bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections
Authors: Benko A S , Cappelletty D M , Kruse J A , Rybak M J
Published: October 2018

The pharmacodynamics and pharmacokinetics of ceftazidime administered by continuous infusion and intermittent bolus over a 4-day period were compared. We conducted a prospective, randomized, crossover study of 12 critically ill patients with suspected gram-negative infections. The patients were randomized to receive ceftazidime either as a 2-g intravenous (i.v.) loading dose followed by a 3-g continuous infusion (CI) over 24 h or as 2 g i.v. every 8 h (q8h), each for 2 days. After 2 days, the patients were crossed over and received the opposite regimen. Each regimen also included tobramycin (4 to 7 mg/kg of body weight, given i.v. q24h). Eighteen blood samples were drawn on study days 2 and 4 to evaluate the pharmacokinetics of ceftazidime and its pharmacodynamics against a clinical isolate of Pseudomonas aeruginosa (R288). The patient demographics (means +/- standard deviations) were as follows: age, 57 +/- 12 years; sex, nine males and three females; APACHE II score, 15 +/- 3; diagnosis, 9 of 12 patients with pneumonia. The mean pharmacokinetic parameters for ceftazidime given as an intermittent bolus (IB) (means +/- standard deviations) were as follows: maximum concentration of drug in serum, 124.4 +/- 52.6 micrograms/ml; minimum concentration in serum, 25.0 +/- 17.5 micrograms/ml; elimination constant, 0.268 +/- 0.205 h-1; half-life, 3.48 +/- 1.61 h; and volume of distribution, 18.9 +/- 9.0 liters. The steady-state ceftazidime concentration for CI was 29.7 +/- 17.4 micrograms/ml, which was not significantly different from the targeted concentrations. The range of mean steady-state ceftazidime concentrations for the 12 patients was 10.6 to 62.4 micrograms/ml. Tobramycin peak concentrations ranged between 7 and 20 micrograms/ml. As expected, the area under the curve for the 2-g q8h regimen was larger than that for CI (P = 0.003). For IB and CI, the times that the serum drug concentration was greater than the MIC were 92 and 100%, respectively, for each regimen against the P. aeruginosa clinical isolate. The 24-h bactericidal titers in serum, at which the tobramycin concentrations were < 1.0 microgram/ml in all patients, were the same for CI and IB (1:4). In the presence of tobramycin, the area under the bactericidal titer-time curve (AUBC) was significantly greater for IB than CI (P = 0.001). After tobramycin was removed from the serum, no significant difference existed between the AUBCs for CI and IB. We conclude that CI of ceftazidime utilizing one-half the IB daily dose was equivalent to the IB treatment as judged by pharmacodynamic analysis of critically ill patients with suspected gram-negative infections. No evaluation comparing the clinical efficacies of these two dosage regimens was performed.
Identification of a class of sulfonamides highly active against dihydropteroate synthase form Toxoplasma gondii, Pneumocystis carinii, and Mycobacterium avium
Authors: Chio L C , Bolyard L A , Nasr M , Queener S F
Published: October 2018

Sulfanilanilides with 3',5'-halogen substitutions had Ki values 6- to 57-fold lower than the Ki of sulfamethoxazole when tested against dihydropteroate synthase from Toxoplasma gondii. The compounds acted as competitive inhibitors. These compounds were also active against dihydropteroate synthase from Pneumocystis carinii, Mycobacterium avium, and Escherichia coli but were not significantly more active than sulfamethoxazole. The compounds were significantly more active in culture than were standard agents. Against T. gondii in culture, 50% inhibitory concentrations were 7- to 30-fold lower than that of sulfadiazine; against P. carinii in culture, a concentration of 100 microM caused 33 to 95% inhibition of growth, compared with 9% inhibition with 100 microM sulfamethoxazole.
Penetration of cefetamet pivoxil and cefuroxime axetil into the maxillary sinus mucosa at steady state
Authors: Stoeckel K , Harell M , Dan M
Published: October 2018

The penetration of cefetamet and cefuroxime into the maxillary sinus mucosa after the administration of cefetamet pivoxil and cefuroxime axetil was investigated in patients undergoing elective surgery of the maxillary sinus. A total of 27 patients, 13 for cefetamet pivoxil and 14 for cefuroxime axetil, ranging from 15 to 70 years of age participated in this study. Each patient received three oral doses of either one tablet of cefetamet pivoxil (500 mg of GLOBOCEF) or two film tablets of cefuroxime axetil (125 and 250 mg of ZINAT) every 12 h. Sinus mucosa tissue samples were removed during surgery at times ranging from 2 to 4.5 h after the last oral administration. Blood samples were collected before drug administration, 2 h after the first and third doses, and concomitantly with tissue sample collection during surgery. All samples were analyzed by high-performance liquid chromatography. The concentrations of cefetamet and cefuroxime in plasma samples measured concomitantly with those in tissue samples ranged between 0.83 and 4.5 micrograms/ml for cefetamet and 0.59 and 3 micrograms/ml for cefuroxime. The mean tissue-to-plasma ratios calculated with reference to total (bound plus unbound) plasma drug concentrations were 0.60 (range, 0.52 to 0.77) for cefetamet (n = 4) and 0.38 (range, 0.28 to 0.44) for cefuroxime (n = 6). Both drugs seem to penetrate freely and easily into the sinus mucosa. The antibacterial activities of cefetamet pivoxil and cefuroxime axetil in cases of sinusitis therefore depend mainly on their achieved active plasma drug concentrations and their intrinsic activities in inhibiting the causative organism(s).
In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis
Authors: Kaatz G W , Seo S M
Published: October 2018

