bluuebunny/crossref_metadata_2025 huggingface dataset:
Resistance to various tetracyclines mediated by transposon Tn10 in Escherichia coli K-12
Authors: Traub B , Beck C F
Published: June 2012

Levels of resistance to tetracycline, chlortetracycline, demethylchlortetracycline, doxycycline, oxytetracycline, methacycline, pyrrolidinotetracycline, minocycline, and beta-chelocardin of Escherichia coli K-12 carrying transposon Tn10 or defined DNA segments of Tn10 were determined. In all cases, tetA was the only gene required for resistance. Doxycycline was the most effective inducer of tetA gene expression.
Inducible phenotypic multidrug resistance in the fungus Mucor racemosus
Authors: Leathers T D , Sypherd P S
Published: June 2012

The dimorphic fungus Mucor racemosus exhibited a single-step, inducible resistance to cycloheximide, trichodermin, and amphotericin B. Cells adapted to inhibitory levels of the antibiotics after 12 to 40 h. The adaptation involved all the cells in the population and was not the result of the selection of resistant mutants. Adaptation to one drug provided cross resistance to other, dissimilar drugs. Resistance was lost within several generations of growth in the absence of the inhibitors.
Enhanced efficacy of liposome-encapsulated ribavirin against Rift Valley fever virus infection in mice
Authors: Kende M , Alving C R , Rill W L , Swartz G M , Canonico P G
Published: June 2012

Administration of liposome-encapsulated ribavirin to mice led to ribavirin concentrations in the liver, the primary site of Rift Valley fever virus proliferation, that were fivefold greater than those attained with the same doses of free ribavirin. Liposomal ribavirin given at a dose of either 25 or 50 mg of drug per kg of body weight protected mice against a rapidly lethal high-titer challenge with Rift Valley fever virus, whereas similar doses of free drug or empty liposomes had no detectable benefit. Hence, tissue targeting of ribavirin with liposomes substantially increased the therapeutic index by increasing the efficacy of the treatment. By using liposomes as drug carriers, a nontoxic, low-dose regimen of ribavirin had a therapeutic effect that was comparable to that achieved with higher but potentially more toxic doses of free ribavirin.
In vitro antibacterial activities of antibiotics against Pseudomonas aeruginosa in peritoneal dialysis fluid
Authors: Shalit I , Welch D F , San Joaquin V H , Marks M I
Published: June 2012

Intraperitoneal antibiotics are used to treat Pseudomonas aeruginosa peritonitis, a serious complication of continuous ambulatory peritoneal dialysis. However, P. aeruginosa killing is often inefficient despite low MBCs. Broth dilution MIC/MBC and time kill curves of tobramycin, amikacin, netilmicin, azlocillin, piperacillin, ceftazidime, cefsulodin, and ciprofloxacin were determined in peritoneal dialysis fluid (PDF), buffered PDF, fluid recovered from patients on continuous ambulatory peritoneal dialysis (RPF), and cation-supplemented Mueller-Hinton broth. MBCs of all antibiotics were 8 to 16 times greater in PDF and RPF than in Mueller-Hinton broth or buffered PDF. Use of the time kill curve technique and Mueller-Hinton broth showed that aminoglycosides killed greater than or equal to 99.9% of P. aeruginosa at 1 h, ciprofloxacin killed greater than or equal to 99.9% at 2 h, and beta-lactams killed greater than or equal to 99.9% at 6 h. In contrast, killing was not demonstrated in PDF by any drug at 6 h and by aminoglycosides only at 24 h. Bactericidal activity was optimal in RPF for ciprofloxacin at 1 h and for aminoglycosides at 2 h; bactericidal activity was not demonstrated in RPF with any beta-lactam (no kill by penicillins; less than 99% kill by cephalosporins). Slow bacterial growth, increased protein binding, and glucose concentrations and other inhibitors may interfere with beta-lactam activity in RPF. These considerations and reported clinical failures and toxicity of aminoglycoside therapy warrant further study of quinolones and drug combinations in P. aeruginosa peritonitis.
Immunological comparison between OXA-2 beta-lactamase and those mediated by other R plasmids
Authors: Holland S , Dale J W
Published: June 2012

Antibodies to the OXA-2 beta-lactamase inhibited both OXA-2 and OXA-3 enzymes, but there was no effect on any other beta-lactamase. The cross-neutralization indicates considerable homology between the OXA-2 and OXA-3 enzymes and supports the suggestion that the OXA-3 beta-lactamase may have been derived from the OXA-2 gene via a deletion.
Comparison of topically applied 5-ethyl-2'-deoxyuridine and acyclovir in the treatment of cutaneous herpes simplex virus infection in guinea pigs
Authors: Spruance S L , Freeman D J , Sheth N V
Published: June 2012

