bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis
Authors: Hughes W T , Gray V L , Gutteridge W E , Latter V S , Pudney M
Published: June 2012

The efficacy of a new class of drugs for Pneumocystis carinii pneumonitis was demonstrated. 566C80, a hydroxynaphthoquinone, administered orally in a dose of greater than or equal to 100 mg/kg of body weight per day prophylactically prevented P. carinii pneumonitis in 90% or more of rats, while all untreated control animals developed pneumonitis. When 566C80 (100 mg/kg per day) was administered for 3 weeks after P. carinii pneumonitis was established, therapy was totally effective and all of the untreated controls had progressive P. carinii pneumonitis. A dose of 566C80 of between 25 and 50 mg/kg per day protected 50% of the rats from P. carinii pneumonitis, and a dose of between 50 and 100 mg/kg per day cured 50% of those treated for P. carinii pneumonitis. Both prophylaxis and treatment with 566C80 were at least as effective as with trimethoprim-sulfamethoxazole. Animals maintained on immunosuppression after completion of treatment remained free of P. carinii, suggesting a killing effect. Clearance of P. carinii was associated with levels of 60 micrograms or more of 566C80 per ml of plasma. This hydroxynaphthoquinone offers promise as an anti-P. carinii drug.
Mechanism of resistance to vancomycin in Enterococcus faecium D366 and Enterococcus faecalis A256
Authors: al-Obeid S , Collatz E , Gutmann L
Published: June 2012

The role of the glycopeptide-inducible proteins of Enterococcus faecium D366 (39.5 kilodaltons) and Enterococcus faecalis A256 (39 kilodaltons) in the mechanism of resistance to vancomycin and teicoplanin was examined. Crude cell walls from noninduced cells or from induced cells treated with sodium dodecyl sulfate to remove the inducible proteins were shown to bind vancomycin, in contrast to cell walls containing the cytoplasmic membrane-associated induced proteins, which did not bind vancomycin. Cytoplasmic membranes from vancomycin-induced cells did not inactivate (bind) vancomycin or teicoplanin, but they could protect the glycopeptides from being bound to the synthetic pentapeptide. This protection could be competitively abolished by D-alanyl-D-alanine. A decrease in glycopeptide binding to the pentapeptide was observed in a time-dependent fashion after treatment of the pentapeptide with the cytoplasmic membranes from induced cells. We hypothesize that the inducible proteins are responsible for glycopeptide resistance due to the binding to, and subsequent enzymatic modification of, the pentapeptide precursor of peptidoglycan, which is considered to be the natural target of glycopeptides.
Tolerance and efficacy of parenterally administered penicillin-streptomycin and orally administered amoxicillin or penicillin V for prophylaxis of experimentally induced streptococcal endocarditis
Authors: Pujadas R , Escriva E , Jane J , Argimon J , Fernandez F , Fava P , Galera M , Garau J
Published: June 2012

A regimen of a single intramuscular dose of penicillin G-streptomycin was compared with regimens of three oral doses of amoxicillin and two oral doses of penicillin V to prevent Streptococcus sanguis endocarditis in rabbits with experimentally induced valvular heart lesions. Challenge doses of 10(4), 10(6), and 10(8) CFU of a strain of S. sanguis highly tolerant to penicillin and amoxicillin were used. The combination of penicillin and streptomycin was the only regimen tested that provided full protection even against the highest inoculum concentration. A single oral dose of penicillin V (36 mg/kg) or amoxicillin (50 mg/kg), two oral doses of penicillin V (36 and 18 mg/kg with a 7-h interval between doses), or six oral doses of amoxicillin (50 mg/kg followed by 8.5 mg/kg at 8-h intervals) protected recipients of the lowest inoculum concentration; protection diminished with increasing inocula. In contrast, administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses provided full protection against challenge doses of 10(4) and 10(6) CFU, preventing endocarditis in 10 (66%) of 15 recipients of 10(8) CFU. All regimens evaluated were highly effective in preventing endocarditis when rabbits were challenged with 10(4) CFU. The combination of penicillin and streptomycin was the best regimen tested. Administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses led to significantly fewer infections when compared with the other oral regimens when rabbits were challenged with 10(6) and 10(8) CFU.
Application of mathematical model to experimental chemotherapy of fatal murine pneumonia
Authors: Hishikawa T , Kusunoki T , Tsuchiya K , Uzuka Y , Sakamoto T , Nagatake T , Matsumoto K
Published: June 2012

Two beta-lactam antibiotics, cefazolin and cefmenoxime, were administered in an experimental model of murine pneumonia caused by Klebsiella pneumoniae in a way which enabled us to approximate the serum antibiotic concentration time course in humans. Bacterial counts during the experiments were subjected to nonlinear least-squares analyses by using a mathematical model that explained the bacterial killing by the antibiotic concentration time course and other factors associated with antimicrobial potency and bacterial growth. Cefazolin gave a killing curve that changed synchronously with the drug levels in serum; in contrast, cefmenoxime gave a curve that was prolonged as compared with the change in the drug levels in serum. Multiple correlation coefficients were about 0.9, and the model worked well for bacterial count data. Parameters relating to antimicrobial potency of the drugs, bacterial growth rate, and drug distribution into the tissue were estimated numerically.
Enhanced phagocytosis of encapsulated Escherichia coli strains after exposure to sub-MICs of antibiotics is correlated to changes of the bacterial cell surface
Authors: Raponi G , Keller N , Overbeek B P , Rozenberg-Arska M , van Kessel K P , Verhoef J
Published: June 2012

