bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological profile and response to anti-pneumocystis agents of Pneumocystis carinii in cell culture
Authors: Pifer L L , Pifer D D , Woods D R
Published: June 2012

Although the growth characteristics of Pneumocystis carinii have been described in several cell culture systems, the response of this organism to the drugs of choice, trimethoprim-sulfamethoxazole and pentamidine isethionate, have not been described in vitro. The effect of various concentrations of drugs against P. carinii on the growth of this potentially hazardous opportunistic organism as well as the methodology for in vitro assay of these agents have been detailed. Fluorescence profiles illustrating size ranges of trophozoites and cysts derived from cell culture are described.
Evaluation of aztreonam in experimental bacterial meningitis and cerebritis
Authors: Scheld W M , Brodeur J P , Gratz J C , Foresman P , Rodeheaver G
Published: June 2012

Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with ampicillin, ampicillin plus chloramphenicol, and gentamicin in rabbits with experimental meningitis induced by, respectively, ampicillin-susceptible Haemophilus influenzae, ampicillin-resistant H. influenzae, and Escherichia coli. Aztreonam was also compared with gentamicin in experimentally induced E. coli cerebritis in rats. Doses of the various agents were delivered that produced near-peak concentrations in serum comparable to those attained in humans on standard parenteral regimens. The percent penetration [( concentration in cerebrospinal fluid/concentration in serum] X 100) of aztreonam into purulent rabbit cerebrospinal fluid was 23% (versus 12, 27, and 21%, respectively, for ampicillin, chloramphenicol, and gentamicin). In experimental meningitis in vivo, aztreonam was more rapidly bactericidal than was ampicillin in ampicillin-susceptible H. influenzae meningitis, ampicillin or chloramphenicol in ampicillin-resistant H. influenzae meningitis, or gentamicin in E. coli meningitis. In the therapy of experimental cerebritis, the early stage of brain abscess formation, aztreonam reduced the numbers of E. coli in rat brain as rapidly as did gentamicin. Aztreonam deserves further evaluation in acute gram-negative bacterial infections of the central nervous system in both experimental animals and in humans.
Multiply resistant viridans streptococci: susceptibility to beta-lactam antibiotics and comparison of penicillin-binding protein patterns
Authors: Farber B F , Eliopoulos G M , Ward J I , Ruoff K L , Syriopoulou V , Moellering R C
Published: June 2012

A unique group of viridans streptococci has been found in South Africa. These organisms were isolated in close temporal and physical proximity to the isolation of penicillin-resistant pneumococci. The strains were resistant to penicillin, oxacillin, the cephalosporins (all generations), piperacillin, azlocillin, and mezlocillin but were susceptible to vancomycin. Penicillin-binding proteins of two penicillin-resistant South African strains of Streptococcus mitis differed markedly from those of two penicillin-susceptible strains but were identical to those seen in a penicillin-resistant strain isolated in Boston. Although both susceptible strains were identified as S. mitis with identical biochemical profiles, their penicillin-binding protein patterns differed from each other. This finding may have significance with regard to the need for additional taxonomic classification of the viridans streptococci.
Evaluation of prodrugs of 9-beta-D-arabinofuranosyladenine for therapeutic efficacy in the topical treatment of genital herpesvirus infections in guinea pigs
Authors: Shannon W M , Arnett G , Baker D C , Kumar S D , Higuchi W I
Published: June 2012

Prodrugs of the antiviral agent 9-beta-D-arabinofuranosyladenine (araA), which were more effective than the parent compound in penetrating vaginal membranes in vitro, were synthesized and examined for efficacy in the topical treatment of genital infections with herpes simplex virus type 2 in female guinea pigs. Treatment with 10% araA-5'-monophosphate or 10% araA-5'-monovalerate twice a day for 7 days, starting 6 h after intravaginal inoculation with virus, completely aborted the primary infection. When initiation of treatment was delayed until 24 h postinfection, araA-5'-monophosphate and araA-5'-monovalerate were no longer effective in reducing the mean lesion scores or mean vaginal virus titers. Treatment with 5% acyclovir, starting at 24 h postinfection, failed to prevent genital lesion development but significantly reduced the peak mean lesion score (approximately 50%). Topical therapy with 10% araA-2',3'-diacetate, initiated at 24 h postinfection, was as effective as, if not more effective than, acyclovir in reducing the severity of herpes genitalis in guinea pigs. Treatment with 10% araA-2',3'-dipropionate or 10% araA-2',3'-dibutyrate was without benefit. Among a series of 5'-monoesters of araA, araA-5'-monobutyrate appeared to be the most effective but was less active than araA-2',3'-diacetate. These data indicate that araA-2',3'-diacetate may be an effective antiviral agent for topical use against genital herpesvirus infections.
Enhanced activity of streptomycin and chloramphenicol against intracellular Escherichia coli in the J774 macrophage cell line mediated by liposome delivery
Authors: Stevenson M , Baillie A J , Richards R M
Published: June 2012