Three percent 5-ethyl-2'-deoxyuridine (EdU) in an aqueous cream base was compared with 5% acyclovir (ACV) in polyethylene glycol ointment and 3% EdU in 95% dimethyl sulfoxide (DMSO) for efficacy in the topical treatment of an experimental dorsal cutaneous herpes simplex virus type 1 infection in guinea pigs. Topical ACV treatment reduced the mean lesion number by 15%, the lesion area by 32%, and the lesion virus titer by 60% when compared with measurements at contralateral sites treated with the vehicle alone. Application of 3% EdU cream was more beneficial, effecting reductions of 29, 44, and 68% in the same measurements. EdU in DMSO was even more effective, reducing the lesion measurements by 39, 60, and 90%, respectively. The penetration of EdU and ACV through guinea pig skin was compared in single-chamber diffusion cells. In the aqueous cream, EdU readily penetrated excised skin and exhibited rates of flux 10-fold greater than those shown by ACV in ointment formulation (0.56 versus 0.05 microgram/cm2 per h; P = 0.05). The flux of EdU in DMSO was 3.39 micrograms/cm2 per h, six times higher than the flux in the cream vehicle. EdU was more effective than ACV in this experimental animal model, most likely due to better percutaneous drug delivery of EdU from the cream and DMSO vehicles.
Binding and neutralization of bacterial lipopolysaccharide by colistin nonapeptide
Authors: Warren H S , Kania S A , Siber G R
Published: June 2012

Polymyxin nonapeptides, proteolytic derivatives of polymyxin antibiotics, are less toxic than their parent compounds but retain some of their antibacterial activities. To confirm and expand observations that polymyxin nonapeptides have anti-endotoxin activity, we studied the ability of colistin nonapeptide to bind to bacterial lipopolysaccharide (LPS) and to inhibit the effects of LPS on Limulus amoebocyte lysate and lymphocyte mitogenicity. Colistin nonapeptide was purified by high-pressure liquid chromatography and was demonstrated to bind to LPS by equilibrium dialysis. The ability of colistin nonapeptide to render E. coli ATCC 25922 cells sensitive to erythromycin was abrogated by 50% after incubation with E. coli O18 LPS in a ratio by weight of LPS to colistin nonapeptide of 3.9:1. The presence of 4 micrograms of colistin nonapeptide or colistin per ml increased by 130- and 800-fold, respectively, the concentration of E. coli O113 LPS required to produce 50% gelation of Limulus amoebocyte lysate as measured by a spectrophotometric assay. Neutralization of LPS by colistin nonapeptide was time and concentration dependent. In contrast to the neutralization seen with LPS derived from a colistin-sensitive organism, colistin nonapeptide neutralized very little LPS extracted from a strain of Serratia marcescens that was resistant to colistin. Colistin nonapeptide also inhibited LPS-induced [3H]thymidine uptake by splenic lymphocytes, but its activity was less than 1/10 that of colistin. We conclude that colistin nonapeptide binds to LPS and possesses antiendotoxin activity. However, the anti-endotoxin activity of the nonapeptide is considerably less than that of its parent compound, colistin.
Tetracycline-resistant Mycoplasma hominis strains contain streptococcal tetM sequences
Authors: Roberts M C , Koutsky L A , Holmes K K , LeBlanc D J , Kenny G E
Published: June 2012

Clinical isolates of Mycoplasma hominis resistant to high levels of tetracycline contained DNA sequences homologous to the streptococcal tetracycline determinant, tetM. In contrast, none of the susceptible M. hominis isolates tested carried this determinant. This is the first description of tetM in an unrelated genus and suggests the spread of tetM from Streptococcus spp. to Mycoplasma spp.
Pharmacokinetics of intravenous amdinocillin in healthy subjects and patients with renal insufficiency
Authors: Patel I H , Bornemann L D , Brocks V M , Fang L S , Tolkoff-Rubin N E , Rubin R H
Published: June 2012

Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14- to 18-h period. Although the clearance from plasma and the half-life of amdinocillin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis.
Efficacy of BMY-28142 in experimental bacteremia and meningitis caused by Escherichia coli and group B streptococci
Authors: Kim K S , Bayer A S
Published: June 2012

We evaluated the activity of BMY-28142 against a K1 E. coli strain and a type III group B streptococcal strain in vitro and in vivo and compared the results with those of cefotaxime and penicillin G, respectively. In vitro, the MICs and MBCs of BMY-28142 were close to those of cefotaxime (less than or equal to 2-fold difference) for E. coli and fourfold less than those of penicillin G for group B streptococci. In vivo studies with an experimental bacteremia and meningitis model in newborn rats revealed that the mean penetration of BMY-28142 into the cerebrospinal fluid was 15% that of concomitant levels in serum and that significantly greater bactericidal titers were achieved in blood and cerebrospinal fluid for both test organisms with BMY-28142 than with cefotaxime and penicillin G. However, the overall efficacy of BMY-28142 was similar to that of cefotaxime for the E. coli infection and that of penicillin G for the group B streptococcal infection. This was shown by similar rates of bacterial clearance from blood and cerebrospinal fluid and similar mortality rates. These findings indicate that the activity of BMY-28142 is bactericidal in vitro and in vivo against E. coli and group B streptococci, suggesting that this agent may be a suitable alternative for the therapy of E. coli and group B streptococcal bacteremia and meningitis.
Pharmacokinetics of three oral formulations of ciprofloxacin
Authors: Davis R L , Koup J R , Williams-Warren J , Weber A , Smith A L
Published: June 2012

