bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical evaluation of piperacillin with observations on penetrability into cerebrospinal fluid
Authors: Dickinson G M , Droller D G , Greenman R L , Hoffman T A
Published: June 2012

Piperacillin, a new semisynthetic penicillin, was evaluated for efficacy and safety in 26 patients, most of whom had pneumonia. Included were four patients with gram-negative meningitis in whom the penetration of piperacillin into cerebrospinal fluid was determined. Cure was achieved in 11 of 17 patients with pneumonia; another 4 were improved. One relapse and one failure occurred among nine patients with gram-negative pneumonia. Cure or improvement occurred in seven of nine patients with gram-negative infection in various extrapulmonary sites. Piperacillin given by continuous infusion in a dosage ranging from 324 to 436 mg/kg of body weight per day to four patients with meningitis resulted in a mean cerebrospinal fluid level of 23 micrograms/ml at 24 h; the mean penetration of piperacillin into the cerebrospinal fluid was 32% at this interval. Levels of piperacillin in cerebrospinal fluid collected later during the course of therapy were also adequate. Adverse effects were noted in six patients, but only one episode of granulocytopenia was serious. Emergence of resistance to piperacillin did not occur, and only one superinfection was noted. Piperacillin appeared to be efficacious in the treatment of pneumonia. It penetrated well into the cerebrospinal fluid of patients with meningitis and may be useful for treatment of selected gram-negative infections in extrapulmonary sites.
Acyclovir therapy of neonatal herpes simplex virus type 2 infections in rabbits
Authors: Sicher S E , Oh J O
Published: June 2012

New Zealand white rabbits less than 30 h old were inoculated subcutaneously with 10(3) 50% tissue culture infectious doses of type 2 herpes simplex virus. The animals were randomly assigned to a treatment schedule of daily intraperitoneal injections of acyclovir, beginning on the day of virus inoculation for 6 or 12 days, on post-inoculation day 1 for 6 days, or on post-inoculation day 2 for 6 days. The acyclovir was given in doses of 50 mg/kg of body weight per day. Similarly infected animals receiving daily intraperitoneal injection of Eagle minimum essential medium served as controls. All of the control animals died on day 4 or 5 after inoculation. At death they exhibited severe skin lesions, viremia, and dissemination of virus in various visceral organs and spinal as well as trigeminal ganglia. In contrast, animals treated with acyclovir failed to develop significant skin lesions, and death did not occur while treatment continued. Termination of treatment after 6 days resulted in late-onset fatal disease and virus isolation from the brain in many rabbits regardless of the treatment schedule. No such late fatality was observed and no virus could be detected from the brain when treatment was initiated on the day of virus inoculation and continued for 12 consecutive days. With respect to all of the variables studied, treatment for 12 days beginning on the day of virus inoculation was most effective.
Intraventricular levels of amikacin after intravenous administration
Authors: Yogev R , Kolling W M
Published: June 2012

Serum and ventricular fluid pharmacokinetic data for amikacin were evaluated prospectively in 10 hydrocephalic children with suspected ventriculitis. After the fourth or fifth intravenous 7.5-mg/kg dose of amikacin given every 8 h, mean peak serum levels were 24.3 +/- 3.2 microgram/ml (achieved at 0.5 h) with a calculated half-life of 2.2 +/- 1.1 h. Mean peak ventricular fluid levels in five patients with bacterial infection were 6.1 +/- 2.0 microgram/ml (achieved at 3 h). In the remaining five patients without bacterial ventriculitis, very low levels (less than or equal to 0.7 microgram/ml) of amikacin were detected. Ventricular fluid pleocytosis was directly correlated and glucose levels were inversely correlated with penetration of amikacin. Systemic therapy with amikacin may be the treatment of choice for children with ventriculitis meningitis caused by bacteria which are highly susceptible to this drug, thereby permitting the avoidance of the potentially hazardous intraventricular route of administration.
Penetration of ocular tissues and fluids by moxalactam in rabbits with staphylococcal endophthalmitis
Authors: Kane A , Barza M , Baum J
Published: June 2012

Moxalactam was administered subconjunctivally in 100-mg doses to rabbits with infected eyes (Staphylococcus aureus endophthalmitis). High concentrations of drug were detected in the sclera, cornea, and choroid; much lower levels were found in the retina, whereas peak concentrations in the vitreous were about 6 microgram/ml. Repeated intramuscular injections of 50 mg/kg every 4 h produced peak serum levels of about 100 microgram/ml. A gradient between the choroid and the retina was again evident, and peak vitreous levels were about 6 microgram/ml after six injections. These data are consistent with the concept of a blood-retina barrier analogous to the blood-brain barrier. Moxalactam appears to penetrate the eye somewhat better than do other beta-lactams; however, the peak levels produced in the vitreous humor in this animal model were below the level required to inhibit most strains of Pseudomonas aeruginosa.
Pharmacokinetics of ceftriaxone in humans
Authors: Patel I H , Chen S , Parsonnet M , Hackman M R , Brooks M A , Konikoff J , Kaplan S A
Published: June 2012