Streptomycin and chloramphenicol were entrapped within large neutral or anionic unilamellar vesicles of egg phosphatidylcholine prepared by an ether injection method. Both antibiotics in liposomal form were inactive against Escherichia coli in a simple tube dilution assay. A comparison was made of the activities of the free and liposomal forms of the antibiotics against E. coli located within the macrophages of the J774.2 murine cell line. The apparent intracellular antibacterial activity of both antibiotics was increased more than 10-fold by entrapment in neutral liposomes and in the case of chloramphenicol in anionic liposomes containing phosphatidylserine. Anionic liposomes containing phosphatidic acid were much less effective carriers than neutral liposomes for either antibiotic in this in vitro system. Incubation at 4 degrees C of cells with liposomes containing antibiotic or carboxyfluorescein inhibited intracellular antibacterial activity and cell-associated fluorescence. The high intracellular activity of the liposomal antibiotics is consistent with their phagocytic uptake by the macrophages followed by intracellular liposomal degradation and antibiotic release. Liposomal modification of cellular uptake and intracellular distribution of antibiotics may be used to extend the activity of existing and new agents against intracellular infection of the reticuloendothelial system.
Mechanism of action of habekacin, a novel amino acid-containing aminoglycoside antibiotic
Authors: Tanaka N , Matsunaga K , Hirata A , Matsuhisa Y , Nishimura T
Published: June 2012

The molecular basis for activity of habekacin was studied by using Escherichia coli Q-13. Electron microscopic studies revealed that numerous blebs, derived from the outer membrane, were formed on cells treated with habekacin. Cytoplasmic contents leaked into the lumina of blebs, and the membrane of some enlarged blebs was disrupted. In a cell-free system, habekacin interfered with polypeptide synthesis, caused codon misreading, and inhibited translocation of N-acetylphenylalanyl-tRNA from the acceptor site to the donor site on ribosomes. [3H]habekacin bound to both 50S and 30S ribosomal subunits. The current experiments indicated that the mechanism of action of habekacin is similar to that of 2-deoxystreptamine-containing aminoglycoside antibiotics such as dibekacin, kanamycin, gentamicin, and related substances. The relationship of membrane damage to inhibition of ribosomal functions remains to be determined.
Activity of AMP against experimental herpes simplex virus type 1 infections in mice
Authors: Blue W T , Macias E A , Sklar S H
Published: June 2012

Administration of AMP soon after inoculation of mice with herpes simplex virus type 1 inhibited development of virus-induced lesions and appeared to prevent establishment of virus latency. These effects were dependent on both the AMP dose and the time of AMP administration. Regression of herpes simplex virus type 1-induced lesions was also accelerated significantly by AMP treatment in a time- and dose-dependent manner.
Synergism of imipenem and amikacin in combination with other antibiotics against Nocardia asteroides
Authors: Gombert M E , Aulicino T M
Published: June 2012

The in vitro activities of imipenem (formerly imipemide, N-formimidoyl thienamycin, or MK0787) and amikacin in combination with cefotaxime, trimethoprim-sulfamethoxazole, and each other were tested against 26 Nocardia asteroides strains. The agar dilution method was used for all tests. Synergy was present in 80% of tests with imipenem-trimethoprim-sulfamethoxazole, in 92% of tests with imipenem-cefotaxime, and in 83% of tests with amikacin-trimethoprim-sulfamethoxazole. Indifference was found on rare occasions, and no antagonism was seen.
Kinetic analysis in cell culture of the reversal of antiherpes activity of nucleoside analogs by thymidine
Authors: Larsson A , Brännström G , Oberg B
Published: June 2012

The inhibition of herpes simplex virus type 1 plaque formation by acyclovir, bromovinyldeoxyuridine, 9-(3,4-dihydroxybutyl)guanine, and 9-(4-hydroxybutyl)guanine at different thymidine concentrations was analyzed in Lineweaver-Burk plots. Linear competitive patterns between thymidine and the nucleoside analogs were observed for the inhibition of herpes simplex virus type 1 plaque formation. A new constant, the reversal constant Kr, was introduced to describe the sensitivity in cell culture of an antiviral drug to the reversal of its viral activity by a metabolite (e.g., thymidine).
Resistance to penicillin-streptomycin synergy among clinical isolates of viridans streptococci
Authors: Farber B F , Eliopoulos G M , Ward J I , Ruoff K , Moellering R C
Published: June 2012

Viridans streptococci are thought to be highly susceptible to penicillin and streptomycin. We recently encountered a unique group of 15 isolates from South Africa epidemiologically related to the isolation of penicillin-resistant pneumococci. These organisms were highly resistant to penicillin (PCN) (minimal inhibitory concentration, 1 to 32 micrograms/ml) and streptomycin (SM) (minimal inhibitory concentration, greater than or equal to 2,000 micrograms/ml). Two additional organisms with high-level streptomycin resistance were identified when 168 clinical isolates from Boston were screened. Time-kill studies with four organisms resistant to high levels of SM demonstrated lack of synergy between PCN and SM but marked synergy between PCN and gentamicin. Adenylylating, acetylating, and phosphorylating activity could not be detected in three organisms studied, and novobiocin failed to cure the SM resistance. Protein synthesis by ribosomes isolated from these organisms was dramatically reduced in the presence of gentamicin but was relatively resistant to inhibition by SM.
Relationship between pNG2, an Emr plasmid in Corynebacterium diphtheriae, and plasmids in aerobic skin coryneforms
Authors: Schiller J , Strom M , Groman N , Coyle M
Published: June 2012

Erythromycin-resistant (Emr) coryneforms from cutaneous lesions and erythromycin-susceptible (Ems) coryneforms from normal skin sites were screened for plasmids. Approximately one-third of the 40 isolates carried one or more plasmids ranging in mass from 2.5 to 36 megadaltons, all exhibiting different restriction enzyme digest patterns. In contrast, only Corynebacterium diphtheriae strains comprising a single cohort of apparently identical Emr, pNG2-carrying isolates have been identified as plasmid carriers. Homology was demonstrated between pNG2 and a number of fragments in restriction enzyme digests of plasmids from both Emr and Ems skin coryneforms under high-stringency conditions. However, none was detected between pNG2 and the genomic or plasmid DNAs of Emr staphylococci or streptococci isolated concurrently with the Emr coryneforms. One coryneform plasmid, pNG34, exhibited extensive homology with pNG2, and many comigrating fragments were observed. Very little relationship was observed between C. diphtheriae and the skin coryneforms when their genomic DNAs were hybridized. The origin and presence of pNG2 in Emr C. diphtheriae is discussed in relation to these findings.
Correlation of microenvironmental drug concentration with inhibition of growth of microorganisms on surfaces
Authors: Cesar E Y , Sonobe T , Higuchi W I
Published: June 2012