We compared the absorption of three formulations of ciprofloxacin after oral administration in 18 normal adult male volunteers. Each subject received 500 mg of ciprofloxacin as two 250-mg tablets, one 500-mg tablet, or a solution in a randomized crossover sequence. Pharmacokinetic parameters were determined by model independent methods. Because a solution is considered to be the ideal oral dosage form, the results determined for the tablets were compared to those for the solution. Mean values for the maximum concentration of drug in serum, the time to maximum concentration of drug in serum, and the elimination half-life were 3.23 micrograms/ml, 1.00 h, and 5.04 h, respectively, for the solution. The mean renal clearance of ciprofloxacin was 372 ml/min and accounted for at least 50% of the total clearance. We recovered 44.4, 48.6, and 55.8% of the administered ciprofloxacin from the urine as unchanged drug within 24 h after dosing with the 250-mg tablets, 500-mg tablets, or solution, respectively. The 500-mg tablets were found to be bioequivalent to the solution with regard to all pharmacokinetic parameters. The 250-mg tablet was not bioequivalent to either of the other formulations; the relative bioavailability values were 78.7 and 74.1%, respectively, for the 500-mg tablet and the solution. The clinical significance of this difference in bioavailability is yet to be determined.
Transfer of amphotericin B from gel state vesicles to mycoplasma cells: biphasic action on potassium transport and permeability
Authors: Vertut-Croquin A , Bolard J , Gary-Bobo C M
Published: June 2012

The action of amphotericin B on the K+ permeability of Mycoplasma mycoides var. capri cells, containing either cholesterol or ergosterol in their membranes, was studied. When the drug, solubilized in dimethyl sulfoxide, was added directly to the cell suspension, a slightly greater sensitivity to permeabilization was observed for ergosterol-containing cells, confirming the data reported in the literature. When amphotericin B bound to gel state phospholipid vesicles was added to the cell suspension, two effects on cholesterol-containing cells were observed. First, the K+ active transport rates increased; membrane permeabilization and K+ leakage were subsequently detected. For ergosterol-containing cells these sequential events were observed only at amphotericin B concentrations below 10(-6) M. At higher concentrations only K+ leakage was observed. The second permeabilization effect varied with the amphotericin B concentration in different ways in the two types of cells. The permeabilization of ergosterol-containing membranes depended on the amphotericin B/phospholipid molar ratio, whereas the permeabilization of cholesterol-containing membranes did not. In general, the latter remained fairly constant when the total amphotericin B concentration in the medium varied.
Inhibition of murine cytomegalovirus lung infection and interstitial pneumonitis by acyclovir and 9-(1,3-dihydroxy-2-propoxymethyl)guanine
Authors: Shanley J D , Morningstar J , Jordan M C
Published: June 2012

We compared the effects of acyclovir (ACV) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on murine cytomegalovirus (MCMV) replication in lung and salivary gland tissues, the evolution of interstitial pneumonitis in vivo, and MCMV replication in mouse embryo cells in vitro. As measured by plaque reduction, ACV was more active than DHPG in vitro. In vivo, whether administered orally by gastric intubation or in the drinking water, or subcutaneously, DHPG was more effective than ACV in reducing MCMV titers in lung or salivary gland tissues. This was true in both normal and cyclophosphamide-treated mice. Neither drug was able to prevent MCMV interstitial pneumonitis, despite substantial reductions in virus titer, but both drugs reduced the severity of the pneumonitis.
Molecular characterization of chloramphenicol-resistant Haemophilus parainfluenzae and Haemophilus ducreyi
Authors: Roberts M C , Actis L A , Crosa J H
Published: June 2012

We examined chloramphenicol-resistant Haemophilus parainfluenzae and Haemophilus ducreyi strains isolated in various parts of the world. The antibiotic resistance determinants were located on conjugative plasmids in H. ducreyi, but were chromosomally located in H. parainfluenzae. Both species produced chloramphenicol acetyltransferases (CATs) that were sensitive to 5,5'-dithiobis(2-nitrobenzoic acid) like the enteric type II and Haemophilus influenzae CAT enzymes, but differed from these enzymes in elution patterns and subunit molecular weight. Southern blot analysis showed the H. parainfluenzae and H. ducreyi CAT genes were molecularly related to the enteric type II class as well as the H. influenzae CAT. Heterogeneity of the physiochemical properties of the CATs was observed; however, the data suggested that all three Haemophilus spp. have a common ancestral source for the CATs.
In vitro susceptibilities of Campylobacter-like organisms to twenty antimicrobial agents
Authors: Flores B M , Fennell C L , Holmes K K , Stamm W E
Published: June 2012

We determined MICs of 20 antimicrobial agents for 50 representative strains of four subgroups of Campylobacter-like organisms (CLOs) by agar dilution. Ampicillin, gentamicin, doxycycline, tetracycline, ceftriaxone, rifampin, spectinomycin, nalidixic acid, and chloramphenicol were active against all strains of CLOs. Most CLO strains (83%) were inhibited by 4 micrograms of sulfamethoxazole per ml and by 8 micrograms of trimethoprim-sulfamethoxazole per ml. Of type 1 strains, 28% were resistant to 8 micrograms of erythromycin per ml. In addition, cross resistance between erythromycin and clindamycin was always present. Type 1 strains exhibited a broad distribution of MICs of metronidazole and streptomycin, whereas all type 2 strains were uniformly susceptible to metronidazole and resistant to streptomycin. Unlike type 1 and 3 strains, type 2 CLOs were susceptible to cephalothin and penicillin G and highly resistant to streptomycin. The type 3 strain was uniquely resistant to cefazolin. The majority of strains were not inhibited by cefoperazone; and all were resistant to trimethoprim. In contrast to Campylobacter jejuni and Campylobacter fetus subsp. fetus, all CLOs tested were susceptible to 0.5 microgram of rifampin per ml.
Protein antigens of encapsulated Klebsiella pneumoniae surface exposed after growth in the presence of subinhibitory concentrations of cephalosporins
Authors: Kadurugamuwa J L , Anwar H , Brown M R , Zak O
Published: June 2012