Pharmacokinetics of the investigational cephalosporin ceftriaxone were studied after 30-min intravenous infusions of three ascending single doses of 0.5, 1, and 2 g crossed over in 12 normal subjects. Serially collected plasma and urine samples were analyzed for ceftriaxone by high-performance liquid chromatography. Plasma concentration-time profiles were characterized by a linear two-compartment open model with the following respective mean (+/- standard deviation) parameters at 0.5-, 1-, and 2-g dose levels: elimination half-life, 6.5 +/- 0.7, 6.2 +/- 0.8, and 5.9 +/- 0.7 h; apparent volume of distribution, 8.5 +/- 1.1, 9.0 +/- 1.1, and 10.1 +/- 1.0 liters; and plasma clearance, 929 +/- 150, 1,007 +/- 130, and 1,190 +/- 150 ml/h. The respective renal excretion parameters were as follows: renal clearance, 373 +/- 60, 399 +/- 50, and 533 +/- 128 ml/h; and percentage of dose excreted unchanged in the 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explainhe 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explainhe 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explained by the concentration-dependent plasma protein binding of ceftriaxone in humans. The impact of the small dose-dependent changes in the pharmacokinetics of ceftriaxone is anticipated to be of negligible clinical significance.
Inhibition of cellular and virus-associated nucleotide polymerases by, and anti-herpes simplex virus activity of, streptovaricin derivatives
Authors: Srivastava B I , DiCioccio R A , Chadha K C , Rinehart K L
Published: June 2012

Fourteen streptovaricin derivatives were tested for inhibition of cellular nucleotide polymerases (deoxyribonucleic acid polymerases alpha, beta, and gamma, terminal deoxynucleotidyltransferase [TdT], and ribonucleic acid polymerase II), simian sarcoma virus deoxyribonucleic acid polymerase, and herpes simplex virus type 1-induced deoxyribonucleic acid polymerase (HSV-DP). Three compounds (strep-tovadienal C, prestreptovarone, and streptoval Fc) preferentially inhibited TdT and HSV-DP over the other enzymes. These compounds inhibited HSV-DP more potently than they inhibited TdT. Evidence indicated that the mode of inhibition of TdT and HSV-DP by streptovadienal C and prestreptovarone was by interaction with the enzymes and not with template-primer, initiator, substrates, or divalent cations required for enzyme activity. Furthermore, data suggested that these compounds bind with greater affinity to HSV-DP than to TdT. Streptovadienal C and prestreptovarone were examined for their effect on the replication of herpes simplex virus type 1 in African green monkey kidney (CV1) cells. These compounds produced 2- and 3-log drops in virus titer, respectively, at concentrations not significantly affecting cell viability. This correlated with evidence indicating a greater binding affinity of these compounds for HSV-DP over cellular nucleotide polymerases.
Anaerobic plate method for assaying antimicrobial agents in serum
Authors: Smith J A , Ngui-Yen J H
Published: June 2012

An anaerobic agar plate method was devised for the assay of antimicrobial agents in serum by using a strain of Clostridium bifermentans. The method gave reproducible and accurate in assays of chloramphenicol, clindamycin, and metronidazole alone or in the presence of beta-lactam or aminoglycoside antibiotics.
Effect of carbon dioxide on in vitro susceptibility of anaerobic bacteria to erythromycin
Authors: Goldstein E J , Sutter V L , Kwok Y Y , Lewis R P , Finegold S M
Published: June 2012