The influence of five antibiotics (netilmicin, ceftriaxone, cefepime, fleroxacin, and ciprofloxacin) on capsular polysaccharide distribution and on opsonophagocytosis by human polymorphonuclear leukocytes of unencapsulated and encapsulated Escherichia coli strains was studied. Unencapsulated E. coli strains were readily opsonized in serum and easily ingested by polymorphonuclear leukocytes, and antibiotics did not further enhance the phagocytosis rates. In contrast, encapsulated bacteria were poorly opsonized in human serum, and phagocytosis was enhanced after overnight exposure to 0.5x the MICs of the antibiotics, with the exception of cefepime. Incubation of unencapsulated as well as encapsulated bacteria in complement-inactivated serum markedly reduced the bacterial uptake by polymorphonuclear leukocytes regardless of the presence of antibiotics. Slide agglutination assays, performed either with a monoclonal antibody for capsular polysaccharide or with an antiserum raised against the stable unencapsulated mutant E. coli O7:K-, showed reduction but not lack of the capsular polysaccharide of encapsulated E. coli O7:K1, and better exposure of subcapsular epitopes, after incubation with 0.5x the MICs of antibiotics. Flow cytometric analysis of encapsulated E. coli exposed to netilmicin, ciprofloxacin, and fleroxacin revealed that the reduction in capsular material was homogeneous among the bacterial population. Treatment with cefepime and ceftriaxone induced two populations of bacteria that differed in the amount of K antigen present. These results indicate that sub-MICs of netilmicin, ceftriaxone, fleroxacin, and ciprofloxacin influenced complement-mediated opsonization, probably due to changes in the capsular polysaccharide structure.
Identification of a group of Haemophilus influenzae penicillin-binding proteins that may have complementary physiological roles
Authors: Malouin F , Parr T R , Bryan L E
Published: June 2012

[35S]penicillin bound to different Haemophilus influenzae proteins in assays performed at 20, 37, or 42 degrees C. Penicillin-binding proteins 3a, 3b, 4, and 4' formed a group characterized by their affinity for moxalactam, cefotaxime, and piperacillin. Penicillin-binding protein 4' showed specific properties that may reflect its complementary role in septation.
In vitro activities of tosufloxacin, temafloxacin, and A-56620 against pathogens of diarrhea
Authors: Bryan J P , Waters C , Sheffield J , Krieg R E , Perine P L , Wagner K
Published: June 2012

Tosufloxacin (A-60969 HCl), a new quinolone with broad activity against gram-positive and anaerobic organisms, was compared in vitro with other quinolones against bacterial pathogens of diarrhea. Tosufloxacin was the most active agent against Salmonella spp., Shigella spp., Campylobacter spp., Aeromonas hydrophila, and Vibrio spp. Temafloxacin (A-62254) also demonstrated good activity against these organisms.
Disposition of roxithromycin in patients with normal and severely impaired renal function
Authors: Halstenson C E , Opsahl J A , Schwenk M H , Kovarik J M , Puri S K , Ho I , Matzke G R
Published: June 2012

The disposition of roxithromycin, an investigational macrolide antibiotic, was evaluated in 20 subjects, 10 with normal renal function (creatinine clearance [CLCR] of 116 +/- 17 ml/min [mean +/- standard deviation]) and 10 with severely impaired renal function (CLCR of 10.2 +/- 2.6 ml/min) after a single 300-mg oral dose. Plasma concentration-time data were analyzed in terms of a one- or two-compartment oral absorption model utilizing nonlinear regression analysis. The terminal elimination half-life was significantly prolonged in the group with severely impaired renal function (15.5 +/- 4.7 h) compared with that of the group with normal renal function (7.9 +/- 2.5 h). Apparent total body clearance was significantly reduced in the renally impaired (25.3 +/- 10.5 ml/min) in relation to the group with normal renal function (48.8 +/- 11.1 ml/min). The first-order absorption rate constants and apparent volumes of distribution did not differ between the two groups. These data indicate that the disposition of roxithromycin is significantly delayed in subjects with CLCRs of less than 15 ml/min and suggest that the roxithromycin dosing interval be doubled for these patients.
Multiple-dose pharmacokinetics of oral zidovudine in hemophilia patients with human immunodeficiency virus infection
Authors: Morse G D , Portmore A , Olson J , Taylor C , Plank C , Reichman R C
Published: June 2012

The disposition of zidovudine (ZDV) was examined during chronic oral dosing (300 mg every 4 h while awake) for 12 weeks in eight asymptomatic patients with hemophilia who were infected with the human immunodeficiency virus. Pharmacokinetic studies were conducted at the initiation of drug administration and after 6 and 12 weeks. Baseline liver function tests indicated normal values for bilirubin, albumin, and prothrombin time, while hepatic enzyme levels ranged from one to three times the normal levels. Initially, the mean peak ZDV concentration in plasma was 2,052 ng/ml with a range of 1,033 to 3,907 ng/ml, while during chronic dosing the peaks were 1,619 +/- 1,062 ng/ml and 1,711 +/- 786 ng/ml at weeks 6 and 12, respectively. ZDV concentrations at 4 h declined to 77 +/- 53 ng/ml, 110 +/- 43 ng/ml, and 101 +/- 49 ng/ml at weeks 1, 6, and 12, respectively. Initially, the plasma concentration-versus-time decay in three patients was linear, with a mean half-life (t1/2) of 1.3 +/- 0.5 h, while five patients had detectable concentrations in plasma after 4 h with an apparent delayed terminal-phase t1/2 of 4.8 +/- 2.8 h. At week 6 the prolonged elimination pattern was noted in all patients (terminal t1/2 = 4.1 +/- 2.0 h). No correlation between hepatic enzyme levels and t1/2 was noted. These findings suggest that ZDV may display a prolonged elimination phase during multiple dosing. Further studies utilizing a more sensitive assay may help to further define this later phase of ZDV elimination.
Use of extracts versus whole-cell bacterial suspensions in the identification of Staphylococcus aureus beta-lactamase variants
Authors: Kernodle D S , McGraw P A , Stratton C W , Kaiser A B
Published: June 2012