It recently has been reported by us that cephalosporins, at a concentration below that influencing growth rate, reduced the production of enterochelin and capsule formation of iron-depleted Klebsiella pneumoniae. We now report on the antigenicity of the outer membrane components and surface-exposed protein antigens of iron-depleted cells grown in the presence or absence of cephalosporins. All major outer membrane proteins, including iron-regulated membrane proteins, were immunogenic. Encapsulated K. pneumoniae grown in antibiotic-free media had three protein antigens (60, 35.5, and 32.5 kilodaltons) exposed on the surface that were accessible to antibodies. Growth of the same cultures in the presence of subinhibitory concentrations of cephalosporins resulted in the exposure of a greater number of protein antigenic determinants, including iron-regulated membrane proteins, which become readily accessible to antibodies. It was also found that immunoblotting was generally more sensitive than conventional staining of the acrylamide gel with Coomassie blue in the detection of proteins.
Evaluation of aztreonam in the treatment of severe bacterial infections
Authors: Romero-Vivas J , Rodríguez-Créixems M , Bouza E , Hellín T , Guerrero A , Martínez-Beltrán J , García de la Torre M
Published: June 2012

We investigated the clinical efficacy and safety of aztreonam in the treatment of 50 episodes of infection in 46 adult patients. The clinical condition of patients at the beginning of treatment was critical or poor in 28 of the episodes of infection. Episodes treated were 39 urinary tract infections (12 of them with concomitant bacteremia), 2 soft tissue infections, 8 patients with osteomyelitis (1 with concomitant bacteremia), and one episode of pneumonia. Significant isolated microorganisms were aerobic or facultative gram-negative rods and were responsible for the following episodes of infection (number of episodes): members of the family Enterobacteriaceae (49), Pseudomonas aeruginosa (5), and Haemophilus influenzae (1). The overall rate of clinical response to aztreonam was 94% of the treated episodes. Colonization or superinfection or both occurred in 29 episodes, but only 8 episodes required antimicrobial therapy. Aztreonam seems to be an effective single agent therapy for many bacterial infections. Colonization and superinfection by Candida sp., Streptococcus faecalis or Staphylococcus aureus must be monitored.
In vitro evaluation of the antimicrobial activity of lichen metabolites as potential preservatives
Authors: Ingólfsdóttir K , Bloomfield S F , Hylands P J
Published: June 2012

Antimicrobial screening of several lichen species and subsequent isolation and structure elucidation of active compounds revealed that the hydrolysis products of certain lichen metabolites, i.e., depsides, were active against gram-negative bacteria and fungi as well as gram-positive bacteria. The active constituents isolated from Stereocaulon alpinum and Peltigera aphthosa were identified, respectively, as methyl beta-orsellinate and a mixture of methyl and ethyl orsellinates. MIC determinations indicated that activity of these compounds was superior to that of the commonly used preservative agents methyl and propyl p-hydroxybenzoates and was of the same order as that of chlorocresol.
Evolution of plasmid-coded resistance to broad-spectrum cephalosporins
Authors: Kliebe C , Nies B A , Meyer J F , Tolxdorff-Neutzling R M , Wiedemann B
Published: June 2012

A clinical isolate of Klebsiella ozaenae with transferable resistance to broad-spectrum cephalosporins produces a beta-lactamase determined by plasmid pBP60. The beta-lactamase had the same isoelectric point as SHV-1 (7.6). From heteroduplex analysis, an extensive homology between the two bla genes could be deduced; therefore, the new beta-lactamase was designated SHV-2. Enzymatic studies revealed that SHV-2 was able to hydrolyze broad-spectrum cephalosporins due to an increased affinity of these compounds for the enzyme. The assumption that SHV-2 is a natural mutant of SHV-1 was strongly supported by the isolation of a laboratory mutant of SHV-1 that showed activities similar to those of SHV-2.
Comparison of high-pressure liquid chromatography and microbiological assay for the determination of biliary elimination of ciprofloxacin in humans
Authors: Brogard J M , Jehl F , Monteil H , Adloff M , Blickle J F , Levy P
Published: June 2012

Serum kinetics and biliary, urinary, and fecal elimination of ciprofloxacin, a new quinolone derivative, were studied in 12 recently cholecystectomized patients provided with T-tube drainage during 24 h after oral administration of a single 500-mg dose of this substance. Drug concentrations were measured by both high-pressure liquid chromatography (HPLC) and microbiological assay. The results were comparable for the concentrations in serum (average of peaks, 2.0 +/- 0.2 micrograms/ml by HPLC and 2.3 +/- 0.3 micrograms/ml by the microbiological method) and urine (0 to 6 h, 267 +/- 74 and 241 +/- 58 micrograms/ml, respectively). This was not the case for biliary values, for which the microbiological assay yielded significantly higher concentrations than did HPLC (average of peak concentrations, 21.2 +/- 2.6 and 16.0 +/- 2.5 micrograms/ml, respectively [P less than 0.02]), nor for total 24-h biliary output (2,167 +/- 288 and 1,587 +/- 222 micrograms, respectively [P less than 0.01]). This suggests hepatic biotransformation of ciprofloxacin into microbiologically active metabolites. The apparent broad antibacterial spectrum of ciprofloxacin and its higher biliary levels than simultaneously determined serum concentrations suggest that this derivative is suitable for the treatment of biliary tract infections.
Comparison of ceftriaxone and ampicillin plus chloramphenicol for the therapy of acute bacterial meningitis
Authors: Bryan J P , Rocha H , da Silva H R , Taveres A , Sande M A , Scheld W M
Published: June 2012