Methodologies have been developed to study the concept of microenvironmental drug concentration (C*) near or around microorganisms. C* may be calculated from data on drug release from a depot site by using appropriate diffusion relationships. By following C* and correlating this with the minimum inhibitory concentration (CMIC), one could attempt to predict the effectiveness of an antiplaque agent. When C* is less than CMIC, growth would be expected to occur; when C* is higher than or equal to CMIC, growth would not be expected. Chlorhexidine diacetate was chosen for this study, which used a system involving microorganisms present on the surface of drug-treated hydroxyapatite pellets. CMIC, defined as the lowest concentration to inhibit bacterial growth, was determined independently and under conditions similar to those used in the C* experiments. Surface growth of adhering microorganisms (Streptococcus mutans SL1) was followed by scanning electron microscopy. The parameters used in the calculation of C* were determined independently. Diffusion coefficients of the drugs and the diffusion layer thickness were determined under conditions similar to those employed in the release rate studies. Surface growth was generally found to be inhibited whenever C* was significantly greater than CMIC, and growth occurred whenever C* was significantly smaller than CMIC. These findings demonstrate how C* may determine the action of a topically administered antimicrobial agent and how the various physical and chemical factors play roles in influencing this quantity.
Antibiotic susceptibilities and auxotypes of Neisseria gonorrhoeae strains from women with pelvic inflammatory disease or uncomplicated infections
Authors: Jacques M , Turgeon P L , deRepentigny J , Mathieu L G
Published: June 2012

The purpose of the present study was to compare the auxotypes and the minimal inhibitory concentrations of four antibiotics for 50 isolates from women with gonococcal pelvic inflammatory disease with those of 55 isolates from uncomplicated anogenital gonococcal infections. No significant differences in auxotype patterns and susceptibilities were found between isolates from the two groups.
Evaluation of three 4"-deoxy-4"-sulfonamido-oleandomycin derivatives with erythromycin-like antibacterial potency
Authors: English A R , Retsema J A , Girard A E , Schelkly W , Lynch J E
Published: June 2012

Three derivatives of oleandomycin in which the C"-4 hydroxyl moiety was replaced for the first time with a nitrogen functionality have been compared with erythromycin base and oleandomycin base. The minimum inhibitory concentrations of these derivatives for 90% of a group of clinical isolates of Staphylococcus aureus were one-half to one-fourth those of erythromycin. The minimum inhibitory concentrations of the experimental macrolides for 50% of a group of S. aureus isolates resistant to greater than 12.5 micrograms of erythromycin per ml ranged from 0.2 to 0.39 micrograms/ml. The activities of these experimental compounds were equivalent to the activities of erythromycin against Staphylococcus epidermidis, Bacteroides fragilis, and Haemophilus influenzae isolates. In general, erythromycin was more active against Streptococcus species. Each experimental macrolide was superior to erythromycin in inhibiting RNA-directed, cell-free polypeptide synthesis. The three experimental compounds were markedly more active than erythromycin base after oral administration to mice infected with S. aureus. The 50% protective doses of the experimental compounds ranged from 27.4 to 45.7 mg/kg; that of erythromycin was approximately 100 mg/kg.
Importance of extracellular and cell-bound beta-lactamase in mediating resistance of Staphylococcus aureus to mezlocillin
Authors: Haller I
Published: June 2012

Most penicillin-resistant staphylococci release a considerable portion of their beta-lactamase into the surrounding medium. Accumulation of this exoenzyme in conventional susceptibility test systems may result in a rapid inactivation of hydrolyzable antibiotics. Since under in vivo conditions the concentration of extracellular beta-lactamase should depend on the site of infection, susceptibility of Staphylococcus aureus to mezlocillin, a broad-spectrum penicillin, was measured in an open test model which prevented build-up of exoenzyme. The staphylococcal cells were immobilized and incubated between two membrane filters, and the excreted beta-lactamase was washed out by a constant flow of broth containing the antibiotic. Two test strains which produced large amounts of extracellular beta-lactamase and which were found to be resistant in the broth dilution test proved to be susceptible to mezlocillin in the open test model. This indicates that resistance to mezlocillin as measured by the broth dilution method was mediated predominantly by the extracellular enzyme fraction. Experiments performed with small infective doses in a model of peritoneal infection in leukopenic mice suggest that mezlocillin exhibits a therapeutic effect against beta-lactamase-producing staphylococci under certain in vivo conditions in which build-up of extracellular beta-lactamase does not occur.
In vitro susceptibility of human and environmental isolates of Mycobacterium avium, M. intracellulare, and M. scrofulaceum to heavy-metal salts and oxyanions
Authors: Falkinham J O , George K L , Parker B C , Gruft H
Published: June 2012

Because of the widespread distribution of Mycobacterium intracellulare and M. scrofulaceum in southeastern U.S. waters, the susceptibility of members of these species to heavy-metal salts and oxyanions was investigated. Isolates with abnormally high tolerance to mercuric chloride or cadmium chloride were identified.
Kinetic studies on the inhibition of Proteus vulgaris beta-lactamase by imipenem
Authors: Hashizume T , Yamaguchi A , Hirata T , Sawai T
Published: June 2012