The new oxazolidinone antimicrobial agents U100592 and U100766 demonstrated good in vitro inhibitory activity against clinical strains of Staphylococcus aureus and Staphylococcus epidermidis regardless of methicillin susceptibility. Both agents appeared bacteriostatic by time-kill analysis. Stable resistance to low multiples of the MIC of either drug could be produced only in methicillin-resistant S. aureus.
Temporal variation in nephrotoxicity of low doses of isepamicin in rats
Authors: Yoshiyama Y , Grenier L , Gourde P , Simard M , Lin L , Morin N J , Bergeron M G , Labrecque G , Beauchamp D
Published: October 2018

The temporal variation in the nephrotoxicity of low doses of isepamicin was studied in male Sprague-Dawley rats treated with a single daily intraperitoneal injection of saline (NaCl, 0.9%) or isepamicin (80 mg/kg of body weight) at either 0800, 1400, 2000, or 0200 h for 4 and 10 days. On day 10, the cellular regeneration (incorporation of [3H] thymidine into DNA of renal cortex) and cortical accumulation of isepamicin were significantly higher in animals treated at 1400 h than at 0200 h (P < 0.01). Immunogold labeling studies showed that isepamicin was essentially localized in the lysosomes of proximal tubular cells in all treated groups, but the density of the gold particles over the lysosomes was higher in animals treated at 1400 than at 0200 h. The results of the present study show that the renal toxicity of isepamicin was maximal at 1400 h (midlight period) and minimal at 0200 h (middark period).
Roxithromycin alone and in combination with either ethambutol or levofloxacin for disseminated Mycobacterium avium infections in beige mice
Authors: Bermudez L E , Kolonoski P , Young L S
Published: October 2018

Roxithromycin alone reduced the level of bacteremia caused by Mycobacterium avium complex liver and splenic infection (in CFU per gram) of beige mice and mortality compared with untreated controls (P < 0.05). Roxithromycin plus ethambutol resulted in a significant reduction in the number of bacteria in splenic tissue compared with those in control splenic tissues of mice and mice treated with roxithromycin alone and ethambutol alone. Roxithromycin plus levofloxacin was not better than roxithromycin alone. Roxithromycin has in vivo activity against M. avium complex strains, and pilot studies with humans may be considered.
GyrB mutations in Staphylococcus aureus strains resistant to cyclothialidine, coumermycin, and novobiocin
Authors: Stieger M , Angehrn P , Wohlgensinger B , Gmünder H
Published: October 2018

The sequence of the gyrase B subunit gene from Staphylococcus aureus strains resistant to the gyrase B subunit inhibitors cyclothialidine, coumermycin, and novobiocin has been determined. The residues altered in the resistant gyrase B subunits map to the ATP-binding region, suggesting that the drugs inhibit ATP binding and hydrolysis. The pattern of cross-resistances indicates that the detailed binding mode of the compounds differs.
Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa
Authors: White R , Friedrich L , Burgess D , Warkentin D , Bosso J
Published: October 2018

MICs are commonly used to assess the in vitro activities of antimicrobial agents; however, they provide minimal information on the pattern of bacterial activities. Time-kill studies with extensive sampling allow assessment of both the rate and extent of bacterial killing and regrowth. We compared imipenem and meropenem by both MIC-MBC testing and a time-kill study with P. aeruginosa 27853. In the time-kill study, concentration/MIC ratios ranging from 0.0625 to 32 times the MIC were studied. The kill rate, time to 99.9% kill, doubling time of regrowth, and area under the bacterial killing curve (AUKC) were evaluated. Degradation during the testing procedure was accounted for by assessing actual drug exposure as determined by the area under the concentration-time curve. Pharmacodynamic parameters were compared by using the Wilcoxon signed-rank test. The modal MIC and MBC for imipenem were 2 and 4 micrograms/ml, respectively, and those for meropenem were 0.25 and 0.5 microgram/ml, respectively. In the time-kill study, both agents displayed concentration-dependent activity over a range of 0.25 to 4 times the MIC. Initial killing (0 to 1 h) was faster with imipenem at the same concentration/MIC ratios (P = 0.0506). The time to 99.9% kill was approximately 5 h for both agents. When regrowth occurred, the doubling rate for imipenem, which was the same as that for the growth control, was twice as rapid as that for meropenem. At the same concentrations, the AUKCs over 24 h were lower for meropenem than for imipenem (P = 0.0280); however, when normalized by MIC, imipenem resulted in smaller AUKCs. Comparison of plots of area under the concentration-time curve versus AUKC, which accounted for drug degradation and actual drug exposure, revealed that meropenem was three times more active than imipenem, rather than the eightfold difference suggested by MICs. Time-kill curves with extensive sampling and measurement of actual drug exposure, rather than traditional MIC testing, may more accurately assess differences in the in vitro activities of antimicrobial agents.
Levels of recombinant human granulocyte colony-stimulating factor in serum are inversely correlated with circulating neutrophil counts
Authors: Takatani H , Soda H , Fukuda M , Watanabe M , Kinoshita A , Nakamura T , Oka M
Published: October 2018