Ceftriaxone, a new third-generation cephalosporin, appears to be promising for the therapy of acute bacterial meningitis. The 90% MBCs of ceftriaxone against 54 recent cerebrospinal fluid isolates of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae were less than or equal to 0.06 to 0.25 micrograms/ml. We examined the efficacy and safety of ceftriaxone therapy of meningitis in Bahia, Brazil. The study was conducted in two phases; in phase A, ceftriaxone was coadministered with ampicillin. The mean cerebrospinal fluid concentrations of ceftriaxone 24 h after an intravenous dose of 80 mg/kg were 4.2 and 2.3 micrograms/ml on days 4 to 6 and 10 to 12 of therapy, respectively. These concentrations were 8- to more than 100-fold greater than the 90% MBCs against the relevant pathogens. In phase B, ceftriaxone (administered once daily at a dose of 80 mg/kg after an initial dose of 100 mg/kg) was compared with conventional dosages of ampicillin and chloramphenicol in a prospective randomized trial of 36 children and adults with meningitis. The groups were comparable based on clinical, laboratory, and etiological parameters. Ceftriaxone given once daily produced results equivalent to those obtained with ampicillin plus chloramphenicol, as judged by cure rate, case fatality ratio, resolution with sequelae, type and severity of sequelae, time to sterility of cerebrospinal fluid, and potentially drug-related adverse effects. The cerebrospinal fluid bactericidal titers obtained 16 to 24 h after ceftriaxone dosing were usually 1:512 to greater than 1:2,048 even late in the treatment course, compared with values of 1:8 to 1:32 in patients receiving ampicillin plus chloramphenicol. Ceftriaxone clearly deserves further evaluation for the therapy of meningitis; the optimal dose, dosing frequency (every 12 h or every 24 h), and duration of therapy remain to be determined.
Performance of a diffusional clearance model for beta-lactam antimicrobial agents as influenced by extravascular protein binding and interstitial fluid kinetics
Authors: Fleishaker J C , McNamara P J
Published: June 2012

A physiological model based on diffusional clearance (CLD) of drug between plasma and interstitial fluid (IF) was used to describe the disposition of beta-lactam antimicrobial agents. The CLD represents the movement of drug in and out of physiological spaces and is dependent only on the transfer properties of the drug. Estimates of CLD obtained by fitting model equations to plasma concentration-time data for 11 cephalosporin studies in human subjects fell in a fairly narrow range, with a mean value of 1,604 ml/min. Estimates of the CLD between plasma and blister fluid for three of the cephalosporins were five orders of magnitude smaller than the CLD. These observations are explained in terms of diffusion principles. Computer simulations with this model were used to assess the effect of changes in IF protein binding on antimicrobial distribution. Increases in the bound fraction of drug in IF enhanced the penetration of total (bound and unbound) drug into IF, but had no effect on the amount of unbound, active antimicrobial agent reaching the IF. The time course of unbound drug in IF was altered, however, by changes in IF protein binding. This model may also be used to predict changes in the IF distribution of beta-lactam antimicrobial agents in disease states, particularly those in which the relative distribution of albumin between plasma and IF has been altered.
In vitro susceptibilities of 25 Giardia lamblia isolates of human origin to six commonly used antiprotozoal agents
Authors: Gordts B , Hemelhof W , Asselman C , Butzler J P
Published: June 2012

The role drug resistance plays in the occurrence of chronic and recurrent giardiasis has not been established. Extensive data on the susceptibility to antimicrobial agents of living Giardia spp. trophozoites from human origin are lacking. We have determined with a macrodilution method in semisolid medium the in vitro susceptibility of 25 Giardia lamblia isolates, all obtained by routine cultivation of the duodenal fluid of children to six commonly used antiprotozoal drugs. The results showed tinidazole to be the most active drug (all isolates have MICs of less than or equal to 0.5 micrograms/ml). Metronidazole was equally active on all but one isolate, for which an MIC between 0.5 and 1 micrograms/ml was found. Furazolidone was the most active nonimidazole compound tested. More than 50% of the isolates were very susceptible to paromomycin, pyrimethamine, and chloroquine. Two of the strains presented an MIC for paromomycin higher than 10 micrograms/ml, and six strains needed more than 50 micrograms of pyrimethamine per ml to be inhibited. Decreased susceptibility of several of the isolates to different agents appears to be linked.
Evaluation of oxacillin tolerance in Staphylococcus aureus by a novel method
Authors: Woolfrey B F , Lally R T , Ederer M N
Published: June 2012

A novel agar dilution plate-count procedure for the quantitative measurement of bacterial inhibition and killing is described. For Staphylococcus aureus versus oxacillin, by the agar dilution plate-count procedure it was found that only 1 of 20 clinical isolates and 1 of 7 allegedly tolerant reference isolates met the conventional definition of tolerance. By using inocula of 10(5) CFU per plate, most isolates were demonstrated to have subpopulations of cells which, although inhibited, persisted for 24 h in concentrations significantly above their MICs. The persister percentages at 24 h appeared to be strain dependent, and all persisters exhibited the paradoxical effect. For each isolate, the persister percentage markedly decreased after action by oxacillin for 48 h, and the paradoxical effect was greatly diminished. Our findings suggest that tolerance is an artificial and arbitrary concept that does not adequately characterize the inhibition and killing dynamics associated with the persister phenomenon.
Molecular analysis of multiple-resistance plasmids transferred from gram-negative bacteria isolated in a urological unit
Authors: Griffin H G , Foster T J , Falkiner F R , Carr M E , Coleman D C
Published: June 2012

