throughout the dose interval (24 h), while it was lower for cefonicid (between 1 and 18). A total of 100% of patients treated with ceftriaxone, and 94% of those treated with cefonicid were cured of their infections (P was not significant). Hospitalization mortality was 37% in the cefonicid group and 30% in the ceftriaxone group (P was not significant). The time that elapsed between the initiation of treatment and the patient's death was shorter in the cefonicid group patients (5.3 +/- 3.90 days) than in the ceftriaxone group patients (11.8 +/- 9.15 days) (P < 0.05). None of the patients presented with superinfections, and only two patients treated with cefonicid and three patients treated with ceftriaxone developed colonizations with Enterococcus faecalis or Candida albicans. Ceftriaxone and cefonicid are safe and useful agents for treating cirrhotic spontaneous bacterial peritonitis, although the pharmacokinetic characteristics of ceftriaxone seem to be more advantageous than those of cefonicid.
Antimicrobial resistance in human oral and intestinal anaerobic microfloras
Authors: Stark C A , Edlund C , Sjöstedt S , Kristensen G , Nord C E
Published: June 2012

In the present study we determined the resistance patterns of anaerobic bacteria from human saliva and stool specimens and investigated whether there were significant differences in resistance between outpatients and hospitalized patients, regardless of whether they had received antimicrobial agents. No bacterial strains resistant to ampicillin, piperacillin, cefoxitin, cefuroxime, imipenem, clindamycin, doxycycline, chloramphenicol, or metronidazole were isolated from the saliva samples. However, resistance to ampicillin, cefoxitin, and cefuroxime was found in strains from 70% of the fecal samples (mainly Bacteroides thetaiotaomicron, Clostridium innocuum, and Bacteroides ovatus). Resistance to both ampicillin and cefuroxime was frequently found in 19% of the isolated strains (mainly B. thetaiotaomicron, B. ovatus, and Bacteroides vulgatus). No strains that were resistant to imipenem, chloramphenicol, or metronidazole were found. Hospitalization and/or intake of antimicrobial agents was associated with an increase in the relative number of resistant anaerobic intestinal bacteria. The percentage of resistant anaerobic strains encountered, compared with the total number of anaerobic bacteria in the normal fecal microflora, was between 5.2 and 14.8%, with the lower value associated with the outpatient group. Two-thirds of the resistant strains from this group had a relative frequency of less than 1% of the total anaerobic flora, while one-third of the strains were present at a level of greater than 1%; for the hospitalized patients, two-thirds of the strains were present at a level of greater than 1%, and one-third of the strains were present at a level of less than 1% (P < 0.001). Patients who had received antimicrobial agents for 6 days or more (n=20) had an average of 1.6 resistant anaerobic strains each, while patients treated for 3 to 5 days (n = 30) had a mean number of 0.87 resistant strains each ( P < 0.05).
Comparison of ciprofloxacin and ceftriaxone as single-dose therapy for uncomplicated gonorrhea in women
Authors: Hook E W , Jones R B , Martin D H , Bolan G A , Mroczkowski T F , Neumann T M , Haag J J , Echols R
Published: June 2012

Although women bear the brunt of gonococcal infection-related morbidity, few large studies of gonorrhea treatment in women have been conducted. In a multicenter, double-blind, placebo-controlled trial, 181 evaluable women with uncomplicated gonorrhea were treated with ciprofloxacin (250 mg orally; 94 women) or ceftriaxone (250 mg intramuscularly; 87 women). Twenty-four percent of the participants were infected with antibiotic-resistant Neisseria gonorrhoeae. Cervical gonorrhea was cured in 100% (93 of 93) of the women treated with ciprofloxacin and 99% (83 of 84) receiving ceftriaxone. All pharyngeal (n = 5) or rectal (n = 20) infections treated with ciprofloxacin were cured, as were ceftriaxone-treated patients with pharyngeal (n = 6) or rectal (n = 21) infection. Geometric mean MICs (range) for 248 pretreatment isolates were: penicillin, 0.28 (0.015 to 8.0); tetracycline, 0.46 (0.06 to 4); ciprofloxacin, 0.003 (0.002 to 0.015); and ceftriaxone, 0.004 (0.001 to 0.125) microgram/ml. Both drugs were well tolerated. Despite the high prevalence of antibiotic-resistant gonococci in these populations, 250 mg of oral ciprofloxacin was as effective as an injection of ceftriaxone.
In vivo effects of rufloxacin and ciprofloxacin on T-cell subsets and tumor necrosis factor production in mice infected with Bacteroides fragilis
Authors: Gollapudi S V , Chuah S K , Harvey T , Thadepalli H D , Thadepalli H
Published: June 2012

We investigated the in vivo effects of rufloxacin and ciprofloxacin on T-cell subsets and tumor necrosis factor production in mice infected with Bacteroides fragilis. These quinolones did not alter the helper/suppressor ratio but did modulate the kinetics of tumor necrosis factor production in infected animals. This result correlated with the observed therapeutic efficacies of the quinolones.
Susceptibilities of Mycoplasma hominis, Mycoplasma pneumoniae, and Ureaplasma urealyticum to a new quinolone, OPC 17116
Authors: Kenny G E , Cartwright F D
Published: June 2012