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is effective in countering chemotherapy-induced neutropenia. However, serum rhG-CSF levels cannot be maintained throughout the course of rhG-CSF therapy. The drop in serum rhG-CSF levels may vary with the duration of rhG-CSF administration or with the circulating neutrophil counts. We investigated the relationship between serum G-CSF levels and circulating neutrophil counts and the pharmacokinetics of rhG-CSF for patients with lung cancer who had been treated with myelosuppressive chemotherapy and then with subcutaneous rhG-CSF (lenograstim, 2 micrograms per kg of body weight per day). Twelve patients were randomly assigned to four groups with different rhG-CSF therapy schedules. Serum G-CSF levels were measured by an enzyme immunoassay method. Serum G-CSF levels during the rhG-CSF therapy greatly exceeded endogenous G-CSF levels and were mainly due to the presence of exogenous rhG-CSF rather than increased levels of endogenous G-CSF. Despite the duration of rhG-CSF administration, serum G-CSF levels during rhG-CSF therapy were inversely correlated with circulating neutrophil counts (r2 = 0.73, P < 0.0001). The value for the area under the concentration-time curve of rhG-CSF on the day of neutrophilia was lower than that on the day of neutropenia (P < 0.05). Our results suggest that the fall in serum G-CSF levels during rhG-CSF therapy may result from increased clearance and/or decreased absorption of rhG-CSF, two processes related to circulating neutrophil counts.
Interaction between ganciclovir and foscarnet as inhibitors of duck hepatitis B virus replication in vitro
Authors: Civitico G , Shaw T , Locarnini S
Published: October 2018

Safe and effective treatments for chronic hepatitis B virus (HBV) infection have yet to be developed. Both ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]guanine) and foscarnet (trisodium phosphonoformate hexahydrate) are potent inhibitors of hepadnavirus replication when used individually in vitro and in vivo. However, the clinical usefulness of each drug is reduced by dose-limiting toxicity, especially during long-term monotherapy. Here we demonstrate additive inhibition of duck HBV DNA replication in cultures of primary duck hepatocytes congenitally infected with duck HBV by combinations of ganciclovir and foscarnet at low, clinically achievable concentrations. These results suggest that the effects of ganciclovir and foscarnet against HBV may be additive in vivo.
Characterization of streptomycin resistance mechanisms among Mycobacterium tuberculosis isolates from patients in New York City
Authors: Cooksey R C , Morlock G P , McQueen A , Glickman S E , Crawford J T
Published: October 2018

From a collection of 367 isolates of Mycobacterium tuberculosis from patients in New York City in 1994, 45 isolates (12.3%) were resistant in vitro to 2 micrograms or more of streptomycin (SM) per ml. We further evaluated these isolates for levels of SM resistance and for mutations previously associated with resistance in the rpsL (S12 ribosomal protein) gene and the rrs (16S rRNA)-coding region. Twenty-four isolates, representing nine distinct patterns of susceptibility to antituberculosis drugs, were resistant to 500 micrograms of SM per ml and shared a common point mutation at nucleotide 128 in the rpsL gene. This mutation, which substitutes lysine for arginine in the S12 ribosomal binding protein, was not present in isolates with low-level SM resistance or in SM-susceptible control isolates. Among 20 isolates with low-level SM resistance, one possessed a substitution (C-->G865) in the 912 loop of the rrs gene. No mutations in the 530 loop of the rrs coding region were detected, suggesting the presence of an alternative SM resistance mechanism in 19 isolates. Single-strand conformation polymorphisms of mutants were readily detected by a nonradioactive gel screen.
In vitro activity of the tricyclic beta-lactam GV104326
Authors: Wise R , Andrews J M , Brenwald N
Published: October 2018

GV104326 is a novel tricyclic beta-lactam (a trinem or, formerly, tribactam). The in vitro activity of GV104326 was compared with those of cefuroxime, cefixime, amoxicillin, amoxicillin-clavulanic acid, cefpirome, and ciprofloxacin. GV104326 had in vitro activity generally similar to that of cefixime against members of the family Enterobacteriaceae (MIC at which 90% of the isolates are inhibited [MIC90], < or = 2 micrograms/ml), with cefuroxime and amoxicillin-clavulanic acid being 8- to 32-fold less active and with cefpirome being 4- to 8-fold more active against members of this family. The trinem had no activity against Pseudomonas aeruginosa or Stenotrophomonas maltophilia (MIC90, > 128 micrograms/ml) but was the most active agent against Acinetobacter calcoaceticus. GV104326 was particularly active against gram-positive cocci. Ninety percent of methicillin-susceptible Staphylococcus aureus strains were susceptible to 0.03 microgram of GV104326 per ml, making it the most active agent studied. Enterococci and Lancefield group A and B streptococci were generally equally or somewhat more susceptible to GV104326 than they were to amoxicillin. Streptococcus pneumoniae strains were highly susceptible to GV104326, and those strains which showed decreased susceptibility to penicillin were generally twofold more susceptible to the trinem than to amoxicillin. Haemophilus influenzae and Moraxella catarrhalis were highly susceptible to GV104326 (MIC90s, 0.12 and 0.03 microgram/ml, respectively). The anaerobes Clostridium perfringens, Bacteroides fragilis, and Peptostreptococcus spp. were more susceptible to the trinems (formerly tribactams) than to the other agents studied.
Comparative kinetic analyses of interaction of inhibitors with Rauscher murine leukemia virus and human immunodeficiency virus reverse transcriptases
Authors: Cherrington J M , Fuller M D , Mulato A S , Allen S J , Kunder S C , Ussery M A , Lesnikowski Z , Schinazi R F , Sommadossi J P , Chen M S
Published: October 2018