Forty-one isolates of multiply resistant gram-negative bacteria causing infection in a urological unit of a Dublin hospital were collected during a 6-month period. Twenty-one isolates transferred multiple resistance to an Escherichia coli K-12 recipient in liquid matings. Serratia marcescens, Proteus morganii, Proteus vulgaris, and E. coli isolates harbored similar 120-megadalton IncC plasmids, whereas Enterobacter cloacae strains transferred a 160-megadalton plasmid of a different Inc group. Southern hybridization experiments were performed with purified fragments cloned from one IncC plasmid as probes. They were hybridized to plasmid sequences in total cellular DNA extracts, showing that the IncC plasmids were very closely related. This suggests that the same plasmid has transferred to different bacterial species in the hospital environment.
Comparison of cefotaxime, imipenem-cilastatin, ampicillin-gentamicin, and ampicillin-chloramphenicol in the treatment of experimental Escherichia coli bacteremia and meningitis
Authors: Kim K S
Published: June 2012

In a search for more effective antimicrobial therapy of neonatal Escherichia coli infection, newer beta-lactam antibiotics, cefotaxime and imipenem, were evaluated for their activities against a K1 E. coli strain in vitro and in vivo, and the results were compared with those of conventional therapeutic regimens for neonatal E. coli infection: ampicillin-gentamicin and ampicillin-chloramphenicol. Measured by MICs and MBCs, cefotaxime and imipenem were 8- to 512-fold more active in vitro than the older agents. For in vivo studies, the following daily doses were used: 50 mg/kg for each of imipenem and cilastatin; 100 mg/kg for each of cefotaxime, ampicillin, and chloramphenicol; and 10 mg/kg for gentamicin. At these doses, the mean bactericidal titers in blood and cerebrospinal fluid were significantly greater with newer agents than with ampicillin-gentamicin and ampicillin-chloramphenicol. However, at the doses used, the newer agents were not more effective in vivo than the older agents. This was shown by the similarities in clearance of bacteria from blood and cerebrospinal fluid, incidences of meningitis in bacteremic animals, and mortality rates. Thus, although these two newer antibiotics are more active in vitro and produce greater bactericidal titers in vivo, they do not appear to be superior to conventional regimens for treatment of neonatal E. coli bacteremia and meningitis.
Variability of IncHI1 plasmids from Salmonella typhi with special reference to Peruvian plasmids encoding resistance to trimethoprim and other antibiotics
Authors: Taylor D E , Chumpitaz J C , Goldstein F
Published: June 2012

In spite of extensive DNA homology among IncHI1 plasmids, ApaI and XbaI restriction digests of plasmids from Peruvian Salmonella typhi varied considerably from other IncHI1 plasmids isolated previously. IncHI1 plasmids appear to be undergoing a process of modular evolution, probably by sequential acquisition of resistance determinants.
Relative rates of transport of peptidyl drugs by Candida albicans
Authors: McCarthy P J , Newman D J , Nisbet L J , Kingsbury W D
Published: June 2012

A variety of peptide drugs are known to be active against Candida albicans; however, little is known about the transport of such agents into the target organism. To provide further information concerning transport of this type, we studied the uptake of two classes of small linear peptides: polyoxins which act intact within the cell and the m-fluorophenylalanyl (m-F-Phe) peptides which require peptidase cleavage to release m-F-Phe. Competition studies with a specific dipeptide detector (alanyl-alpha-thiophenylglycine) enabled us to determine Ki values of 2.6 microM for nikkomycin Z and 350 microM for polyoxin D. Rates of uptake of the peptidyl-nucleosides are approximately 30 times lower than those of the m-F-Phe peptides (apparent maximal velocities: nikkomycin Z, 62 pmol min-1 mg (dry weight) of cells-1; M-F-Phe alanine 1.3 nmol min-1 mg (dry weight) of cells-1). For both the m-F-Phe peptides and the peptidyl-nucleosides, the affinity of the drug for the transport system is an important determinant of its whole-cell activity.
Effect of ketoconazole in combination with other inhibitors of sterol synthesis on fungal growth
Authors: Sud I J , Feingold D S
Published: June 2012

The effect of combination of ketoconazole with other sterol synthesis inhibitors on fungal growth was tested against a variety of fungi selected for resistance to ketoconazole. All of the sterol inhibitors, at concentrations lower than their MICs, caused an increase greater than fourfold in the ketoconazole susceptibility of some fungi. Some of the sterol synthesis inhibitors showed this effect with ketoconazole at levels that may be achieved clinically.
Pharmacokinetics of sulfisoxazole in renal transplant patients
Authors: Shermantine M , Gambertoglio J , Amend W , Vincenti F , Oie S
Published: June 2012