The activity of erythromycin against 317 strains of anaerobic bacteria, including 133 strains of the Bacteroides fragilis group, was tested by the agar dilution method in an anaerobic atmosphere with two different concentrations of carbon dioxide and without CO2. The effect of the atmosphere of incubation on the agar surface pH was also determined. All strains grew well in the GasPak (GP) environment. However, 3.5 and 30.3% of strains failed to grow in the 2 and 0% CO2 environments, respectively. The quality of growth was best in the GP environment and poorest in the 0% CO2 environment. Minimal inhibitory concentrations in the GP and 2% CO2 environments were frequently the same or one dilution lower in the 0% than in the GP environment. In the 0% CO2 atmosphere, minimal inhibitory concentrations were usually two to three dilutions lower than in the GP environment. Consequently, only 24% of B. fragilis strains were susceptible to erythromycin in the GP environment, whereas 77% were susceptible in the 0% CO2 environment. For Fusobacterium species, 12% were susceptible to erythromycin in the GP environment, and 73% were susceptible in the 0% CO2 environment. There was a comparable decrease in pH in all three atmospheres tested. In vitro susceptibility testing of erythromycin against anaerobic bacteria should be performed in an atmosphere containing carbon dioxide.
Penicillin-binding proteins in Clostridium perfringens
Authors: Murphy T F , Barza M , Park J T
Published: June 2012

The penicillin-binding proteins (PBPs) of Clostridium perfringens were studied. Six PBPs ranging in molecular weight from approximately 42,000 to 100,000 were detected in the cytoplasmic membrane. The relative affinities of the PBPs for 16 beta-lactam antibiotics were determined. Most of the drug saturated PBP 3 and 4 at concentrations equal to their minimal inhibitory concentrations, suggesting that these PBPs are the killing targets for beta-lactams. Mecillinam showed unique properties; it had a higher affinity for PBP 5 than for other PBPs, and it was the only agent tested which caused inhibition of growth without saturating PBP 4. Interestingly, all beta-lactam antibiotics tested induced filament formation despite having different binding patterns to the PBPs of C. perfringens.
Antibiotic action of pyocyanin
Authors: Baron S S , Rowe J J
Published: June 2012

Biologically produced pyocyanin was purified, and the nature of its antibacterial action was determined for several bacteria. The pigment was shown to be bactericidal for all susceptible organisms. The bactericidal effect was dependent upon pyocyanin concentration and resulted in decreases in viability ranging from 1 to 8 log viable cells ml-1. The gram-positive bacteria were more susceptible as a group to the antibiotic action than were the gram-negative bacteria. All apyocyanogenic pseudomonads tested were totally resistant to the pigment, suggesting that resistance may be a characteristic of the genus. Pseudomonas aeruginosa, the producer organism, was also essentially unaffected by high concentrations of pyocyanin. Facultative anaerobes were twofold or more times resistant to the action of the pigment under fermentative conditions; however, the antibiotic action did not require oxygen since denitrifying bacteria were more susceptible during anaerobic respiration than during aerobic respiration.
Bioavailability of Bacampicillin and Talampicillin, Two Oral Prodrugs of Ampicillin
Authors: Sjövall Jan , Magni Lennart , Vinnars Erik
Published: June 2012

A 200-mg amount of bacampicillin showed a significantly higher relative extent of bioavailability than did a 250-mg amount of talampicillin, possibly due to their different stability in the digestive juices.
In Vitro Susceptibility of
Nocardia asteroides
to
N
-Formimidoyl Thienamycin and Several Cephalosporins
Authors: Cynamon Michael H. , Palmer Gregory S.
Published: June 2012

The susceptibility of
N. asteroides
to
N
-formimidoyl thienamycin, cefamandole, cefoxitin, and moxalactam was determined by agar dilution.
N
-Formimidoyl thienamycin was the most active, inhibiting eight of nine strains at 1.56 μg/ml.
Susceptibility of
Clostridium septicum
to 23 Antimicrobial Agents
Authors: Gabay Elizabeth L. , Rolfe Rial D. , Finegold Sydney M.
Published: June 2012

The in vitro susceptibility of
Clostridium septicum
was studied with a microtiter broth dilution method. Several antimicrobial agents demonstrated consistently good activity against the organism.
Novel antibiotic resistance transfer in Bacteroides
Authors: Mays T D , Smith C J , Welch R A , Delfini C , Macrina F L
Published: June 2012