We previously have shown that extracts of S. aureus isolates which produce the recognized serotypes of staphylococcal beta-lactamase (A, B, C, D) differ in the rates at which they hydrolyze selected cephalosporins, exhibiting substrate profiles which are distinctive for each serotype. In an effort to simplify the methods employed in identifying the different staphylococcal beta-lactamases, we evaluated whether distinctive substrate profiles could be obtained by using whole-cell suspensions of 115 beta-lactamase-producing isolates of S. aureus. Compared with extracts from the same strains, the whole-cell bacterial suspensions not only were simpler to prepare but enabled beta-lactamase typing of a higher proportion of the evaluated strains (86 versus 97%, respectively). Furthermore, the use of whole-cell bacterial suspensions enabled the simultaneous quantitation of the beta-lactamase activity exhibited by each strain. Additionally, by comparing the quantitative activity of beta-lactamase-induced and -uninduced preparations of the same strain, induction ratios (i.e., induced/uninduced activity) could be derived, yielding information regarding the regulation of beta-lactamase production by each strain. We believe that the utilization of whole-cell methods, such as those employed in this study, will facilitate the investigation of qualitative and quantitative differences in beta-lactamase production among clinical and reference isolates of S. aureus.
Comparative activities of newer beta-lactam agents against members of the Bacteroides fragilis group
Authors: Cuchural G J , Tally F P , Jacobus N V , Cleary T , Finegold S M , Hill G , Iannini P , O'Keefe J P , Pierson C
Published: June 2012

A nationwide susceptibility survey of 557 isolates of the Bacteroides fragilis group was continued in 1986. The most active beta-lactam drugs were imipenem and ticarcillin-clavulanic acid, which had 0.2 and 1.7% resistance, respectively. The rank order of activity of beta-lactam drugs was imipenem, ticarcillin-clavulanic acid, cefoxitin, piperacillin, moxalactam, ceftizoxime, cefotetan, cefotaxime, cefoperazone, and ceftazadime.
Cross resistance to ciprofloxacin and other antimicrobial agents among clinical isolates of Acinetobacter calcoaceticus biovar anitratus
Authors: Shalit I , Dan M , Gutman R , Gorea A , Berger S A
Published: June 2012

Using an agar dilution assay, for 66 of 104 (63.5%) clinical isolates of Acinetobacter calcoaceticus biovar anitratus, the MIC of ciprofloxacin was greater than or equal to 1.0 micrograms/ml. Cross resistance was demonstrable to ciprofloxacin and gentamicin (P less than 0.001), amikacin (P less than 0.01), cefotaxime (P less than 0.001), azlocillin (P less than 0.001), ceftazidime (P less than 0.001), trimethoprim-sulfamethoxazole (P less than 0.001), and minocycline (P less than 0.05). The mean MIC of ciprofloxacin for drug-susceptible isolates was consistently lower than that for resistant isolates; however, these differences were significant only for amikacin (P = 0.036).
In vitro and in vivo activities of Sch 39304, fluconazole, and amphotericin B against Histoplasma capsulatum
Authors: Kobayashi G S , Travis S J , Rinaldi M G , Medoff G
Published: June 2012

The antifungal activities of amphotericin B and two triazoles, Sch 39304 and fluconazole, were tested against Histoplasma capsulatum. In this study Sch 39304 compared favorably with amphotericin B in treating histoplasmosis in normal and leukopenic mice, whereas fluconazole was much less active. The differences in the efficacies of the triazoles appeared to be due to differences in their pharmacokinetics and the dosage schedule that was used. For amphotericin B there was a good correlation between in vitro and in vivo efficacy, but this was not true of the triazole derivatives. These results further demonstrate that, with the methods used in this study, in vitro susceptibility testing of triazoles may not be predictive of in vivo activity against isolates of H. capsulatum.
Penicillin-binding protein 3 of Listeria monocytogenes as the primary lethal target for beta-lactams
Authors: Vicente M F , Pérez-Dáz J C , Baquero F , Angel de Pedro M , Berenguer J
Published: June 2012

Penicillin-binding proteins (PBPs) of Listeria monocytogenes were detected by their ability to bind to [2,3-3H]benzylpenicillin. Five proteins with Mrs of 95,000, 84,000, 80,000, 76,000, and 49,000 were detected. PBPs 1 to 4 had a high affinity for [2,3-3H]benzylpenicillin and were relatively scarce (80 to 150 molecules per cell). In contrast, PBP 5 was more abundant (600 molecules per cell) but had a low affinity for [2,3-3H]benzylpenicillin. L. monocytogenes has a relatively high natural resistance to cephalosporins. Competition experiments showed that cephalosporins bound very poorly to PBP 3 but were good inhibitors of PBPs 1, 2, and 4, which were completely blocked at concentrations well below the MIC. Analysis of a spontaneous imipenem-resistant mutant revealed that resistance was likely due to an altered PBP 3 with a reduced affinity for [2,3-3H]benzylpenicillin. These results suggest that PBP 3 is a primary lethal target for beta-lactams in L. monocytogenes.
Role of penicillinase plasmids in the stability of the mecA gene in methicillin-resistant Staphylococcus aureus
Authors: Hiramatsu K , Suzuki E , Takayama H , Katayama Y , Yokota T
Published: June 2012