Imipenem was found to inhibit Proteus vulgaris beta-lactamase in a progressive manner. Kinetic experiments confirmed that the inactivated enzyme was not completely recovered after intact imipenem had been exhausted.
Combined interferon-alpha 2, rimantadine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro
Authors: Hayden F G , Schlepushkin A N , Pushkarskaya N L
Published: June 2012

Recombinant DNA-produced human interferon-alpha 2 inhibited the replication of influenza A and B viruses in primary rhesus monkey kidney cells (RMK). Human interferon-alpha 2 interacted additively or synergistically with rimantadine hydrochloride or ribavirin in reducing the yield of clinical isolates of either H3N2 or H1N1 subtype influenza A viruses. The combination of human interferon-alpha 2 and ribavirin also inhibited the replication of an influenza B virus to a greater extent than either single agent. In addition to drug concentration, the virus inoculum and duration of culture were important variables in determining the degree of inhibition. Single drugs or combinations did not significantly inhibit the growth of uninfected RMK cells, which indicated that the observed interactions with respect to antiviral activity were not due to cell cytotoxicity.
Mezlocillin pharmacokinetics in pediatric oncology patients
Authors: Kramer W G , Pickering L K , Culbert S , Frankel L S
Published: June 2012

The pharmacokinetics of mezlocillin were studied in 31 children (age, 2 to 19 years) with malignancies and normal renal and hepatic functions. Mezlocillin was administered intravenously over 30 min every 4 h at doses ranging from 12.2 to 125 mg/kg. Blood samples were obtained over one dosage interval at steady state. For all patients, the mean clearance was 0.21 +/- 0.11 liter/h per kg, the mean distribution volume was 0.26 +/- 0.13 liter/kg, and the mean elimination half-life was 0.97 +/- 0.51 h. Trough concentrations were 23.0 +/- 29.9 mg/liter before the dose was administered and 20.4 +/- 27.5 mg/liter at the end of the dosing interval. Peak concentrations averaged 245 +/- 90.4 mg/liter, and average concentrations for the dosing interval were 83.7 +/- 40.4 mg/liter. There were no apparent effects of sex, malignancy, age, or dose on either the kinetic parameters or plasma concentrations. Overall, the disposition parameters for mezlocillin in this patient group were comparable to those reported in adults.
Synergism between penicillin, clindamycin, or metronidazole and gentamicin against species of the Bacteroides melaninogenicus and Bacteroides fragilis groups
Authors: Brook I , Coolbaugh J C , Walker R I , Weiss E
Published: June 2012

Clinical isolates of the Bacteroides melaninogenicus and Bacteroides fragilis groups were tested for in vitro and in vivo susceptibility to penicillin, clindamycin, and metronidazole, used singly or in combination with gentamicin. The in vitro tests consisted of determinations of minimal inhibitory concentrations (MICs) carried out with or without constant amounts of gentamicin. When used alone, gentamicin had negligible effects on the bacteria but significantly reduced the MICs of penicillin, clindamycin, and metronidazole against 11, 10, and 3, of the 15 strains of the B. melaninogenicus group, respectively. The 15 strains of the B. fragilis group were all beta-lactamase producers and were highly resistant to penicillin or the combination of penicillin and gentamicin. However, gentamicin reduced the MICs of clindamycin and metronidazole against 1 and 7 strains of this group, respectively. The in vivo tests were carried out in mice and consisted of measurements of the effects of the antimicrobial agents on the sizes and bacterial content of abscesses induced by subcutaneous injection of bacterial suspensions. The results of the in vivo tests were generally consistent with those obtained in vitro with strains of the B. melaninogenicus group. Synergism between gentamicin and penicillin, clindamycin, or metronidazole was shown in 13, 10, and 3 strains of this group, respectively. In vivo synergism was not clearly demonstrated with the strains of the B. fragilis group, possibly because clindamycin and metronidazole used alone were highly efficacious. We suggest that the synergistic effect of gentamicin is due to its increased transport into the bacterial cell in the presence of penicillin and, possibly, other antimicrobial agents. The newly recognized in vitro and in vivo synergism between penicillin and other antimicrobial agents and an aminoglycoside in B. melaninogenicus may have clinical implications that deserve to be investigated.
Immunology of the monobactam aztreonam
Authors: Adkinson N F , Swabb E A , Sugerman A A
Published: June 2012

To assess the immunological cross-reactivity of the monobactam antibiotic aztreonam (AZ), rabbits were immunized with protein conjugates of benzylpenicillin, cephalothin (CEPH), and AZ. The resulting antibenzylpenicilloyl (BPO) and anti-CEPH rabbit antibodies showed negligible cross-reactivity with AZ conjugated to human serum albumin (AZ-HSA), whereas anti-AZ showed negligible cross-reactivity with BPO-HSA and CEPH-HSA. Unlike benzylpenicillin and CEPH, unconjugated AZ was as effective as AZ conjugated to epsilon aminocaproic acid (AZ-EACA) in inhibiting the binding of homologous antibody. Studies with various analogs of AZ confirmed that immunoglobulin G (IgG) anti-AZ was entirely side-chain specific. The inhibition of the binding of human IgE anti-penicilloyl to BPO-HSA was studied in the presence of AZ-EACA, BPO-formyl lysine, and CEPH-EACA. Whereas CEPH-EACA displayed 3% cross-reactivity with BPO-lysine, AZ-EACA showed little or no cross-reactivity (much less than 0.9%). To assess the immunogenicity of AZ in humans, IgE and IgG antibodies were measured in sera from 36 healthy male volunteers receiving 0.5 or 1 g intravenously or intramuscularly every 8 h for 7 days. None of the subjects had detectable preexisting IgE reactive with AZ or demonstrated an IgE response to antibiotic administration. Four subjects gave evidence for naturally occurring IgG cross-reactive with AZ, but only one subject demonstrated a rise in IgG levels after exposure to AZ. This anti-AZ IgG did not cross-react with BPO or CEPH conjugates of bovine thyroglobulin and was completely side-chain specific. These studies suggest that AZ displays very low immunological cross-reactivity with other beta-lactam antibiotics and may be only weakly immunogenic in humans.
Pharmacokinetics of ceftazidime in patients with renal insufficiency
Authors: Welage L S , Schultz R W , Schentag J J
Published: June 2012