Resistance to tetracycline and lincosamide antibiotics was transferred en bloc from a strain of Bacteroides fragilis (V503) to a plasmidless strain of Bacteroides uniformis (V528) during in vitro filter matings. Resistance transfer was detected at frequencies of 10(-5) to 10(-6) drug-resistant progeny per input donor cell and was dependent on cell-to-cell contact of donors and recipients. Transfer was insensitive to DNase and was not mediated by chloroform- or filter-sterilized donor broth cultures. A determinant for resistance to cefoxitin in V503 was not transferred in this system. V503 contained a 3.7 x 10(6)-dalton plasmid (pVA503). Drug-resistant progeny of V503 x V528 matings usually contained pVA503, but up to 20% of the total progeny of such crosses were plasmid free. Filter blot DNA hybridization studies (Southern method) confirmed that pVA503 was not integrated into the host chromosome of the plasmidless progeny. Drug-resistant progeny from V503 x V528 matings (with or without pVA503) conjugally transferred clindamycin resistance an tetracycline resistance to a suitable recipient strain. None of the drug resistance determinants of V503 were affected by treatment with standard plasmid curing regimens, and methods designed to detect very large plasmid molecules failed to suggest the involvement of extrachromosomal DNA in this resistance transfer system. The well-characterized Bacteroides R plasmid, pBF4 (conferring clindamycin resistance), was found to share hybridizing sequences with bulk cellular V503 DNA when examined by filter blot hybridization. Similarly sized sequences were found in drug-resistant progeny recovered from matings. Neither of the two pBF4 derivatives carrying deletions that abolished clindamycin resistance hybridized with V503 DNA.
In vivo inhibition of respiratory syncytial virus by ribavirin
Authors: Hruska J F , Morrow P E , Suffin S C , Douglas R G
Published: June 2012

Ribavirin reduced the amount of respiratory syncytial virus in nasal turbinates and lung tissues of experimentally infected cotton rats by over 90%. An effect was seen when the drug was given either intraperitoneally or by aerosol; however, the antiviral effect was achieved at much lower doses when delivered by the aerosol route. No animal deaths due to the drug were seen.
Pharmacokinetics of single-dose erythromycin in normal and alcoholic liver disease subjects
Authors: Kroboth P D , Brown A , Lyon J A , Kroboth F J , Juhl R P
Published: June 2012

Six normal males and eight male subjects with alcoholic liver disease (ALD) and ascites were given a single 500-mg dose of erythromycin base. Twelve serum samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, and 24 h after dosing and assayed microbiologically for erythromycin concentration. Absorption was characterized by a zero-order model for both groups. ALD subjects demonstrated a shorter lag time (2.0 versus 3.0 h), an earlier peak (4.6 versus 6.3 h, P less than 0.05), and higher peak concentrations (2.04 versus 1.50 micrograms/ml) than normal subjects. Previously unreported biphasic elimination kinetics after oral dosing were observed in five and four ALD subjects. In the ALD group, the mean half lives for the first (alpha) and terminal (beta) phases were 1.6 and 4.5 h, respectively, and in normal subjects, were 1.3 and 6.6 h. The difference in alpha between groups was significant, P less than 0.05. The clinical significance of this finding for ALD patients receiving prolonged courses of erythromycin is discussed.
Plasmid-mediated sulfonamide resistance in Haemophilus ducreyi
Authors: Albritton W L , Brunton J L , Slaney L , MacLean I
Published: June 2012

Clinical isolates of Haemophilus ducreyi from patients with chancroid were shown to have one or more 4.9- to 7.0-megadalton non-self-transferable plasmids and to have in vitro resistance to sulfonamides. Transformation of Escherichia coli to sulfonamide resistance was associated with the acquisition of a 4.9-megadalton plasmid, which did not confer linked resistance to streptomycin. The guanine-plus-cytosine content of this plasmid was found to be 57%. Filter-blot hybridization and restriction endonuclease digestion studies suggested a relationship of this plasmid to RSF1010. Electron microscope heteroduplex analysis confirmed this relationship. The identification in H. ducreyi of a plasmid closely related to plasmids found in enteric species, rather than transposition of a resistance determinant to an indigenous plasmid, suggests that further dissemination of the enteric plasmid pool to this genus is possible since plasmid transfer between certain Haemophilus species is readily demonstrated.
In vitro activity of BRL 17421 against Haemophilus influenzae, Neisseria gonorrhoeae, and Branhamella catarrhalis
Authors: Piot P , Van Dyck E
Published: June 2012

BRL 17421, a novel beta-lactam antibiotic, was tested in vitro against fastidious gram-negative bacteria and compared with amoxicillin and amoxicillin plus clavulanic acid. The compound showed good activity against Haemophilus influenzae (range of minimal inhibitory concentrations, 0.2 to 1 microgram/ml), Neisseria gonorrhoeae (0.007 to 0.5 microgram/ml), and Branhamella catarrhalis (0.03 to 0.1 microgram/ml). BRL 17421 exhibited excellent stability against the TEM-type beta-lactamase of H. influenzae and N. gonorrhoeae, and its activity was little affected by inoculum size. Minimal lethal concentrations of BRL 17421 for 10(7) colony-forming units of H. influenzae ranged between 0.5 and 4 micrograms/ml.
Activities of tobramycin and azlocillin alone and in combination against experimental osteomyelitis caused by Pseudomonas aeruginosa
Authors: Norden C W , Shaffer M A
Published: June 2012