We studied the elimination of sulfisoxazole in eight renal transplant patients. The patients received sulfisoxazole prophylactically for urinary tract infection commencing 7 days postoperatively. The renal elimination of sulfisoxazole (unbound renal clearance) was decreased in this patient population and was highly correlated with creatinine clearance. The unbound metabolic clearance and apparent unbound formation clearance of N4-acetyl sulfisoxazole did not differ from values found in healthy volunteers. The protein binding was marginally lower in this patient population than in healthy subjects after a single dose. The reduced binding was compatible with a reduced albumin concentration. In contrast to the situation for healthy subjects, the binding of sulfisoxazole decreased upon multiple dosing. This is probably due to a relatively higher sulfisoxazole and N4-acetyl sulfisoxazole-to-albumin ratio in this patient population than in healthy subjects. No complications of sulfisoxazole therapy were seen, although in three subjects concentration of the N4-acetyl sulfisoxazole in urine exceeded its theoretical solubility on a few occasions.
Comparative evaluation of the 2-methyl-5-nitroimidazole compounds dimetridazole, metronidazole, secnidazole, ornidazole, tinidazole, carnidazole, and panidazole against Bacteroides fragilis and other bacteria of the Bacteroides fragilis group
Authors: Jokipii L , Jokipii A M
Published: June 2012

Tube-dilution MICs of seven 2-methyl-5-nitroimidazole compounds varying at the 1-substitution were determined against Bacteroides fragilis. Activities on a molar basis were ranked: tinidazole greater than panidazole greater than ornidazole greater than metronidazole greater than or equal to secnidazole greater than carnidazole greater than dimetridazole. Geometric mean MICs varied from 0.5 to 6.6 microM, and MICs against individual strains varied up to 50-fold between compounds. In general, the MIC of each drug correlated with that of each of the other drugs, but with tinidazole the correlation coefficients tended to be small and were not significant versus metronidazole and secnidazole. MICs against 14 other bacteria of the B. fragilis group, including B. distasonis, B. ovatus, B. thetaiotaomicron, B. uniformis, and B. vulgatus, were within the range determined for B. fragilis.
Cefotiam therapy of lower respiratory tract infections
Authors: Polis M A , Tuazon C U
Published: June 2012

Cefotiam, a new cephalosporin, was evaluated in the treatment of lower respiratory tract infections in 29 patients. The bacteria isolated from the sputum of these patients included Streptococcus pneumoniae (31%), Klebsiella pneumoniae (31%), and Haemophilus influenzae (28%). Satisfactory response was observed in 90% of the patients. There were three treatment failures, two superinfections, and four colonizations with gram-negative organisms resistant to the drug. Superficial phlebitis was noted in two patients. The results of this study suggest that cefotiam is an effective and well-tolerated antibiotic for the treatment of lower respiratory tract infections due to susceptible organisms.
Activity of arildone with or without interferon against acute hemorrhagic conjunctivitis viruses in cell culture
Authors: Langford M P , Carr D J , Yin-Murphy M
Published: June 2012

Arildone (WIN 38020; 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione) inhibited the infectivity of acute hemorrhagic conjunctivitis viruses in tissue culture. Arildone did not inhibit interferon (IFN) production or IFN activity. Treatment of cultures with combinations of arildone and IFN resulted in an additive inhibition of acute hemorrhagic conjunctivitis virus production.
Determination of ticarcillin levels in serum by high-pressure liquid chromatography
Authors: Shull V H , Dick J D
Published: June 2012

A high-pressure liquid chromatographic method for determining the concentrations of ticarcillin in serum was developed and compared, with 93 patient sera, to a standard agar well diffusion bioassay. For analysis, serum plus temocillin, the internal standard, were extracted with chloroform-n-amyl alcohol and back extracted into phosphate buffer. A reverse-phase C18 column and an ammonium acetate-methanol mobile phase were used with detection at 242 nm. Reproducibility studies yielded coefficients of variation ranging from 2.4 to 4.7% for low, mid, and high controls. Although cefoxitin, cephalothin, and cefuroxime exhibited retention similar to that of ticarcillin, a wide range of commonly administered antibiotics and other drugs did not interfere. The high-pressure liquid chromatographic assay is an accurate, reproducible method for determining the concentration of ticarcillin in serum during multiple antibiotic therapy or when rapid results are required.
Comparison of penicillin and vancomycin, individually and in combination with gentamicin and amikacin, in the treatment of experimental endocarditis induced by nutritionally variant streptococci
Authors: Bouvet A , Cremieux A C , Contrepois A , Vallois J M , Lamesch C , Carbon C
Published: June 2012

Six different antibiotic treatment regimens were compared for efficacy in rabbits with endocarditis induced by inoculation with a nutritionally variant strain of streptococcus. Seven untreated animals, sacrificed at day 11, had vegetations containing 8.89 +/- 1.35 log10 CFU/g, none of which was sterile. The vegetations from the rabbits in all treated groups had bacterial titers significantly lower than those of the controls (P less than 0.001). Vegetations from penicillin-treated animals averaged 5.14 +/- 1.00 log CFU/g, and no vegetations were sterile. Treatment with penicillin plus gentamicin or amikacin was more effective than treatment with penicillin alone, resulting in 3.99 +/- 0.94 log CFU/g of vegetation and sterile lesions in 5 of 12 animals. Treatment with vancomycin alone was as least as efficient as that with penicillin plus an aminoglycoside, resulting in an average of 3.33 +/- 0.96 log CFU/g of vegetation and sterile lesions in five of eight animals. Treatment with vancomycin plus an aminoglycoside was not superior to treatment with vancomycin alone, resulting in an average of 3.68 +/- 1.37 log CFU/g of vegetation and sterile lesions in 8 of 13 animals. These in vivo results correlated poorly with the in vitro susceptibility of the strain to the various antibiotics, as measured by the time-kill method. These results support the current practice of using vancomycin as alternative therapy when a penicillin-aminoglycoside combination is ineffective or contraindicated in patients with endocarditis caused by nutritionally variant streptococci.
Uptake, intracellular activity, and influence of rifampin on normal function of polymorphonuclear leukocytes
Authors: Höger P H , Vosbeck K , Seger R , Hitzig W H
Published: June 2012