The susceptibilities of human mycoplasmas to OPC 17116 (Otsuka America Pharmaceutical, Inc., Rockville, Md.) and temafloxacin (Abbott Laboratories, Chicago, Ill.) were determined by the agar dilution method and were compared with those to sparfloxacin and ofloxacin. The MICs of OPC 17116 for 90% of Mycoplasma pneumoniae (0.25 microgram/ml) and Mycoplasma hominis (0.125 micrograms/ml) isolates tested were closely similar to those of sparfloxacin and were four- to eightfold greater than those of ofloxacin. Temafloxacin was two- to fourfold more active than ofloxacin. Ureaplasma urealyticum was less susceptible; the MICs of OPC 17116 and temafloxacin for 90% of isolates tested were 2 and 4.0 micrograms/ml, respectively.
Dose ranging and fractionation of intravenous ciprofloxacin against Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of infection
Authors: Marchbanks C R , McKiel J R , Gilbert D H , Robillard N J , Painter B , Zinner S H , Dudley M N
Published: June 2012

The effect of dose or dose interval on the pharmacodynamics of simulated high-dose intravenous ciprofloxacin therapy on infection due to Pseudomonas aeruginosa and Staphylococcus aureus was studied in an in vitro hollow-fiber model of infection. Simulated doses of 1,200 mg of ciprofloxacin per day as either 400 mg every 8 h or 600 mg every 12 h against P. aeruginosa resulted in selection of ciprofloxacin-resistant bacteria. The results with one test strain that was isolated from a patient prior to administration of intravenous ciprofloxacin demonstrated selection of a gyrA mutant in the model, as had occurred in vivo. A single 1,200-mg dose every 24 h did not select for bacterial resistance; however, breakthrough regrowth of ciprofloxacin-susceptible bacteria occurred. Dosages of 400 or 600 mg of ciprofloxacin every 12 h effectively reduced bacterial counts of one strain each of methicillin-susceptible or -resistant S. aureus, with no bacterial resistance detected at the end of experiment; in contrast, 200 mg every 12 h resulted in bacterial regrowth due to the selection of drug-resistant bacteria. These data show the need for high-dose intravenous ciprofloxacin, particularly with regimens producing high peak levels, for treatment of infections where selection for bacterial resistance is a clinical problem.
Penetration of foscarnet into cerebrospinal fluid of AIDS patients
Authors: Raffi F , Taburet A M , Ghaleh B , Huart A , Singlas E
Published: June 2012

The diffusion of foscarnet into cerebrospinal fluid (CSF) was studied in 27 patients with AIDS. Foscarnet was administered intravenously at various dosages at 12-h intervals. Concentrations in plasma and CSF at the end of foscarnet infusion or 1, 3, 5, 6, and 12 h after infusion were determined by high-performance liquid chromatography. Thirty-seven samples were obtained. The median concentration of foscarnet in CSF was 80 mumol/liter (range, 0 to 500 mumol/liter). The CSF foscarnet concentration was greater than the 50% inhibitory concentration for human immunodeficiency virus type 1 and was equal to or greater than the 50% inhibitory concentration for cytomegalovirus in most cases. The penetration of foscarnet into CSF, as expressed by the ratio of the concentration in CSF to the simultaneous concentration in plasma, ranged from 0 to 3.4 (median, 0.27) and was highly correlated with the presence of cells within CSF and the length of foscarnet therapy. Good diffusion of foscarnet in CSF allows evaluation of this drug in central nervous system cytomegalovirus and human immunodeficiency virus infections in patients with AIDS.
Alterations in pharmacokinetics and protein binding behavior of cefazolin in endotoxemic rats
Authors: Nadai M , Hasegawa T , Kato K , Wang L , Nabeshima T , Kato N
Published: June 2012

The possible alterations in the pharmacokinetics and protein binding behavior of the beta-lactam antibiotic cefazolin (CEZ) were investigated in endotoxemic rats induced by Klebsiella pneumoniae O3 lipopolysaccharide (LPS). LPS (250 micrograms/kg of body weight) was infused for 20 to 30 min 2 h before an intravenous administration of CEZ (20 mg/kg). Significant decreases in systemic clearance and renal clearance of CEZ were observed in LPS-treated rats without any changes in fraction of urinary excretion in unchanged CEZ (> 0.8). The volume of distribution at steady state showed a tendency to increase. The protein binding parameters of CEZ, the binding capacity, and number of binding sites on the albumin molecule were decreased by LPS, whereas the dissociation constant did not change. Significant decreases in systemic and renal clearances for unbound CEZ were observed in LPS-treated rats. The glomerular filtration rate estimated as inulin clearance was also decreased by LPS. The ratio of renal clearance of unbound CEZ to glomerular filtration rate (clearance ratio) dropped to 70% of that in control rats, and the net tubular secretion of CEZ was also dramatically reduced. The present study suggests that LPS has an effect on the pharmacokinetics of CEZ by changes which occur in renal handling and protein binding.
Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients
Authors: Wingard J R , Merz W G , Rinaldi M G , Miller C B , Karp J E , Saral R
Published: June 2012

Because the use of fluconazole prophylaxis had been associated with an increased rate of Candida krusei infections at The John Hopkins Oncology Center, early empiric amphotericin B plus flucytosine were given to febrile neutropenic patients colonized by C. krusei. By this practice, the proportion of fungemias attributable to C. krusei was low (12.5%) in patients receiving fluconazole over a 6-month interval. However, Torulopsis (Candida) glabrata assumed a much higher proportion of fungemias (75%) among patients receiving fluconazole. In vitro susceptibility testing combined with this clinical experience suggests that some T. glabrata isolates are not susceptible to fluconazole and can cause breakthrough infections in patients receiving fluconazole.