Azlocillin and tobramycin were used alone and in combination in the treatment of chronic osteomyelitis due to Pseudomonas aeruginosa in rabbits. This combination showed in vitro synergy measured by both the checkerboard technique and time-kill curves. A marked inoculum effect was demonstrated in vitro with azlocillin and the infecting strain of P. aeruginosa. The minimal inhibitory concentration of azlocillin, with an inoculum of 10(5) organisms, was 12.5 micrograms/ml; when the inoculum size was increased to 10(7) organisms, the minimal inhibitory concentration rose to more than 500 micrograms/ml. In therapeutic trials, the combination of azlocillin and tobramycin, given for 28 days, was significantly better than either no therapy or azlocillin alone, but was not significantly better than tobramycin alone. Even after 4 weeks of combined therapy with azlocillin and tobramycin, P. aeruginosa was recovered from the bones of 60% of the treated rabbits.
Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria
Authors: Sykes R B , Bonner D P , Bush K , Georgopapadakou N H
Published: June 2012

Azthreonam (SQ 26,776) is a synthetic monocyclic beta-lactam antimicrobial agent belonging to the monobactam family (Sykes et al., Nature [London] 291:489-491, 1981), members of which are characterized by having the 2-oxoazetidine-1-sulfonic acid moiety. Azthreonam exhibits a high degree of stability to beta-lactamases and is specifically active against aerobic gram-negative bacteria, including Pseudomonas aeruginosa. Its activity against these organisms was in general equal or superior to that observed with the third-generation cephalosporins, cefotaxime and ceftazidime. Like penicillins and cephalosporins, azthreonam interacts with essential penicillin-binding proteins of gram-negative bacteria. Azthreonam protected mice against experimental infections produced by a range of gram-negative bacteria, exhibiting efficacy comparable to that of cefotaxime and ceftazidime.
Experimental infections for the evaluation of beta-lactamase resistance
Authors: Xerri L , Orsolini P , Erani E , Broggio R
Published: June 2012

The antibacterial activity and pharmacokinetics of the beta-lactamase-stable cephalosporin cefuroxime and the gram-negative beta-lactamase-susceptible cephalosporin cefazolin were compared in two contrasting infection models in which Proteus morganii 82, which produces chromosomally mediated beta-lactamase, was the pathogen. In the rat paw model, characterized by high numbers of localized bacteria, cefazolin was destroyed at the site of infection and consequently did not produce a therapeutic response. In the mouse intraperitoneal model cefazolin was also inactive, despite peritoneal concentrations being unaffected by high counts of the beta-lactamase-producing P. morganii in the body cavity. In contrast the pharmacokinetics of cefuroxime was unaffected by the presence of the beta-lactamase-producing P. morganii, and good therapeutic responses were seen in both models.
Outer membrane permeability in Pseudomonas aeruginosa: comparison of a wild-type with an antibiotic-supersusceptible mutant
Authors: Angus B L , Carey A M , Caron D A , Kropinski A M , Hancock R E
Published: June 2012

The Pseudomonas aeruginosa mutant Z61 has been shown to be highly supersusceptible to a wide range of antibiotics, including beta-lactams, aminoglycosides, rifampin, tetracycline, and chloramphenicol (W. Zimmerman, Int. J. Clin. Pharmacol. Biopharm. 17:131-134, 1979). Spontaneous revertants were isolated, using gentamicin or carbenicillin as selective agents, and shown to have two patterns of susceptibility to a group of 12 antibiotics. Partial revertants had 2- to 10-fold greater resistance to these antibiotics than mutant Z61, whereas full revertants had antibiotic susceptibilities indistinguishable from those of the wild-type strain K799, from which mutant Z61 had been derived. Uptake of a chromogenic beta-lactam nitrocefin was studied in both uninduced and induced cells of all strains by measuring the steady-state rate of nitrocefin hydrolysis by the inducible, periplasmic beta-lactamase in both whole and broken cells. This demonstrated that outer membrane permeability decreased as antibiotic resistance increased in the series mutant Z61, partial revertants, wild type, and full revertants. The data were consistent with the idea of low outer membrane permeability being caused by a low proportion of open functional porins in the outer membrane as the reason for the high natural antibiotic resistance of wild-type P, aeruginosa strains. In addition, it was observed that levels of benzylpenicillin below the minimal inhibitory concentration for mutant Z61 failed to induce beta-lactamase production. The possibility that this was related to the observed increase in outer membrane permeability is discussed. Preliminary evidence is presented that the pore-forming outer membrane porin protein F is not altered in mutant Z61.
Pharmacokinetics of cefadroxil after oral administration in humans
Authors: La Rosa F , Ripa S , Prenna M , Ghezzi A , Pfeffer M
Published: June 2012