Quinone and hydroquinone forms of rifampin accumulated in normal polymorphonuclear leukocytes (PMN) (maximal cellular to extracellular concentration ratio [C/Emax] +/- standard error of the mean, 9.36 +/- 0.54 and 8.82 +/- 0.65, respectively, after 5 to 10 min) and chronic granulomatous disease PMN (C/Emax, 13.76 +/- 0.77 and 14.29, respectively). Uptake of rifampin was influenced by incubation temperature and extracellular pH but not by phorbol myristate acetate stimulation or metabolic inhibitors. At extracellular concentrations between 0.06 and 5.0 mg/liter, rifampin significantly reduced the number of staphylococci surviving inside chronic granulomatous disease PMN, thus compensating for the bactericidal defect inherent with this disease. Spontaneous migration and chemotaxis of normal PMN were unaffected by rifampin. However, phagocytosis of yeast particles and oxygen consumption of stimulated PMN were moderately depressed, and O2- production and chemiluminescence were significantly depressed in a dose-dependent manner. The bactericidal activity of normal PMN was not impaired. Inhibition of chemiluminescence and O2- release were also observed in a cell-free system. We conclude that rifampin possesses favorable characteristics for the effective elimination of intracellular microorganisms. Further studies are needed to evaluate the in vivo significance of ion scavenging by rifampin, which could be hazardous to immunocompromised patients.
In vitro activity of fosfomycin, alone and in combination, against methicillin-resistant Staphylococcus aureus
Authors: Alvarez S , Jones M , Berk S L
Published: June 2012

We tested 148 strains of clinical isolates of methicillin-resistant Staphylococcus aureus against fosfomycin alone and in combination with methicillin, cefamandole, gentamicin, trimethoprim, and vancomycin. Fosfomycin inhibited 90% of the 148 methicillin-resistant S. aureus strains at a concentration of 4 micrograms/ml. Synergism was observed in 97 strains (66%) with fosfomycin-cefamandole and in 69 strains (46%) with fosfomycin-methicillin. The combinations of fosfomycin with vancomycin, gentamicin, and trimethoprim were indifferent in most strains.
Susceptibility of feline herpesvirus 1 and a feline calicivirus to feline interferon and recombinant human leukocyte interferons
Authors: Fulton R W , Burge L J
Published: June 2012

Feline lung monolayer cultures were treated with either a feline interferon (IFN) or one of two recombinant human alpha-IFNs and then challenged with feline herpesvirus 1 (FHV-1), feline calicivirus (F-9 strain), or vesicular stomatitis virus. Treatment with these IFNs reduced the viral yield for each of these three viruses as compared with that of control cultures. Vesicular stomatitis virus was more sensitive to each IFN than were FHV-1 or feline calicivirus F-9.
Comparative in vitro activity of coumermycin against methicillin-resistant Staphylococcus aureus
Authors: Meyers B R , Srulevitch E S , Hirschman S Z
Published: June 2012

Coumermycin was the most active agent in vitro against methicillin-resistant Staphylococcus aureus when compared with fusidic acid, imipenem, rifampin, trimethoprim-sulfamethoxazole, and vancomycin. The MICs of coumermycin ranged from 0.002 to greater than 4 micrograms/ml and from 0.5 to greater than 4 micrograms/ml for inocula of 10(4) and 10(6) CFU/ml, respectively. The combination of coumermycin with either cephalothin or ciprofloxacin showed some synergy; antagonism was found with gentamicin.
Pharmacokinetics of ceftazidime in elderly volunteers
Authors: LeBel M , Barbeau G , Vallee F , Bergeron M G
Published: June 2012

The pharmacokinetics of ceftazidime after a 1-g bolus dose were studied in six elderly volunteers and 12 young subjects. Serum and urine samples were collected in serial order for 24 h and assayed by high-pressure liquid chromatography. The ceftazidime renal clearance was reduced in elderly subjects, a symptom related to normal aging of the kidneys. The decrease in volume of distribution in the elderly group may be explained by a reduction in total body water and an increase in fat tissue. Dosage adjustment is probably not necessary for otherwise healthy elderly patients requiring ceftazidime.
Antimicrobial therapy of experimental Legionella micdadei pneumonia in guinea pigs
Authors: Pasculle A W , Dowling J N , Frola F N , McDevitt D A , Levi M A
Published: June 2012

Several antimicrobial agents were evaluated for activity against experimental Legionella micdadei pneumonia in guinea pigs. Erythromycin, rifampin, doxycycline, and sulfamethoxazole-trimethoprim produced significant reductions in mortality. Penicillin, cefazolin, cefoxitin, chloramphenicol, and gentamicin were not efficacious even though, at the doses administered, the peak concentrations of these agents in serum substantially exceeded their MICs for the test strain. It is suggested that the poor performance of the latter group of agents resulted from poor penetration into cells in which L. micdadei was multiplying.