The stability of methicillin resistance (Mcr) in three independent clinical isolates, MR108, MR6, and MR61, of methicillin-resistant Staphylococcus aureus (MRSA) was studied. The Mcr phenotype was stably maintained in the progeny of all three MRSA clones carrying penicillinase plasmids. However, when the clones were tested after elimination of the plasmids, methicillin-susceptible (Mcs) subclones appeared at various frequencies. Seven Mcs subclones were classified into two groups based on their stabilities. Five Mcs subclones, which were derived from homogeneous strains MR108 and MR61, were stably susceptible. They lost penicillin-binding protein 2' production, and moreover, the mecA gene was deleted in four of five subclones. Two subclones were derived from heterogeneous strain MR6. They were very unstable, and more than half of their progeny were Mcr revertants. However, the remainder were stably Mcs and had lost penicillin-binding protein 2' and the mecA gene. We propose that penicillinase plasmids, which are present in most MRSA strains, play an important role in the stability and phenotypic expression of the mecA gene.
Determination of optimal dosage regimen for amikacin in healthy volunteers by study of pharmacokinetics and bactericidal activity
Authors: Garraffo R , Drugeon H B , Dellamonica P , Bernard E , Lapalus P
Published: June 2012

The pharmacokinetics and serum killing curves of amikacin, which was administered by a 30-minute intravenous infusion of single doses of 7.5 mg/kg and then 15 mg/kg, were investigated in six healthy volunteers who received the two doses in a crossover study with a washout period of 20 days. The serum killing curves were determined for four bacterial species: Escherichia coli, Serratia marcescens, Enterobacter cloacae, and Pseudomonas aeruginosa. All strains were serum resistant, and the bactericidal activity was analyzed by separating the early phase (first 5 h) and the late phase (24 h) of the killing curve. For the early phase, the bactericidal activity was evaluated by correlating an index of surviving bacteria with amikacin concentrations. This methodology allowed determination of two parameters: the maximal effective concentration and the lowest effective concentration. For the late phase, the threshold values separating bacteriostatic and bactericidal activities were lower than 10 mg/liter for each strain. The concentration dependence of amikacin bactericidal activity was confirmed for Escherichia coli and Enterobacter cloacae and, to a lesser extent, for Serratia marcescens and Pseudomonas aeruginosa. Correlation of these data with amikacin pharmacokinetic data in volunteers indicated that a daily dose of 15 mg/kg may be effective in the treatment of Escherichia coli and Enterobacter cloacae infections. For Pseudomonas aeruginosa and Serratia marcescens, the partially time-dependent activity probably necessitates two daily administrations and combination with another antibiotic.
The dhfrI trimethoprim resistance gene of Tn7 can be found at specific sites in other genetic surroundings
Authors: Sundström L , Sköld O
Published: June 2012

The dhfrI gene, mediating high-level trimethoprim resistance, was earlier found only on Tn7. Evidence is given here for an alternative location of this gene at a site identical to sites observed earlier for dhfrII on plasmid R388, dhfrV on pLMO20, and aadA on Tn21. All these genes and dhfrI are precisely inserted as discrete GTTA-flanked elements at distinct loci in very conserved surrounding sequences. One of these dhfrI insertions was observed to occur in association with a similarly inserted aadA nucleotidyltransferase gene, which mediates streptomycin and spectinomycin resistance. Close to the insertion site, there is an open reading frame translating into a 337-amino-acid peptide which shows striking similarities to recombinases of the integrase family, sulI, the sulfonamide resistance gene, is very often found close to the insertion point forming a genetic surrounding, originally observed as a part of Tn21-like transposons. The alleged integration mechanism thus provides a recombination pathway for the genetic linkage of sulfonamide and other antibiotic resistance genes, including the most frequently encountered gene for trimethoprim resistance, dhfrI. Furthermore, the newly observed location of dhfrI could shed light on the evolution of the antibiotic resistance region of Tn7, which could be able to take up genes by the same mechanism as that of Tn21-like transposons.
Randomized, double-blind trial of cefonicid and nafcillin in the treatment of skin and skin structure infections
Authors: Daly J S , Worthington M G , Andrews R J , Brown R B , Schwartz R , Sexton D J
Published: June 2012

We compared treatment with one daily intravenous dose of cefonicid and multidose nafcillin in 65 patients with severe infections of the skin or skin structure. Clinical cure or improvement was achieved in 91% of the patients given cefonicid and in 87% of the patients given nafcillin (P = 0.97). The use of cefonicid may allow outpatient therapy of some severe infections.
Exposure of health care workers to ribavirin during therapy for respiratory syncytial virus infections
Authors: Bradley J S , Connor J D , Compogiannis L S , Eiger L L
Published: June 2012

Health care workers (HCW) are exposed to ribavirin aerosol during therapy of infants with respiratory syncytial virus infections. To assess the degree of HCW exposure, we analyzed air samples from patient rooms and HCW personal breathing zones during ribavirin aerosol delivery by ventilator (two samples), oxygen hood (two samples), and a new vacuum exhaust hood (four samples). HCW exposure to ribavirin during aerosol delivery by ventilator or vacuum exhaust hood system was substantially lower than HCW exposure during aerosol delivery by oxygen hood in rooms with adequate ventilation.
Susceptibilities of species of the Bacteroides fragilis group to 10 antimicrobial agents
Authors: Betriu C , Campos E , Cabronero C , Rodriguez-Avial C , Picazo J J
Published: June 2012