The human oral pharmacokinetics of cefadroxil were studied in parallel at doses of 250, 500, and 1,000 mg in three groups of 10 healthy young male volunteers. Renal excretion of intact cefadroxil, accounted for 82, 79, and 77% of the above doses. Mean peak serum levels were dose linear: 9, 18, and 35 microgram/ml at 250, 500, and 1,000 mg, respectively. However, overall pharmacokinetics were linear only in the 250- to 500-mg dose range; apparent serum clearances were 10 liters/h, and true renal clearances were 9 and 8 liters/h at 250 and 500 mg. At 1,000 mg, apparent serum clearance dropped to about 7 liters/h, true renal clearance, dropped to 6 liters/h, and the area under the curve increased disproportionately. At 250 and 500 mg, mean half-life was about 1.2 h; at 1,000 mg, however, it was 1.6h. The nonlinear decrease in clearance could be related to saturation of active renal tubular secretion of cefadroxil between the 500- and 1,000-mg doses. Previous results indicating that cefadroxil has greater persistence than other oral cephalosporins such as cephalexin, cephradine, cefaclor were confirmed.
Cefamandole treatment of Salmonella bacteremia
Authors: De Carvalho E M , Martinelli R , De Oliveira M M , Rocha H
Published: June 2012

The efficacy of cefamandole in the treatment of 19 patients with salmonella bacteremia was evaluated. Although all of the salmonella strains isolated were highly susceptible to cefamandole in vitro, a therapeutic failure was observed in 7 (36.8%) of the 19 patients.
Microcin 15m from Escherichia coli: mechanism of antibiotic action
Authors: Aguilar A , Pérez-Díaz J C , Baquero F , Asensio C
Published: June 2012

It has been previously established that a high proportion of enterobacteria isolated from the intestinal content of humans, mostly Escherichia coli strains, secrete into the culture media antibiotic substances of low molecular weight, which have been called microcins. It was also found that the synthesis of these antibiotics is determined by plasmids. In this paper, a method for the purification of microcin 15m is described, and experimental data are given on the mechanism of its action. The data indicate that this action is based mainly on the inhibition of the first enzyme of the methionine biosynthetic pathway, homoserine-O-transsuccinylase, a similar way to the allosteric inhibition caused by this amino acid.
Penetration of ceforanide and cefamandole into the right atrial appendage, pericardial fluid, sternum, and intercostal muscle of patients undergoing open heart surgery
Authors: Mullany L D , French M A , Nightingale C H , Low H B , Ellison L H , Quintiliani R
Published: June 2012

Doses of 30 mg of ceforanide or cefamandole per kg were administered intravenously to 26 patients just before their chests were opened for coronary artery bypass or cardiac valve replacement surgery. Samples of right atrial appendage, pericardial fluid, plasma, aortic wall, intercostal muscle, and sternum were obtained at different times after the antibiotic was injected, and these samples were assayed for cephalosporin concentration. For ceforanide the pre-bypass plasma half-life was 2.5 h, and the atrial appendage half-life was 2.1 h; for cefamandole the pre-bypass plasma half-life was 0.75 h and the atrial appendage half-life was 0.72 h. At 3 h the concentrations of ceforanide and cefamandole in atrial appendages were 28.0 and 5.0 micrograms/g, respectively. Ceforanide achieved higher and more sustained concentrations in other tissues than cefamandole. Considering the minimal inhibitory concentrations of these drugs for staphylococci, cefamandole and ceforanide should provide adequate protection against infection by these organisms for the duration of the surgical procedure.
Cefotaxime therapy of serious bacterial infection in adults
Authors: Mullaney D T , John J F
Published: June 2012

We evaluated the efficacy, safety, and tolerance of cefotaxime in 35 adults (25 with pleuropulmonary infections, 7 with genitourinary tract infections, and 3 with soft tissue infections). Of these 35 patients, 18 (51.4%) were seriously or critically ill. In vitro susceptibility testing revealed that 90.4% of the pathogens isolated were susceptible to cefotaxime (minimal inhibitory concentration, less than 8 micrograms/ml), 4.8% were intermediately susceptible (minimal inhibitory concentration, 8 to 32 micrograms/ml), and 4.8% were resistant (minimal inhibitory concentration, greater than 32 micrograms/ml). A total of 34 of the 35 patients (97%) were clinically and bacteriologically cured of their infections. Adverse reactions occurred in two patients, but these reactions did not require interruption of therapy.
Comparative tolerability of ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole suspensions in children with otitis media
Authors: Feder H M
Published: June 2012