The inhibitory effects of several nucleoside triphosphate analogs on Rauscher murine leukemia virus (RMuLV) and human immunodeficiency virus (HIV) type 1 reverse transcriptases (RTs) were studied. With RNA as the template, the apparent K(m) and apparent K(i) values of HIV RT toward its substrates and inhibitors are 12 to 500 times lower than the corresponding values for RMuLV RT. However, the k(i)/k(m) ratios (inhibition efficiencies) for HIV and RMuLV RTs'are similar for AZTTP (zidovudine triphosphate), d4TTP [3'-deoxythymidine-2'-ene-(3'-deoxy-2',3'-didehydrothymidine) triphosphate], PMEADP [9-(2-phosphonylmethoxyethyl)adenine diphosphate], FIAUTP [1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodouracil triphosphate], and HPMPCDP [(S)-1-(3-hydroxy-2-phosphylmethoxypropyl) cytosine diphosphate]. With DNA as the template, the K(m) values are similar for HIV and RMuLV RTs. However, the K(i)/K(m) values of HIV and RMuLV RTs are significantly different for ddCTP, ddATP, and 3TCTP (2',3'-dideoxy-3'-thiacytidine). The RTs of RMuLV and HIV are sufficiently different from one another that the kinetic inhibition constants for a particular antiviral compounds should be determined to indicate whether anti-RMuLV activity is likely to be predictive for the anti-HIV activity of the compound. This information, in conjunction with species-specific drug metabolism differences and tissue culture antiviral activity, is important in determining the suitability of a particular animal model.
Concentrations of ceftriaxone (1,000 milligrams intravenously) in abdominal tissues during open prostatectomy
Authors: Martin C , Viviand X , Cottin A , Savelli V , Brousse C , Ragni E , Richaud C , Mallet M N
Published: October 2018

Ceftriaxone concentrations in abdominal tissues were evaluated at different stages of open prostatectomy. Ceftriaxone was administered as antibiotic prophylaxis, and 15 consecutive patients were given a single dose of ceftriaxone (1,000 mg intravenously in 1 min) 30 min before surgery. Ceftriaxone concentrations in tissue were determined at three stages of the surgical procedure; upon the opening of the abdominal cavity, during the prostatectomy, and upon the closure of the abdominal cavity. Samples of the following tissues or sample were assayed: epiploic and abdominal-wall fat; Retzius' space, bladder, and prostate tissue; and urine. During the different stages of the surgical procedure, for all patients, and in the different tested tissues, ceftriaxone concentrations greater than or equal to the cutoff point (4 micrograms/g of tissue) were measured. The highest concentrations were obtained in the bladder (43 +/- 18 micrograms/g) and in the prostate (35 +/- 18 micrograms/g). In fatty tissues, concentrations were between 13 +/- 5 and 22 +/- 8 micrograms/g. All patients (15 of 15) had ceftriaxone levels in tissue greater than the MICs for the potential pathogens (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis). In conclusion, during open prostatectomy and after the use of a single dose of ceftriaxone (1,000 mg), high antibiotic levels were obtained throughout the surgical procedure in the tissues potentially involved in postoperative infection.
Variation in fluconazole efficacy for Candida albicans strains sequentially isolated from oral cavities of patients with AIDS in an experimental murine candidiasis model
Authors: Barchiesi F , Najvar L K , Luther M F , Scalise G , Rinaldi M G , Graybill J R
Published: October 2018

Four strains of Candida albicans, isolated from two patients with AIDS who had undergone prolonged fluconazole therapy for oral candidiasis, were studied in a model of disseminated murine candidiasis. Pre- and posttreatment isolates from each patient were genetically related, and the fluconazole MICs for the strains had increased significantly, from 0.25 to 32 micrograms/ml for the strains isolated from patient 1 and from 1.0 to 16 micrograms/ml for the strains isolated from patient 2. Mice were infected intravenously and were treated orally with fluconazole. For survival studies, mice were treated from day 1 to day 10 postinfection and were observed through day 30. The fluconazole dosages were as follows: 0.25, 0.5, 1.0, and 5.0 mg/kg of body weight twice a day. For tissue burden studies, two groups of mice (each group received fluconazole at 0.25 or 5.0 mg/kg) were treated from day 1 to day 7 and were sacrificed 1 day later for quantitative tissue cultures of the spleen and both kidneys. For pretreatment isolates from both patients, all fluconazole dosing regimens were effective at prolonging survival compared with the survival of the control groups. For posttreatment isolates, only fluconazole at 5.0 mg/kg was effective at prolonging survival. Both fluconazole dosing regimens used in the tissue burden studies significantly reduced the counts of the pretreatment isolate from patient 1 in the spleen and kidney, while fluconazole at 5.0 mg/kg was effective at reducing the counts of the posttreatment isolate. For both isolates from patient 2, only fluconazole at 5.0 mg/kg was effective at reducing the counts in the spleen and kidney. The study indicates that C. albicans mutation to resistance to fluconazole may play a critical role in fluconazole-refractory oral candidiasis in AIDS patients.
Rifapentine is active in vitro and in vivo against Toxoplasma gondii
Authors: Araujo F G , Khan A A , Remington J S
Published: October 2018