The pharmacokinetics of ceftazidime were studied in 14 adult volunteers with different degrees of renal function. The elimination of ceftazidime was totally dependent on renal excretion. The clearance of ceftazidime ranged from 7.5 to 145.1 ml/min and correlated with both renal ceftazidime clearance and creatinine clearance (ClCR). It is recommended that 0.5 to 2.0 g of ceftazidime be given in extended dosages, with intervals dependent on the renal function of the patient. Patients with a ClCR of greater than 50 ml/min should be given ceftazidime every 8 h, those with a ClCR of 30 to 50 ml/min should be given the drug every 12 h, those with a ClCR of 15 to 30 ml/min should be given the drug once a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a day, and individuals with a ClCR of less than 15 ml/min should be given the drug on a 36- to 48-h regimen.
Pharmacokinetics of cefpiramide (SM-1652) in humans
Authors: Nakagawa K , Koyama M , Matsui H , Ikeda C , Yano K , Nakatsuru N , Yoshinaga K , Noguchi T
Published: June 2012

The pharmacokinetics of cefpiramide (SM-1652) were studied after the intravenous administration of single or multiple doses to 21 healthy volunteers. The cefpiramide concentration in plasma at time zero after a bolus intravenous injection of 500 or 1,000 mg was 152 or 303 micrograms/ml, respectively. The maximum cefpiramide level in plasma at the end of a 1-h infusion of 1,000 or 2,000 mg was 166 or 317 micrograms/ml, respectively. The mean plasma half-life of cefpiramide in 15 subjects who received a single dose of 500 or 1,000 mg was 4.44 h. There was no evidence of drug accumulation in plasma when 500 or 1,000 mg of cefpiramide was administered 11 times at 12-h intervals. Urinary excretion of cefpiramide over a 24-h period was ca. 22.5%, regardless of the intravenous administration technique and the dosage. Fecal recoveries of cefpiramide varied from 0 to 36.9% in different subjects.
Amoxicillin plus clavulanic acid in the treatment of recurrent urinary tract infections
Authors: Brumfitt W , Hamilton-Miller J M
Published: June 2012

Forty-four patients (43 female, 1 male), all with a history of recurrent urinary tract infections, were treated with 250 mg of amoxicillin plus 125 mg of clavulanic acid (one tablet of Augmentin) every 8 h for 7 days. The microbiological cure rates were 84% 1 week after the end of treatment and 67% 1 month later. Side effects, which were reported by 20% of the patients, were mild and in no case caused interruption of treatment. In view of the increasing trend in resistance to agents commonly used for the treatment of urinary tract infections in outpatients, the combination of amoxicillin and clavulanic acid may now be considered a first-line drug in patients with recurrent urinary tract infections.
In vitro activities of aztreonam, piperacillin, and ticarcillin combined with amikacin against amikacin-resistant Pseudomonas aeruginosa and P. cepacia isolates from children with cystic fibrosis
Authors: Aronoff S C , Klinger J D
Published: June 2012

Amikacin, combined with aztreonam, piperacillin, or ticarcillin, synergistically inhibited amikacin-resistant sputum isolates of Pseudomonas aeruginosa and P. cepacia from children with cystic fibrosis. Ticarcillin-amikacin was the least active combination. Aminoglycoside resistance should not preclude the use of beta-lactam-aminoglycoside combinations in the treatment of pulmonary infections in cystic fibrosis.
In vitro activities of two new antifungal azoles
Authors: Hoeprich P D , Merry J M
Published: June 2012

The antifungal activities of equimolar quantities of three azole compounds, Bay n 7133 [1-(4-chlorophenoxy)-3,3-dimethyl-2-(1,2,4-triazole-1-yl)methylbutan-2-O1], Bay 1 19139 [1-(4-chlorophenoxy)-1-(1-imidazolyl)-3,3-dimethyl-2-butanol hydrochloride], and ketoconazole, were compared by testing the susceptibility in vitro of 10 clinical isolates each of Candida albicans, Candida parapsilosis, Torulopsis glabrata, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, Rhizopus spp., Mucor spp., and Coccidioides immitis. Molecule for molecule, ketoconazole was consistently the most active drug. All three azoles were primarily fungistatic, although they were fungicidal at clinically relevant concentrations against some strains of A. niger.
Pharmacokinetics and tolerance of cefuroxime axetil in volunteers during repeated dosing
Authors: Sommers D K , Van Wyk M , Williams P E , Harding S M
Published: June 2012