A total of 94 clinical isolates of the Bacteroides fragilis group was tested for susceptibility to metronidazole, chloramphenicol, clindamycin, cefoxitin, cefotetan, cefmetazole, moxalactam, mezlocillin, amoxicillin-clavulanic acid, and imipenem. All the strains tested were susceptible to imipenem, metronidazole, amoxicillin-clavulanic acid, and chloramphenicol. The rate of resistance to clindamycin was 21%. The results of this study demonstrate a difference in resistance rates from one species of the B. fragilis group to another.
Different doses of cefetamet pivoxil (Ro 15-8075) in the treatment of acute uncomplicated gonococcal urethritis in men
Authors: Tio T T , Sindhunata I R , Wagenvoort J H , Michel M F , Stolz E
Published: June 2012

In an open, dose-finding study, a 100% cure rate was observed in patients suffering from uncomplicated gonococcal urethritis who were treated with a single oral dose of either 1.2 g (n = 10), 0.8 g (n = 11), or 0.4 g (n = 10) of cefetamet pivoxil. The MICs of cefetamet for all gonococcal strains ranged from 0.001 to 0.12 micrograms/ml, and the MIC for 90% of the strains tested was 0.008 micrograms/ml. Cefetamet pivoxil was ineffective against Chlamydia trachomatis in 3 of 31 patients. Side effects were minor.
Diffusion of beta-lactam antibiotics through liposome membranes reconstituted from purified porins of the outer membrane of Pseudomonas aeruginosa
Authors: Satake S , Yoshihara E , Nakae T
Published: June 2012

Determination of the rates of diffusion of beta-lactam antibiotics through purified Pseudomonas aeruginosa porins C, D2, and E in liposomes yielded the following results. (i) The rates of carbapenem (imipenem and meropenem) diffusion through the protein D2 pore were roughly 2 to 70 times higher than those through other porin pores. It is not clear why the protein D2 pore allowed rapid diffusion of carbapenems. The rates of diffusion of glucosamine and triglycine through the protein D2 pore were about 14 and 4 times higher, respectively, than that of an uncharged test solute with a similar Mr, glucose. (ii) The rates of diffusion of antipseudomonal anionic beta-lactams such as piperacillin, ceftazidime, cefsulodin, and aztreonam through the protein C pore were higher than those through other porin pores. This was probably due to the slightly larger pore size and the slight anion selectivity of protein C, since the apparent exclusion limit of the protein C pore for uncharged saccharides is higher than that of other porins and the rate of diffusion of gluconic acid through the protein C pore is about double that for glucose. (iii) The rates of diffusion of cefoperazone through all three species of porin were relatively high. These results indicate that the antipseudomonal beta-lactams permeate the P. aeruginosa outer membrane via newly identified porins.
Evaluation of piperacillin-tazobactam in experimental meningitis caused by a beta-lactamase-producing strain of K1-positive Escherichia coli
Authors: Kern W , Kennedy S L , Sachdeva M , Sande E R , Gunderson D , Täuber M G
Published: June 2012

We evaluated the pharmacokinetics and therapeutic efficacy of piperacillin combined with tazobactam, a novel beta-lactamase inhibitor, in experimental meningitis due to a beta-lactamase-producing strain of K1-positive Escherichia coli. Different doses of piperacillin and tazobactam, as single agents and combined (8:1 ratio; dosage range, 40/5 to 200/25 mg/kg per h), and of ceftriaxone were given to experimentally infected rabbits by intravenous bolus injection followed by a 5-h constant infusion. The mean (+/- standard deviation) rates for penetration into the cerebrospinal fluid of infected animals after coadministration of both drugs were 16.6 +/- 8.4% for piperacillin and 32.5 +/- 12.6% for tazobactam. Compared with either agent alone, combination treatment resulted in significantly better bactericidal activity in the cerebrospinal fluid. The bactericidal activity of piperacillin-tazobactam was dose dependent: cerebrospinal fluid bacterial titers were reduced by 0.37 +/- 0.19 log10 CFU/ml per h with the lowest dose versus 0.96 +/- 0.25 log10 CFU/ml per h with the highest dose (P less than 0.001). At the relatively high doses of 160/20 and 200/25 mg of piperacillin-tazobactam per kg per h, the bactericidal activity of the combination was comparable to that of 10 and 25 mg of ceftriaxone per kg per h, respectively.
Patterns and mechanisms of beta-lactam resistance among isolates of Escherichia coli from hospitals in the United States
Authors: Cooksey R , Swenson J , Clark N , Gay E , Thornsberry C
Published: June 2012

To study the national distribution of beta-lactam resistance patterns and mechanisms among Escherichia coli organisms isolated in U.S. hospitals, 652 ampicillin-resistant (Am(r)) or ampicillin-intermediate (Ami) isolates were submitted to the Centers for Disease Control from March 1983 through July 1984 by nine hospitals participating in the National Nosocomial Infections Study. Among the isolates (most of which caused urinary tract infections), 78% were Am(r) and 22% were Ami by the interpretative criteria established by the National Committee for Clinical Laboratory Standards. Resistance to carboxypenicillins ranged from 73 to 74%, and that to acylureidopenicillins ranged from 43 to 66%. A total of 26% of the isolates were resistant to cephalothin, and 4% were resistant to cefazolin. Resistance to cefoxitin was 1%, while resistances to cefuroxime and cefamandole were 2 and 7%, respectively. With the exception of cefsulodin (98% resistant) and cefoperazone (1% resistant), there was no resistance to newer cephalosporins or aztreonam. In general, only minor differences in the incidence of resistance to beta-lactam antibiotics were noted in hospital-acquired versus non-hospital-acquired isolates as well as among isolates from various regions of the United States. TEM beta-lactamases were produced by 87% of the 237 Am(r) isolates examined. By our methods, OXA and chromosomal (type I) beta-lactamases were detected in 2 and 28 isolates, respectively, and plasmid-mediated extended-spectrum cephalosporinases were detected in none of the isolates. Disk substrate and clavulanic acid inhibition assays revealed that TEM beta-lactamase conferred Am(r) and resistance to carboxypenicillins, acylureidopenicillins, cephalothin, cefamandole, cefsulodin, and cefoperazone. A total of 391 isolates were screened for plasmids, and 259 isolates were examined by DNA hybridization with a TEM probe. Among 462 plasmids probed, 129 plasmids, ranging from 4 to 140 megadaltons, harbored TEM sequences. Although beta-lactam resistance in clinical isolates of E. coli is predominantly mediated by TEM beta-lactamase, the diverse spectrum of resistance appears to be related to additional strain=dependent factors.
Theophylline dosage adjustment during enoxacin coadministration
Authors: Koup J R , Toothaker R D , Posvar E , Sedman A J , Colburn W A
Published: June 2012