The tolerabilities of ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole (TMP-SMX) suspensions were evaluated in 263 children with otitis media. Because of watery stools, therapy was discontinued in 6 of 83 patients treated with ampicillin, in none of 89 patients treated with amoxicillin (P less than 0.01), and in 1 of 91 patients treated with TMP-SMX (P less than 0.03). Of the patients who completed the treatment courses, 13 recipients of ampicillin suffered loose or watery stools for 4 or more days, compared with 6 of the amoxicillin recipients (P less than 0.04) and 5 of the TMP-SMX recipients (P less than 0.02). Thus, ampicillin was clearly less well tolerated than either amoxicillin or TMP-SMX.
Treatment of Infections Caused by Ampicillin-Resistant Pathogens with a Combination of Ampicillin and CP-45,899
Authors: Plouffe Joseph F.
Published: June 2012

Eleven patients infected with ampicillin-resistant organisms were treated with a combination of CP-45,899, a β-lactamase inhibitor, and ampicillin. All infections were controlled within 7 days without any signs of toxicity.
In vitro activity of moxalactam alone and in combination with penicillin against common meningeal pathogens
Authors: Azimi P H , Dunphy M G
Published: June 2012

Moxalactam demonstrated marked activity against beta-lactamase-positive and -negative Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis by both standard minimal inhibitory concentration testing and growth curve studies. Moxalactam was ineffective against S. pneumoniae partially susceptible to penicillin G. Moxalactam (5 micrograms/ml) and penicillin (1 microgram/ml) in combination were indifferent to each other's antibacterial activity, exerting neither synergism nor antagonism against these organisms.
Antibiotic susceptibility and synergy of clinical isolates of Listeria monocytogenes
Authors: Tuazon C U , Shamsuddin D , Miller H
Published: June 2012

Antibiotic susceptibility and synergy were studied in 12 clinical isolates of Listeria monocytogenes from patients with meningitis and septicemia. Rifampin and trimethoprim-sulfamethoxazole (TMP-SMX) were the most potent single drugs tested. Approximately 80% of the strains demonstrated full synergistic bactericidal activity with rifampin in combination with penicillin or ampicillin. Clinical experience dictates that ampicillin or penicillin should remain the antibiotic of choice in the treatment of severe infections, such as meningitis caused by L. monocytogenes. Where the use of penicillin is contraindicated (e.g., allergy or failure to respond), use of TMP-SMX might be considered. Further in vitro and vivo studies are needed before therapy with rifampin or TMP-SMX in combination with penicillin or ampicillin can be recommended.
Moxalactam penetration into cerebrospinal fluid in patients with bacterial meningitis
Authors: Modai J , Wolff M , Lebas J , Meulemans A , Manuel C
Published: June 2012

Penetration of moxalactam into the cerebrospinal fluid was studied in 11 patients with bacterial meningitis undergoing treatment with other antibiotics. Moxalactam at a dose of 20 mg/kg was administered as three 30- to 45- min infusions at 8-h intervals, once between days 2 and 4 and a second time between days 11 and 20 of treatment with the other antibiotics. Serum and cerebrospinal fluid were sampled 60, 90, or 120 min after the third moxalactam dose for measurement of the concentration of this drug by high-performance liquid chromatography. The concentration of moxalactam in cerebrospinal fluid ranged from 1.5 to 11 micrograms/ml, depending on the sampling time and the time elapsed since the onset of the disease. These concentrations in cerebrospinal fluid were equal to or higher than the minimum inhibitor concentrations for Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae (including ampicillin-resistant strains), and most of the gram-negative bacilli except for Pseudomonas aeruginosa. These results show that moxalactam has good penetrability when the meninges are inflamed and that it might be considered in cases of bacterial meningitis when the susceptibility of the pathogen indicates its usefulness.
The antimalarial drug mefloquine binds to membrane phospholipids
Authors: Chevli R , Fitch C D
Published: June 2012