Rifapentine, a derivative of rifamycin, was examined for its in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. The drug inhibited the intracellular replication of parasites and was not cytotoxic for the host cells at inhibitory concentrations. Mice infected either intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain were protected against death by treatment with rifapentine. The degree of protection was similar to that induced by atovaquone and apparently higher than that induced by rifabutin. Rifapentine may be a useful drug for the treatment of toxoplasmosis in immunocompromised individuals.
Indole and (E)-2-hexenal, phytochemical potentiators of polymyxins against Pseudomonas aeruginosa and Escherichia coli
Authors: Kubo A , Lunde C S , Kubo I
Published: October 2018

Combinations of polymyxins and phytochemicals were tested for antimicrobial activity against two gram-negative bacteria. Various degrees of potentiation were found against Pseudomonas aeruginosa and Escherichia coli with (E)-2-hexenal and indole. Three-compound combinations were found to further increase the activity of polymyxin B sulfate and colistin methanesulfonate against both bacteria. Combinations with colistin against P. aeruginosa resulted in the highest degree of potentiation, with a 512-fold increase in colistin antimicrobial activity. These results indicate the potential efficacy of phytochemical combinations with antibiotics to enhance total biological activity.
Radioimmunoassay for quantitation of 2',3'-didehydro-3'-deoxythymidine (D4T) in human plasma
Authors: Zhou X J , Chakboub H , Ferrua B , Moravek J , Guedj R , Sommadossi J P
Published: October 2018

2',3'-Didehydro-3'-deoxythymidine (D4T, or stavudine) has been recently approved for the treatment of AIDS. In the present study, a specific and sensitive radioimmunoassay (RIA) was developed for the quantitation of D4T in human plasma. The RIA is a double-antibody competitive binding assay which uses anti-D4T antiserum raised in rabbits as the primary antibody, a tritiated derivative of D4T as the radioactive tracer, and goat anti-rabbit immunoglobulin G as the secondary antibody. No cross-reaction between D4T and various nucleoside analogs was detected. The limit of quantitation of the method approximated 20 ng/ml. Replicate analyses of quality control samples (40 to 3,500 ng/ml) had satisfactory intra- and interassay precision (coefficient of variation, 1.7 to 16.7%) and accuracy (deviation, -9.5 to +21.0). This newly developed RIA was successfully used in the monitoring of plasma drug levels in healthy volunteers receiving an oral dose of D4T.
Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin
Authors: Brouqui P , Badiaga S , Raoult D
Published: October 2018

Despite appropriate antibiotic treatment, Lyme disease patients may have relapses or may develop chronic manifestations. The intracellular location of Borrelia burgdorferi suggests that antibiotics that penetrate cells will have greater efficiency. Doxycycline or erythromycin was more effective than penicillin or ceftriaxone in killing B. burgdorferi when the organism was grown in the presence of eucaryotic cells.
Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients
Authors: Davey R T , Chaitt D G , Reed G F , Freimuth W W , Herpin B R , Metcalf J A , Eastman P S , Falloon J , Kovacs J A , Polis M A , Walker R E , Masur H , Boyle J , Coleman S , Cox S R , Wathen L , Daenzer C L , Lane H C
Published: October 2018

Delavirdine mesylate (DLV) is a potent nonnucleoside reverse transcriptase inhibitor with activity specific for human immunodeficiency virus type 1. In the present phase I/II study we evaluated the safety, toxicity, pharmacokinetics, and antiretroviral activities of two-drug and three-drug combinations of DLV and conventional doses of nucleoside analogs compared with those of both DLV monotherapy and two-drug nucleoside analog therapy. A total of 85 human immunodeficiency virus type 1 infected patients with CD4 counts of 100 to 300 cells per mm3 were enrolled in two periods: in the first period patients were randomized to receive either zidovudine (ZDV) plus didanosine (group 1) or ZDV plus didanosine plus escalating doses (400 to 1,200 mg/day) of DLV (group 2). In the second period, patients were randomized to receive either 1,200 mg of DLV alone per day (group 3) or ZDV plus 1,200 mg of DLV per day (group 4). DLV demonstrated good oral bioavailability at all five doses tested. The major toxicity was a transient mild rash which appeared in 44% of all DLV recipients. Overall, group 2 patients demonstrated more sustained improvements in CD4 counts, percent CD4 cells, branched DNA levels, p24 antigen levels, and virus titers in plasma than group 1, 3, or 4 patients. The magnitude of the response correlated with the intensity of prior nucleoside analog treatment, the non-syncytium-inducing or syncytium-inducing viral phenotype at baseline, and the presence of a wild-type codon at amino acid position 215 in the baseline reverse transcriptase genotype. Despite a transient rash, DLV therapy was well tolerated. Combination therapy with DLV and nucleoside analogs appears promising, with the three-drug combination appearing to be more potent that either two-drug combinations or monotherapy.
Distribution of systemically administered ampicillin, benzylpenicillin, and flucloxacillin in excisional wounds in diabetic and normal rats and effects of local topical vasodilator treatment
Authors: Cross S E , Thompson M J , Roberts M S
Published: October 2018