Based on the results of a previous study which demonstrated a 50% reduction in theophylline clearance during coadministration of 400 mg of enoxacin twice a day (b.i.d.), a sequential-design study was completed with seven nonsmoking, healthy adult female human volunteers. The subjects were given 200 mg of theophylline (Theo-Dur) orally every 12 h for 4 days. On day 5, the subjects began receiving 400 mg of enoxacin with each theophylline dose, and the dosage of theophylline was reduced to 100 mg b.i.d. This regimen was continued through day 8, after which enoxacin was discontinued. The theophylline dosage was increased to 200 mg b.i.d. on day 9, and theophylline monotherapy continued through day 12. The mean apparent theophylline clearance decreased by approximately 50% during enoxacin coadministration. No significant differences in mean theophylline maximum concentration in serum, time to maximum concentration in serum, lowest concentration observed, or area under the concentration-time curve during the steady-state dosing were observed before, during, or after enoxacin coadministration when the theophylline dosage was reduced to 100 mg b.i.d. Reduction of the theophylline dose by 50% at the onset of enoxacin dosing maintained constant theophylline concentrations in plasma. A return to the original theophylline dose immediately upon cessation of enoxacin therapy resulted in a transient 35% increase in theophylline concentrations in plasma which lasted 24 to 48 h before returning to preenoxacin values. Although a 50% reduction in the theophylline dose maintained constant mean theophylline concentrations when enoxacin was administered concomitantly, it appears that larger dose reductions (up to 75%) could be required in patients with high theophylline clearances. In addition, larger transient increases in the theophylline concentration in plasma may be observed in these patients upon cessation of enoxacin therapy if the theophylline dose is immediately returned to normal. Thus, it is recommended that theophylline concentrations in plasma be monitored when concurrent enoxacin therapy is required.
Inhibition of herpes simplex virus type 2 growth by phosphorothioate oligodeoxynucleotides
Authors: Gao W Y , Hanes R N , Vazquez-Padua M A , Stein C A , Cohen J S , Cheng Y C
Published: June 2012

Phosphorothioate homo-oligodeoxynucleotides were found to be potent inhibitors of herpes simplex virus type 2 (HSV-2) but less potent for HSV-1 in cell culture studies. Oligomers with longer chain lengths were more active against HSV-2 than those with shorter ones. Of all the compounds examined, the 28-mer phosphorothioate homo-oligodeoxynucleotides were the strongest inhibitors of HSV-2. The degree of inhibition was related to the base moiety on the order of deoxycytidine = thymidine greater than deoxyadenosine. The inhibition of HSV-2 growth by S-dC28 was dose dependent with a 90% inhibitory dose of 1 microM. At 50 microM, S-dC28 inhibited HeLa S3 cell growth by less than 10%. The anti-HSV-2 activity was time and schedule dependent. The oligomer was most inhibitory to viral growth when present during the 1-h viral adsorption period, and this effect could be enhanced by continuous drug exposure after the adsorption period. S-dC28 was also an effective inhibitor of two HSV-2 drug-resistant mutants: a phosphonoformate-resistant mutant that induces an altered DNA polymerase and a 9-(1,3-dihydroxy-2-propoxymethyl)guanine-resistant mutant that does not induce the viral thymidine kinase. In drug combination studies, phosphonoformate was shown to potentiate the action of S-dC28 against HSV-2 growth. In conclusion, because of their potency and selectivity, phosphorothioate homo-oligodeoxynucleotides are a promising new class of anti-HSV agents.
Activities of beta-lactam antibiotics against Escherichia coli strains producing extended-spectrum beta-lactamases
Authors: Jacoby G A , Carreras I
Published: June 2012

Seven extended-spectrum beta-lactamases related to TEM and four enzymes derived from SHV-1 were transferred to a common Escherichia coli host so that the activity of a variety of beta-lactams could be tested in a uniform genetic environment. For most derivatives, penicillinase activity was 10% or less than that of strains making TEM-1, TEM-2, or SHV-1 beta-lactamase, suggesting that reduced catalytic efficiency accompanied the broader substrate spectrum. Despite this deficit, resistance to aztreonam, carumonam, cefdinir, cefepime, cefixime, cefmenoxime, cefotaxime, cefotiam, cefpirome, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, and E1040 was enhanced. For strains producing TEM-type enzymes, however, MICs of carumonam, cefepime, cefmenoxime, cefotiam, cefpirome, and ceftibuten were 8 micrograms/ml or less. Susceptibilities of cefmetazole, cefotetan, cefoxitin, flomoxef, imipenem, meropenem, moxalactam, temocillin, FCE 22101, and Sch 34343 were unaffected. FCE 22101, imipenem, meropenem, and Sch 34343 were inhibitory for all strains at 1 microgram/ml or less. In E. coli an OmpF- porin mutation in combination with an extended-spectrum beta-lactamase enhanced resistance to many of these agents, but generally by only fourfold. Hyperproduction of chromosomal AmpC beta-lactamase increased resistance to 7-alpha-methoxy beta-lactams but not that to temocillin. When tested at 8 micrograms/ml, clavulanate was more potent than sulbactam or tazobactam in overcoming resistance to ampicillin, while cefoperazone-sulbactam was more active than ticarcillin-clavulanate or piperacillin-tazobactam, especially against TEM-type extended-spectrum beta-lactamases.
Antibiotic inhibition of the respiratory burst response in human polymorphonuclear leukocytes
Authors: Hand W L , Hand D L , King-Thompson N L
Published: June 2012