A total of 158 volunteers each received 21 repeated oral doses of 500 mg of cefuroxime axetil (CAE) during four comparative cross-over trials. Pharmacokinetics were studied in 8 volunteers (CAE versus ampicillin), relative bioavailability and tolerance were studied in 100 volunteers (CAE versus pivmecillinam and CAE versus pivampicillin), and tolerance alone was studied in 50 volunteers (CAE versus ampicillin). Overall, urinary recoveries of the active antibiotics ranked absorption of the drugs in the order least to greatest: pivmecillinam, ampicillin, CAE, and pivampicillin. The pharmacokinetics of CAE and ampicillin did not change after repeated dosing. Peak serum levels of cefuroxime were significantly higher than those of ampicillin after doses 1 and 21 but the urinary recoveries of both antibiotics were around 35% of the dose. CAE was as well tolerated as ampicillin but there were smaller numbers of episodes of fluid bowel motions on pivmecillinam and pivampicillin than on CAE, which may have been due to the smaller amounts of active antibiotic in the doses of the pivaloyloxymethyl esters.
Biliary excretion of aztreonam in patients with biliary tract disease
Authors: Martinez O V , Levi J U , Devlin R G
Published: June 2012

The biliary excretion of aztreonam was studied in 10 post-cholecystectomy patients with T-tube biliary drainage (group A) and four other subjects with obstructive biliary tract disease who had recent placement of external biliary drainage (group B). Maximum biliary levels ranged from 9.7 to 88.2 micrograms/ml (mean, 42.9 +/- 7.9 micrograms/ml) and occurred 2.4 h after injection of a single 1-g dose intravenously. Peak biliary levels observed in group B patients were approximately one-third those in group A. Cumulative 12-h biliary excretion (group B) accounted for 0.18 +/- 0.06% of the total dose. In the same period, urinary excretion accounted for 65 to 72% of the total dose. The lower biliary levels of aztreonam observed in group B patients relative to those in group A suggest that in patients with total biliary tract obstruction the liver may not recover full secretory capacity, at least within 3 to 7 days after biliary decompression.
Resistance of Pseudomonas aeruginosa mutants with altered control of chromosomal beta-lactamase to piperacillin, ceftazidime, and cefsulodin
Authors: Bryan L E , Kwan S , Godfrey A J
Published: June 2012

Examination of beta-lactam susceptibility of mutants altered in the control of chromosomal beta-lactamase of Pseudomonas aeruginosa supports the view that a constitutive level of beta-lactamase is not an adequate explanation for resistance to cefsulodin and ceftazidime but could be for resistance to piperacillin which has an efficiency of hydrolysis ca. 10 times higher than does cefsulodin or ceftazidime.
Antibiotic resistance of Erysipelothrix rhusiopathiae isolated from pigs with chronic swine erysipelas
Authors: Takahashi T , Sawada T , Ohmae K , Terakado N , Muramatsu M , Seto K , Maruyama T , Kanzaki M
Published: June 2012

The susceptibility of 258 isolates of Erysipelothrix rhusiopathiae from slaughtered pigs affected with chronic erysipelas in Japan to antimicrobial agents was determined. A total of 111 (43.0%) strains showed resistance to erythromycin, oleandomycin, oxytetracycline, or dihydrostreptomycin. Plasmids were not detected. This is the first report of resistance of E. rhusiopathiae to these antibiotics.
Ribosomal resistance of clinical enterococcal to streptomycin isolates
Authors: Eliopoulos G M , Farber B F , Murray B E , Wennersten C , Moellering R C
Published: June 2012

The mechanism of high-level resistance to streptomycin was studied in 12 clinical isolates of Streptococcus faecalis. Six strains produced streptomycin-modifying enzymes. Each of three enzyme-negative strains tested demonstrated ribosomal resistance to streptomycin. Lack of ribosomal susceptibility is a significant cause of high-level streptomycin resistance among clinical enterococcal isolates.
Susceptibility of vaccine strains of varicella-zoster virus to antiviral compounds
Authors: Preblud S R , Arbeter A M , Proctor E A , Starr S E , Plotkin S A
Published: June 2012

Using a plaque reduction assay, we determined the 50% effective doses of six antiviral compounds against low- and high-passage viruses of the KMcC and Oka strains of varicella-zoster virus vaccine. The potency, as indicated by the ranges of 50% effective doses (micrograms per milliliter) of the antiviral compounds, in decreasing order was as follows: (E)-5-(2-bromovinyl)-2'-deoxyuridine, 0.0007 to 0.0035; 1-(2'-flouro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine, 0.0063 to 0.0091; aphidicolin, 0.092 to 0.180; acyclovir, 0.79 to 1.81; vidarabine, 0.62 to 2.10; and phosphonoformic acid, 8.18 to 16.4. Susceptibility to the various antiviral compounds was independent of passage level or strain. These data, along with the available in vivo data, indicate that varicella-zoster virus vaccine infections requiring antiviral therapy most probably would be treated as effectively as would natural varicella infections.
Ceftriaxone pharmacokinetics in patients with various degrees of renal impairment
Authors: Patel I H , Sugihara J G , Weinfeld R E , Wong E G , Siemsen A W , Berman S J
Published: June 2012

The effects of renal impairment on the pharmacokinetics of ceftriaxone in humans were examined after intravenous infusion of a 1-g dose over 15 min to 30 renally impaired patients. The study included 12 dialysis patients and 18 patients with severe, moderate, or mild renal impairment. Plasma and, where appropriate, urine and dialysate samples were collected at predetermined times and analyzed for ceftriaxone by high-pressure liquid chromatography. The elimination half-life (group mean ranged from 11.7 to 17.3 h) and plasma clearance (group mean ranged from 529 to 705 ml/h) did not correlate linearly with creatinine clearance. The renal clearance and fraction of dose excreted unchanged in urine were related linearly, however weakly, with creatinine clearance. Ceftriaxone was not removed from plasma to a significant extent during hemodialysis. The half-life was prolonged twofold, the plasma clearance was lowered less than 50%, and the volume of distribution was relatively unchanged in renally impaired patients compared with young or elderly healthy subjects with normal renal function at an equivalent dose. Since these changes are moderate, adjustment in the dosage regimen of ceftriaxone for patients with impaired renal function should not be necessary when ceftriaxone dosage is 2 g or less per day (2 g every 24 h or 1 g every 12 h). It was reported that the elimination half-life of ceftriaxone is substantially prolonged in a small percentage of patients with end-stage renal disease maintained on hemodialysis. Therefore, plasma concentrations of ceftriaxone should be monitored in dialysis patients to determine whether dosage adjustments are necessary.
Energetics of tetracycline transport into Escherichia coli
Authors: Smith M C , Chopra I
Published: June 2012