The present study assessed the suitability of the streptozotocin-treated diabetic rat as a model for the study of diabetes-impaired wound healing. The distribution of three antibiotics, ampicillin, benzylpenicillin, and flucloxacillin, in wound and adjacent tissue sites on the abdomens and legs of normal and diabetic rats was determined 30 min after intravenous administration of a single bolus containing 50 mg of all three antibiotics per kg of body weight. Tissue/plasma ratios showed that antibiotic tissue penetration appeared to be related to protein binding. The treatment of wound sites with vasodilators (1% solution) to increase local blood flow and antibiotic delivery to the site was then determined and appeared to be more effective with endothelium-independent sodium nitroprusside than with endothelium-dependent acetylcholine in diabetic rats. These results suggest that coadministration of topical vasodilators to wound sites in neuropathic diabetic patients undergoing antibiotic therapy for infected ulcers could increase antibiotic delivery to wound tissue sites.
Effect of combination therapy with ciprofloxacin and clarithromycin on theophylline pharmacokinetics in healthy volunteers
Authors: Gillum J G , Israel D S , Scott R B , Climo M W , Polk R E
Published: October 2018

Five adults completed this four-way randomized crossover study to compare the effects of oral treatment with ciprofloxacin, clarithromycin, and a combination of the two drugs on theophylline pharmacokinetics. The area under the concentration-time curve for theophylline during combination therapy was not different from that for ciprofloxacin alone. Beta error may explain this finding, but any real effect from combination treatment appears to be clinically unimportant.
Early bactericidal activity of rifabutin versus that of placebo in treatment of disseminated Mycobacterium avium complex bacteremia in AIDS patients
Authors: Dautzenberg B , Castellani P , Pellegrin J L , Vittecoq D , Truffot-Pernot C , Pirotta N , Sassella D
Published: October 2018

Rifabutin, 600 mg/day, was compared with a placebo in the early treatment of culture-proven Mycobacterium avium bacteremia in patients with AIDS. Following 14 days' treatment, bacteriological success, defined as a negative culture or a reduction in the number of CFU of M. avium organisms per milliliter of blood by a factor of > or = 0.5 log from the baseline, was observed in 7 of 10 (70%) evaluable rifabutin patients and in 1 of 13 (8%) evaluable placebo patients (P = 0.002). Rifabutin is active against M. avium as a single agent and can make a significant contribution to combination regimens for the treatment of disseminated M. avium infection in AIDS patients.
Novel method for assessing postantibiotic effect by using the Coulter counter
Authors: Li R C , Lee S W , Lam J S
Published: October 2018

To study postantibiotic effect, viable counts are routinely acquired by the pour plate technique. However, this technique is laborious and time-consuming; the required sample dilutions also cause excessive errors and material wastage. A new total cell counting technique in which a Coulter counter is used to obtain more efficient postantibiotic effect measurements has been developed.
Group of peptides that act synergistically with hydrophobic antibiotics against gram-negative enteric bacteria
Authors: Vaara M , Porro M
Published: October 2018

A synthetic peptide, KFFKFFKFFK [corrected], consisting of cationic lysine residues and hydrophobic phenylalanine residues was found to sensitize gram-negative bacteria to hydrophobic and amphipathic antibiotics. At a concentration of 3 micrograms/ml, it decreased the MIC of rifampin for smooth, encapsulated Escherichia coli by a factor of 300. Other susceptible bacterial species included Enterobacter cloacae, Klebsiella pneumoniae, and Salmonella typhimurium, but Pseudomonas aeruginosa was resistant. Similar results were obtained with another synthetic peptide, IKFLKFLKFLK [corrected]. The fractional inhibitory concentration indices for the synergism of these peptides with rifampin, erythromycin, fusidic acid, and novobiocin were very close to those determined for the previously characterized potent outer-membrane-disorganizing agents polymyxin B nonapeptide and deacylpolymyxin B. KFFKFFKFFK [corrected] had direct activity against the gram-positive organism Micrococcus strain ML36, was strongly hemolytic, and was as active on polymyxin-resistant E. coli mutants as on their parent. These three attributes made KFFKFFKFFK [corrected] different from polymyxin derivatives and similar to cationic detergents, such as cetylpyridinium chloride. However, whereas the MIC of cetylpyridinium chloride for E. coli is low (0.5 to 4 micrograms/ml), that of KFFKFFKFFK [corrected] is much higher (30 to 100 micrograms/ml). Other groups of synthetic peptides studied included polymyxin-like peptides with an intrachain disulfide bridge. Their synergism with antibiotics was less marked. Still other peptides, including KEKEKEKEKE and KKKKKKFLFL, lacked any synergism with the probe antibiotics.
In vitro activities of azithromycin and doxycycline against 15 isolates of Chlamydia pneumoniae
Authors: Gnarpe J , Eriksson K , Gnarpe H
Published: October 2018