Recently we found that certain antibiotics which are markedly concentrated by human polymorphonuclear leukocytes (PMN) failed to kill susceptible, intraphagocytic Staphylococcus aureus, even though cellular drug levels were quite high. The possibility that specific antibiotics might adversely affect phagocyte antibacterial function was considered. Thus, we studied the effects of multiple antibiotics and adenosine, a known modulator of the PMN respiratory burst response, on neutrophil antibacterial function. At nontoxic concentrations, these drugs had no effect on degranulation in stimulated PMN. Adenosine was a potent inhibitor of formyl-methionyl-leucyl-phenylalanine (FMPL)-stimulated superoxide and hydrogen peroxide generation in PMN but produced less inhibition of microbial particle-induced respiratory burst activity. Three of the tested antibiotics, all of which reach high concentrations in phagocytic cells, had a marked modulatory effect on the PMN respiratory burst. Clindamycin, which enters phagocytes by the cell membrane adenosine (nucleoside) transport system, had only a modest effect on FMLP-mediated superoxide production but inhibited the microbial particle-induced response by approximately 50%. Roxithromycin and trimethoprim were efficient inhibitors of PMN superoxide generation stimulated by FMLP and concanavalin A (also inhibited by erythromycin) but had less effect on zymosan-mediated respiratory burst activity. Antibiotics which entered phagocytes less readily had no effect on the respiratory burst response in PMN. These results, as well as those of experiments with inhibitors of cell membrane nucleoside receptors, indicated that the antibiotic effect is mediated through intraphagocytic pathways. The possibility that antibiotic-associated inhibition of the PMN respiratory burst response might alter leukocyte antimicrobial and inflammatory function deserves further evaluation.
Berberine derivatives as antileishmanial drugs
Authors: Vennerstrom J L , Lovelace J K , Waits V B , Hanson W L , Klayman D L
Published: June 2012

Berberine, a quaternary alkaloid, and several of its derivatives were tested for efficacy against Leishmania donovani and Leishmania braziliensis panamensis in golden hamsters. Tetrahydroberberine was less toxic and more potent than berberine against L. donovani but was not as potent as meglumine antimonate (Glucantime), a standard drug for the treatment of leishmaniasis. Only berberine and 8-cyanodihydroberberine showed significant activity (greater than 50% suppression of lesion size) against L. braziliensis panamensis.
Cloning and heterospecific expression of the resistance determinant vanA encoding high-level resistance to glycopeptides in Enterococcus faecium BM4147
Authors: Brisson-Noël A , Dutka-Malen S , Molinas C , Leclercq R , Courvalin P
Published: June 2012

Fragments of plasmid pIP816, which confers high-level glycopeptide resistance in Enterococcus faecium BM4147, were cloned into a conjugative gram-negative-gram-positive shuttle vector. The resulting hybrids were transferred by conjugation from Escherichia coli to Enterococcus faecalis and Bacillus thuringiensis. A 4-kilobase EcoRI fragment from pIP816 was found to confer vancomycin resistance in these hosts but not in E. coli or Bacillus subtilis.
Efficacy of SCH39304 and fluconazole in a murine model of disseminated coccidioidomycosis
Authors: Clemons K V , Hanson L H , Perlman A M , Stevens D A
Published: June 2012

The efficacies of SCH39304 (SCH) and fluconazole (FLU) were tested in a murine model of coccidioidomycosis. CD-1 mice were infected with Coccidioides immitis and dosed with SCH at 2, 10, 25, or 50 mg/kg per day or FLU at 10 or 100 mg/kg per day. Survival was enhanced (P less than 0.001) by both drugs at all doses. Residual burdens of C. immitis in the organs of mice treated with SCH at 25 or 50 mg/kg per day were lower than in mice treated with FLU at 100 mg/kg per day (P less than 0.001). These results indicate that SCH is an effective therapy for coccidioidomycosis and is superior to FLU in this comparison.
Pharmacokinetics and tissue penetration of ceftibuten
Authors: Wise R , Nye K , O'Neill P , Wostenholme M , Andrews J M
Published: June 2012

The pharmacokinetics of the cephalosporin ceftibuten were determined after the fifth and final dose of 200 mg given every 12 h. Concentrations in plasma and cantharidin-induced inflammatory fluid were determined by a microbiological assay. Samples for three volunteers were assayed by a high-performance liquid chromatographic procedure to determine levels for both cis and trans ceftibuten. The mean peak level of ceftibuten in serum was 10.9 micrograms/ml at a mean time of 1.8 h after administration, and the mean elimination half-life from plasma was 2.5 h. Penetration into the inflammatory fluid was good, the mean peak level being 9.2 micrograms/ml at a mean time of 3.7 h. The mean percent penetration into the inflammatory fluid was 113.4%. High-performance liquid chromatography analysis showed that the mean peak level of the trans isomer was 5.7% that of the cis isomer. This study suggests that twice-daily doses of ceftibuten should be sufficient to treat urinary or systemic infections caused by susceptible pathogens.
Chemoprophylactic efficacy against experimental endocarditis caused by beta-lactamase-producing, aminoglycoside-resistant enterococci is associated with prolonged serum inhibitory activity
Authors: Bayer A S , Tu J
Published: June 2012