The nature of energy coupling for the active transport of tetracycline into Escherichia coli was examined under conditions in which antibiotic uptake was directly compared with transport of proline (proton motive force dependent) and glutamine (phosphate bond dependent). Tetracycline transport was partially inhibited by osmotic shock and by exposure of bacteria to arsenate, two procedures which substantially reduced glutamine transport. Tetracycline transport was also partially inhibited in an uncB mutant (AN283) exposed to the uncoupler carbonyl cyanide-m-chlorophenyl hydrazone (CCCP) under conditions that inhibited proline transport. Taken together, these data indicate involvement of both phosphate bond hydrolysis and the proton motive force for the active transport of tetracycline into E. coli.
Penetration of cefoperazone into surgical wound drainage in patients undergoing head and neck surgery
Authors: Muder R R , Yu V L , Johnson J , Thearle P , Lyon J , Diven W
Published: June 2012

Cefoperazone penetration into skeletal muscle and wound drainage in patients undergoing major surgery of the head and neck was measured by high-pressure liquid chromatography. Cefoperazone (2 g) was infused over 30 min before surgery and every 8 h for three postoperative doses. Simultaneous samples of serum and sternomastoid muscle were collected in 18 patients at 135 to 480 min after infusion. Mean cefoperazone concentrations in muscle tissue were 17.1% of those in simultaneously collected serum. Steady-state wound drainage concentrations after the fourth dose of cefoperazone averaged 55.2 micrograms/ml at 1 to 2 h and 62.1 micrograms/ml at 2 to 3 h. Simultaneous steady-state serum and wound fluid samples were obtained at regular intervals in six patients. In all patients, the peak level in wound fluid exceeded 25 micrograms/ml. Thus, cefoperazone reaches interstitial fluid concentration in soft tissue that exceeds the MICs required to inhibit the usual pathogens found at the site of wound infection after head and neck surgery.
Stability of plasmid content in Salmonella wien in late phases of the epidemic history
Authors: Casalino M , Comanducci A , Nicoletti M , Maimone F
Published: June 2012

Prevalence, genetic characteristics, and EcoRI cleavage analysis of plasmids identified in clinical strains of Salmonella wien isolated in recent years showed that the plasmid content in this serotype has remained uniform and stable over more than a decade and also late in the epidemic history. No correlation between decrease in S. wien isolations and naturally occurring systematic changes in the DNA of its most common FIme plasmid was structurally detectable.
In vitro comparison of the activity of RU 28965, a new macrolide, with that of erythromycin against aerobic and anaerobic bacteria
Authors: Barlam T , Neu H C
Published: June 2012

RU 28965, a novel macrolide antibiotic, inhibited most gram-positive species at concentrations similar to that of erythromycin but was not active, even at alkaline pH, against Pseudomonas spp. or members of the family Enterobacteriaceae. Staphylococci and streptococci resistant to erythromycin were resistant to RU 28965. RU 28965 inhibited Haemophilus influenzae, including a number of beta-lactamase, ampicillin-resistant isolates, and Neisseria meningitidis and Neisseria gonorrhoeae at concentrations similar to those of erythromycin. Against anaerobic species, Bacteroides fragilis and Clostridia and Fusobacterium spp., RU 28965 was less active than erythromycin, but its activity against Campylobacter and Legionella spp. was similar to that of erythromycin.
In vitro synergistic activities of aminoglycosides and new beta-lactams against multiresistant Pseudomonas aeruginosa
Authors: Giamarellou H , Zissis N P , Tagari G , Bouzos J
Published: June 2012

The in vitro interactions between amikacin, netilmicin, tobramycin, gentamicin, and various antipseudomonal beta-lactams were studied by the agar dilution checkerboard technique against 30 Pseudomonas aeruginosa strains resistant to all tested antibiotics. Amikacin produced more frequent synergy both at the total and clinically applicable level. Among the beta-lactams, clinically relevant synergistic interactions were obtained in the following order: ceftazidime and ceftriaxone greater than moxalactam greater than aztreonam greater than cefotaxime greater than azlocillin greater than cefoperazone greater than cefsulodin greater than carbenicillin.
Tetracyclines of various hydrophobicities as a probe for permeability of Escherichia coli outer membranes
Authors: Leive L , Telesetsky S , Coleman W G , Carr D
Published: June 2012