Fourteen isolates of Chlamydia pneumoniae, 12 from clinically ill patients and 2 from subjectively healthy individuals from an area within a 400-km proximity of Gävle, Sweden, and strain IOL-207, originally from the eye of an Iranian child, were tested for susceptibilities to the antibiotics doxycycline and azithromycin. MICs and minimum chlamydiacidal concentrations were found to correlate well with values reported earlier by other investigators. In addition to MIC and minimum chlamydiacidal concentration testing, testing for the viability of C. pneumoniae after exposure to antibiotic concentrations as high as 50 mg/liter was carried out by passaging antibiotic-treated, infected cell cultures four times in the absence of antibiotics. It was found that all Chlamydia strains were viable after four passages, regardless of antibiotic concentration in the cell culture.
4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum
Authors: Ridley R G , Hofheinz W , Matile H , Jaquet C , Dorn A , Masciadri R , Jolidon S , Richter W F , Guenzi A , Girometta M A , Urwyler H , Huber W , Thaithong S , Peters W
Published: October 2018

We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.
Development and evaluation of a Bayesian pharmacokinetic estimator and optimal, sparse sampling strategies for ceftazidime
Authors: Kashuba A D , Ballow C H , Forrest A
Published: October 2018

Data were gathered during an activity-controlled trial in which seriously ill, elderly patients were randomized to receive intravenous ceftazidime or ciprofloxacin and for which adaptive feedback control of drug concentrations in plasma and activity profiles was prospectively performed. The adaptive feedback control algorithm for ceftazidime used an initial population model, a maximum a posteriori (MAP)-Bayesian pharmacokinetic parameter value estimator, and an optimal, sparse sampling strategy for ceftazidime that had been derived from data in the literature obtained from volunteers. Iterative two-stage population pharmacokinetic analysis was performed to develop an unbiased MAP-Bayesian estimator and updated optimal, sparse sampling strategies. The final median values of the population parameters were follows: the volume of distribution of the central compartment was equal to 0.249 liter/kg, the volume of distribution of the peripheral compartment was equal to 0.173 liter/kg, the distributional clearance between the central and peripheral compartments was equal to 0.2251 liter/h/kg, the slope of the total clearance (CL) versus the creatinine clearance (CLCR) was equal to 0.000736 liter/h/kg of CL/1 ml/min/1.73 m2 of CLCR, and nonrenal clearance was equal to + 0.00527 liter/h/kg. Optimal sampling times were dependent on CLCR; for CLCR of > or = 30 ml/min/1.73 m2, the optimal sampling times were 0.583, 3.0, 7.0, and 16.0 h and, for CLCR of < 30 ml/min/1.73 m2, optimal sampling times were 0.583, 4.15, 11.5, and 24.0 h. The study demonstrates that because pharmacokinetic information from volunteers may often not be reflective of specialty populations such as critically ill elderly individuals, iterative two-stage population pharmacokinetic analysis, MAP-Bayesian parameter estimation, and optimal, sparse sampling strategy can be important tools in characterizing their pharmacokinetics.
Quinolone resistance mutations in topoisomerase IV: relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus
Authors: Ng E Y , Trucksis M , Hooper D C
Published: October 2018

Mutations in the flqA (formerly ofx/cfx) resistance locus of Staphylococcus aureus were previously shown to be common after first-step selections for resistance to ciprofloxacin and ofloxacin and to map on the S. aureus chromosome distinctly from gyrA, gyrB, and norA.grlA and grlB, the genes for the topoisomerase IV of S. aureus, were identified from a genomic lambda library on a common KpnI fragment, and grlB hybridized specifically with the chromosomal SmaI A fragment, which contains the flqA locus. Amplification of grlA sequences (codons 1 to 251) by PCRs from nine independent single-step flqA mutants, one multistep mutant, and the parent strain identified mutations encoding a change from Ser to Phe at position 80 in four mutants, a novel change from Ala to either Glu or Pro at position 116 in three mutants, and no change in three mutants. In the multistep mutant, another resistance locus, flqC, was mapped by transformation to the chromosomal SmaI G fragment by linkage to omega(ch::Tn551)1051 (58%) and nov (97.9%), which encodes resistance to novobiocin. This fragment contains the gyrA gene, and flqC mutants had a mutation in gyrA encoding a change from Ser to Leu at position 84, a change previously found in resistant clinical isolates. In genetic outcrosses, the flqC (gyrA) mutation expressed resistance only in flqA mutants, including those with both types of grla mutations. The silent mutant allele of gyrA was present in a flqA background and expressed resistance only upon introduction of a grlA mutation. At fourfold the MIC of ciprofloxacin, the bactericidal activity of ciprofloxacin was reduced in a grlA mutant and was abolished in gyrA grlA double mutants. These findings provide direct genetic evidence that topoisomerase IV is the primary target of current fluoroquinolones in S. aureus and that this effect may result from the greater sensitivity of topoisomerase IV relative to that of DNA gyrase to these agents. Furthermore, resistance from an altered DNA gyrase requires resistant topoisomerase IV for its expression.
Comparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci
Authors: Ednie L M , Visalli M A , Jacobs M R , Appelbaum P C
Published: October 2018