We studied the prevention of experimental aortic endocarditis caused by a beta-lactamase-producing, aminoglycoside-resistant strain of Enterococcus faecalis (HH22) in 146 catheterized rabbits. Both vancomycin and ampicillin-sulbactam readily killed this resistant enterococcus strain in vitro. At a challenge inoculum of approximately 10(9) CFU, vancomycin (40 mg/kg intravenously [i.v.]), ampicillin (40 mg/kg i.v.), or a combination of ampicillin plus a beta-lactamase inhibitor, sulbactam (20 mg/kg, i.v.), did not prevent the development of endocarditis in any of the animals, although mean intravegetation bacterial densities were significantly lower in animals that received vancomycin than they were in animals that received other therapies (P less than 0.001). At a challenge inoculum of 10(6) CFU, vancomycin was 100% effective in preventing enterococcal endocarditis compared with ampicillin (29%; P less than 0.00001) and ampicillin-sulbactam (65%; P less than 0.01). Factors associated with the superior prophylactic efficacy of vancomycin in this model included prolonged serum inhibitory activity and time above MICs. Factors not associated with the antienterococcal prophylactic efficacy of vancomycin included the duration of the in vitro postantibiotic effect of the drug and the magnitude of the ability of this drug to enhance enterococcal in vitro opsonophagocytic killing by polymorphonuclear leukocytes. The superior prophylactic efficacy of vancomycin in this endocarditis model related to the superior pharmacokinetic profile of the drug when it was given intermittently at dose intervals of every 6 h.
Ampicillin killing curve patterns for ampicillin-susceptible nontypeable Haemophilus influenzae strains by the agar dilution plate count method
Authors: Woolfrey B F , Enright M A
Published: June 2012

Ampicillin killing curve patterns for 20 strains of ampicillin-susceptible nontypeable Haemophilus influenzae were determined by the agar dilution plate count method. The paradoxical effect was detected in the 24-h killing curve patterns for each strain. For the biphasic effect, minimum survivor percentages (maximum killing) occurred over a narrow range of ampicillin concentrations immediately above the MIC, with survivor percentages then rising rapidly to peak at approximately 1-log10-unit increment higher. The 24-h minimum survivor percentages for the 20 strains ranged from approximately 0.01% (rapid killing) to greater than 10% (slow killing). In comparison with the previous results for typeable strains, the present findings suggest that nontypeable stains are, on average, killed much more slowly. Based on the initial 24-h killing curve patterns for the 20 strains, 4 strains were selected as putative representatives of the range of bactericidal responses encountered. These strains were then studied to examine the reproducibility of the 24-h patterns and to determine sequential killing curves. These patterns were found to be reproducible and served to characterize the relative killing responses of the strains. In the sequential studies of three of the four strains, tiny colonies having the gross and microscopic characteristics of L-forms were found to be present on the agar dilution plate count plates prior to the application of penicillinase at 48 and 72 h. Such colonies reverted to vegetative forms within 24 to 48 h after application of penicillinase to the panels. Of particular interest was the observation that the paradoxical effect was manifested both by the L-form colonies and by the reverted vegetative colonies. The late development of L-forms was observed for both rapidly and slowly killed strains.
Interactions of ceftazidime and tobramycin in patients with normal and impaired renal function
Authors: Aronoff G R , Brier R A , Sloan R S , Brier M E
Published: June 2012

We studied the in vivo interaction of ceftazidime and tobramycin in normal volunteers and anuric patients given each drug separately or both drugs in combination. Kinetic analysis of plasma concentration data showed minor changes in the disposition of these agents when they were given concurrently. However, the resulting clearance of both tobramycin and ceftazidime was unchanged when these drugs were given concurrently. The volume of distribution of tobramycin at steady state was increased by 20% in normal volunteers when given with ceftazidime. The increase in distribution was accompanied by a slight decrease in ceftazidime elimination rate. No additional alteration in dosing over those necessary to adjust for a decrease in renal function is necessary when giving this combination.
Apparent biliary pseudolithiasis during ceftriaxone therapy
Authors: Heim-Duthoy K L , Caperton E M , Pollock R , Matzke G R , Enthoven D , Peterson P K
Published: June 2012

Biliary pseudolithiasis has been reported in patients who received ceftriaxone therapy. To examine this phenomenon further, serial gallbladder sonograms were evaluated in 44 adult patients who received intravenous ceftriaxone at 2 g or a placebo daily for 14 days in a double-blind controlled study. Ultrasound examinations of gallbladders were performed on days 1 and 14 of therapy and 2 weeks posttherapy if abnormalities were observed on day 14. Eight patients were unevaluable because of abnormal base-line gallbladder sonograms. Thirty-six patients (ceftriaxone, n = 28; placebo, n = 8) demonstrated normal baseline gallbladder sonograms and were evaluated for the development of change. A total of 6 of 28 (21.4%) ceftriaxone-treated patients and 1 of 8 (12.5%) patients who received the placebo demonstrated abnormal gallbladder sonograms on day 14 (P = 0.491). Four of the six ceftriaxone-treated patients demonstrating abnormal sonograms were clinically asymptomatic, while two patients reported vomiting. The abnormal sonograms of gallbladders of patients treated with ceftriaxone returned to normal between 9 and 26 days posttherapy. These data suggest an association between ceftriaxone treatment and the development of gallbladder abnormalities on ultrasound examination which resolve spontaneously on discontinuation of ceftriaxone therapy.