The outer membrane of gram-negative cells excludes hydrophobic molecules and is responsible for the resistance of these cells to a number of dyes, detergents, and antibiotics. We describe a test for hydrophobic permeability in which a series of tetracyclines with various hydrophobicities are used. Normal Escherichia coli cells became more resistant as hydrophobicity was increased in this series, but mutants altered in outer membrane permeability remained susceptible. A mutant lacking all polysaccharide except 2-keto-3- deoxyoctonic acid in its lipopolysaccharide is virtually as susceptible to the hydrophobic drug 13- phenylmercapto -alpha-6- deoxytetracycline as to oxytetracycline (MIC 100 times lower than that of the wild type), and a mutant with another, as yet undefined outer membrane defect, acrA , also shows increased, although somewhat lesser, susceptibility (MIC 20 times lower than that of the wild type). Increased susceptibility to this tetracycline derivative is associated with greater fluorescence of the derivative when added to the cells, which we interpret as increased interaction of the derivative with hydrophobic domains, such as membranes, in the mutants. This series of tetracyclines may provide an assay for measuring the permeability of gram-negative organisms and their mutants to hydrophobic molecules.
Pharmacokinetic properties of mezlocillin in newborn infants
Authors: Odio C , Threlkeld N , Thomas M L , McCraken G H
Published: June 2012

The pharmacokinetic properties of mezlocillin were evaluated in newborn infants. Mean peak and trough concentrations of drug in plasma, after 75 mg of mezlocillin per kg given intravenously, were 252 and 72 micrograms/ml, respectively, in infants who were less than 38 weeks gestation and less than or equal to 7 days old, compared with 139 and 9 micrograms/ml, respectively, in infants greater than or equal to 38 weeks gestation and greater than 7 days old. The mean elimination half-life values were from 4.5 h in preterm infants who were less than or equal to 7 days old to 1.8 h in term infants greater than or equal to 7 days old. Median peak and trough bactericidal titers of drug in plasma from neonates treated with mezlocillin were 1:8 and 1:4, respectively, against a resistant (minimal bactericidal concentration, 512 micrograms/ml) Escherichia coli strain and 1:64 and 1:32, respectively, against a susceptible (minimal bactericidal concentration, 2 micrograms/ml) E. coli strain. We propose a dosage schedule of 75 mg of mezlocillin per kg administered every 12 h to preterm (gestational age less than 38 weeks) infants less than or equal to 7 days old, every 8 h to preterm infants greater than 7 days old or term infants less than or equal to 7 days old, and every 6 h to term infants greater than 7 days old.
Effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine on synthesis of herpes simplex virus type 1-specific polypeptides
Authors: Siegel S A , Otto M J , De Clercq E , Prusoff W H
Published: June 2012

The antiherpesvirus agent (E)-5-(2-bromovinyl)-2'-deoxyuridine caused marked alterations in the synthesis and processing of several herpes simplex virus type 1 (HSV-1)-infected-cell polypeptides. Analogous to other thymidine analogs, there was a dose-dependent decrease in several beta and gamma polypeptides and an accumulation of HSV-1 thymidine kinase. In contrast to the action of other thymidine analogs, there were alterations in alpha polypeptides, including an increase in the synthesis and phosphorylation of infected-cell polypeptide 4b and a decrease in the synthesis of infected-cell polypeptide 27. The phosphorylation of several other HSV-1 phosphoproteins was mildly inhibited. (E)-5-(2-Bromovinyl)-2'-deoxyuridine inhibited the glycosylation of the major HSV-1 glycoproteins, and this activity appeared to be independent of the incorporation of the drug into the viral DNA. Thus, the alterations in HSV-1 polypeptide expression appear to be due to the presence of the drug in a low-molecular-weight form as well as its presence in the viral DNA. This suggests that this analog or a phosphorylated derivative might act as an inhibitor of an enzyme(s) responsible for posttranslational modification of polypeptides.
Effect of synthetic protease inhibitors of the amidine type on cell injury by Rickettsia rickettsii
Authors: Walker D H , Tidwell R R , Rector T M , Geratz J D
Published: June 2012

To evaluate the importance of proteolytic activity in the pathogenesis of cell injury by Rickettsia rickettsii, a series of four aromatic amidine inhibitors of trypsin-like proteases were introduced into the plaque model. The compounds were shown to be active toward plaque reduction with their order of effectiveness parallel to their antitrypsin activity. One of the compounds, bis(5-amidino-2-benzimidazolyl)-methane, at a concentration of 10(-5) M demonstrated complete inhibition of plaque formation on day 6. Bis(5-amidino-2-benzimidazolyl)methane at the same concentration reduced cell injury even when added to the system after 72 h of rickettsial infection. The reduction in morbidity in guinea pigs experimentally infected with R. rickettsii and treated with bis(5-amidino-2-benzimidazolyl)methane as compared with morbidity in infected, untreated animals, comprised delay in the onset of fever and slightly fewer febrile animals. Because bis(5-amidino-2-benzimidazolyl)methane had no effect on phospholipase A2, the enzyme activity associated with penetration-induced cell injury, it is likely that a trypsin-like protease also plays an essential role either in the physiology of R. rickettsii or as its pathogenic mechanism.
Improved genetically modified Escherichia coli strain for prescreening antineoplastic agents
Authors: Bartus H R , Mirabelli C K , Auerbach J I , Shatzman A R , Taylor D P , Johnson R K , Rosenberg M , Crooke S T
Published: June 2012

Clinical experience suggests that drugs that interact with and damage DNA are useful in cancer chemotherapy (H. Umezawa , p. 43-72, in V. T. DeVita , Jr., and H. Busch [ed.], Methods in Cancer Research; Cancer Drug Development, vol. XVI, 1979). Prescreening systems for antitumor agents in natural products require assays that are exquisitely sensitive, since the active components are often produced in quantities of micrograms per milliliter or less. One assay used to identify agents that interact with DNA is the biochemical induction assay, utilizing Escherichia coli BR 513 (R. K. Elespuru and R. J. White, Cancer Res. 43:2819-2830, 1983). In this paper we describe a genetic modification of strain BR 513 that displays an expanded spectrum of activity. This strain may provide an improved prescreen for detecting natural products that interact with DNA.