Activities of clarithromycin, erythromycin, and azithromycin against 120 pneumococci from the United States were tested by agar dilution MIC. All three compounds yielded MICs at which 90% of the isolates were inhibited (MIC90S) of < or = 0.125 micrograms/ml against penicillin-susceptible and -intermediate strains, but MIC90S against resistant strains were > 128.0 micrograms/ml. All erythromycin-resistant strains were also resistant to clarithromycin and azithromycin. Clarithromycin yielded MICs which were generally one or two dilutions lower than those of the other two compounds for all strains. The respective bacteriostatic and bactericidal values (micrograms per milliliter) for two susceptible, two intermediate, and two resistant strains were 0.004 to 0.03 and 0.016 to 0.03 (0.004 to 0.03/0.016 to 0.03) (clarithromycin), 0.008 to 0.06/0.016/0.016 to 0.125 (erythromycin), and 0.016 to 0.06/0.03 to 0.125 (azithromycin); clarithromycin yielded the lowest values. All compounds were uniformly bactericidal after 24 h only; erythromycin was bactericidal at eight times the MIC, and azithromycin and clarithromycin were both bactericidal at two time the MIC. The relevance of these in vitro differences requires clarification by clinical trials.
Molecular aspects of high-level resistance to sulbactam-cefoperazone in Klebsiella oxytoca clinical isolates
Authors: Kimura K , Arakawa Y , Ohsuka S , Ito H , Suzuki K , Kurokawa H , Kato N , Ohta M
Published: October 2018

Nine Klebsiella oxytoca strains which demonstrated resistance to the combination of sulbactam and cefoperazone were isolated from geographically separate hospitals in Japan in 1995. Among them, K. oxytoca SB23 showed high-level resistance to sulbactam-cefoperazone (MIC > 128 micrograms/ml) and aztreonam (MIC, 128 micrograms/ml). The sulbactam-cefoperazone resistance was not transferred from strain SB23 to Escherichia coli CSH2 by conjugation, beta-Lactamase RbiA, produced by strain SB23, was purified, and the molecular mass was estimated to be 29 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Kinetic parameters for RbiA revealed that cefoperazone and aztreonam were hydrolyzed efficiently by this enzyme. Moreover, ceftazidime and imipenem were also hydrolyzed weakly by RbiA, although strain SB23 did not show any resistance to these agents. Clavulanate, sulbactam, and tazobactam failed to block the hydrolysis of cefoperazone by RbiA. The structural gene of RbiA (blaRBI) was cloned and sequenced, and the deduced amino acid sequence of RbiA demonstrated high-level similarities to those of the beta-lactamases found in K. oxytoca D488, E23004, and plasmid-mediated MEN-1, which have been classified into Bush functional group 2be. Although RbiA demonstrates high-level molecular similarity to the enzymes in group 2be, from an enzymological point of view, this enzyme might be differentiated from the enzymes in that group. Hybridization analysis revealed that beta-lactamase genes highly similar to blaRBI were generally encoded on the chromosome of the sulbactam-cefoperazone-resistant clinical isolates of K. oxytoca tested in the study, despite their different derivations. This observation suggests that sulbactam-cefoperazone-resistant A. oxytoca strains which produce RbiA-type beta-lactamases have been proliferating in many hospitals in Japan.
Bacterial biofilms and the bioelectric effect
Authors: Wellman N , Fortun S M , McLeod B R
Published: October 2018

Bacterial biofilms are acknowledged to be a major factor in problems of ineffective sterilization often encountered in clinics, hospitals, and industrial processes. There have been indications that the addition of a relatively small direct current electric field with the sterilant used to combat the biofilm greatly increases the efficacy of the sterilization process. The results of the experiments reported in this paper support the concept of the "bioelectric effect" as reported by J.W. Costerton, B. Ellis, K. Lam, F. Johnson, and A.E. Khoury (Antimicrob. Agents Chemother, 38:2803-2809, 1994). With a current of 1 mA flowing through the chamber containing the biofilm, an increase in the killing of the bacteria of about 8 log orders was observed at the end of 24 h (compared with the control with the same amount of antibacterial agent but no current). We also confirmed that the current alone does not affect the biofilm and that there appear to be optimum levels of both the current and the sterilant that are needed to obtain the maximum effect.
Native oligodeoxynucleotides specifically active against human immunodeficiency virus type 1 in vitro: a G-quartet-driven effect?
Authors: Tondelli L , Colonna F P , Garbesi A , Zanella S , Marongiu M E , Corrias S , Loi A G , La Colla P
Published: October 2018

Among a series of unmodified phosphodiester (PO)-oligodeoxynucleotides (PO-ODNs) complementary to some of the human immunodeficiency virus type 1 (HIV-1) regulatory genes, several PO-ODN sequences complementary to the vpr gene (PO-ODNs-a-vpr, where a-vpr is the antisense vpr sequence) emerged as potent inhibitors (at concentrations of 0.8 to 3.3 microM) of HIV-1 multiplication in de novo infected MT-4 cells, while they showed no cytotoxicity for uninfected cells at concentrations up to 100 microM. Unlike phosphorothioate counterparts, PO-ODN-a-vpr sequences were not inhibitory to HIV-2 multiplication in de novo infected C8166 cells and neither prevented the fusion between chronically infected and bystander CD4+ cells nor inhibited the activity of the HIV-1 reverse transcriptase in enzyme assays. Moreover, they were not inhibitory to HIV-1 multiplication in chronically infected cells. Delayed addition experiments showed that PO-ODNs-a-vpr inhibit an event in the HIV-1 replication cycle following adsorption to the host cell, but preceding reverse transcription. Structure-activity relationship studies indicated that the antiviral activity of the test PO-ODN-a-vpr sequences is not related to an antisense mechanism but to the presence, within the active sequences, of contiguous guanine residues. Physical characterization of the test PO-ODNs suggested that the active structure is a tetramer stabilized by G quartets (i.e., four G residues connected by eight hydrogen bonds).