The new antimalarial drug mefloquine bound with high affinity (Kd approximately 3 X 10-7 M) to membrane lipids of normal mouse erythrocytes and of erythrocytes infected either with chloroquine-susceptible or chloroquine-resistant Plasmodium berghei. Approximately 80 nmol of mefloquine was bound per mg of total lipid. Mefloquine also bound to purified phospholipids with high affinity (Kd approximately 3 X 10-7 M). Phosphatidylinositol and phosphatidylserine bound 300 to 400 nmol of mefloquine per mg. Phosphatidylcholine and phosphatidylethanolamine bound approximately 100 nmol of mefloquine per mg. Mefloquine did not bind to hemoglobin with high affinity, but it bound to free ferriprotoporphyrin IX with a Kd of approximately 3 X 10-7 M. In comparison with mefloquine, chloroquine did not bind effectively to purified phospholipids, although it is known to bind with high affinity to free ferriprotoporphyrin IX. Greater binding to phospholipids may account for the superiority of mefloquine in the treatment of chloroquine-resistant malaria.
In vitro antibacterial activity of norfloxacin (MK-0366)
Authors: King A , Warren C , Shannon K , Phillips I
Published: June 2012

The in vitro activity of norfloxacin (MK-0366) compared with that of beta-lactam antibiotics and, where appropriate of gentamicin or metronidazole was assessed against recent clinical isolates of common bacteria. The compound was highly active against most enterobacteria (minimal inhibitory concentrations [MICs], 0.008 to 32 micrograms/ml; 90% inhibited by 0.25 micrograms/ml), Haemophilus influenzae (MICs, 0.03 to 0.12 micrograms/ml), and Neisseria gonorrhoeae (MICs, 0.008 to 0.016 micrograms/ml). It was also active against Pseudomonas aeruginosa (MICs, 0.12 to 2 micrograms/ml), most other pseudomonads (MICs, 0.03 to 32 micrograms/ml), and Acinetobacter calcoaceticus (MICs 0.06 to 4 micrograms/ml). Norfloxacin was somewhat less active against staphylococci (MICs, 0.25 to 4 micrograms/ml; 1 microgram/ml required to inhibit 50% of isolates) and streptococci (MICs, 0.5 to 64 micrograms/ml). Members of the Bacteroides fragilis group of anaerobes were relatively resistant to norfloxacin (MICs, 8 to 128 micrograms/ml), as were most other anaerobes.
Comparative efficacy of antiherpes drugs in different cell lines
Authors: De Clercq E
Published: June 2012

A selection of antiherpes compounds including bromovinyldeoxyuridine (BVDU), acyclovir (ACV), and fluoroiodoaracytosine (FIAC) were compared for their inhibitory effects on herpes simplex virus type 1 (strain KOS) replication in a wide variety of human, simian, feline, and murine cell lines. The 50% inhibitory doses of the compounds varied considerably from one cell line to another, i.e., from 0.01 to 2 micrograms/ml for ACV and from 0.004 to 0.2 micrograms/ml for BVDU and FIAC. However, the relative order of antiviral potency remained constant, thus (in order of decreasing potency) BVDU greater than FIAC greater than ACV, for all cell lines studied except for the murine embryo cells, in which the order of decreasing potency was BVDU greater than ACV greater than FIAC, and for the feline lung cells, in which the order of decreasing potency was FIAC greater than ACV greater than BVDU.
Methicillin-resistant Staphylococcus aureus susceptibility testing with Abbott MS-2 system
Authors: Carlson J R , Conley F E , Cahall D L
Published: June 2012

The antimicrobial susceptibilities of 100 methicillin=resistant Staphylococcus aureus strains were concurrently determined by the Abbott MS-2 System and by the standard disk diffusion method. Agreement between the two methods was 94% or greater for all of the antibiotics tested except for methicillin and gentamicin. This study indicates that the Abbott MS-2 cannot be relied upon for detection of methicillin resistance in clinical S. aureus isolates.
In vitro comparison of N-formimidoyl thienamycin (MK0787) and Azlocillin with three aminoglycosides and ticarcillin against Pseudomonas aeruginosa
Authors: Matzkowitz A J , Baltch A L , Smith R P , Sutphen N T , Hammer M C , Conroy J V
Published: June 2012

The activities of N-formimidoyl thienamycin and azlocillin were compared with those of tobramycin, gentamicin, amikacin, and ticarcillin against 175 Pseudomonas aeruginosa isolates, including 24 strains with known mechanisms of resistance to aminoglycosides. The 50% mean inhibitory concentration for azlocillin was lower than for ticarcillin, but the 90% mean inhibitory concentration was similar for both drugs. All susceptible and multidrug-resistant strains were susceptible to N-formimidoyl thienamycin.
Variables in demonstrating methicillin tolerance in Staphylococcus aureus strains
Authors: Ishida K , Guze P A , Kalmanson G M , Albrandt K , Guze L B
Published: June 2012

Certain technical considerations which affected the status of methicillin tolerance in Staphylococcus aureus strains were studied. Methods which consistently demonstrated tolerance or intolerance of a given strain were avoidance of inoculum splashing, use of stationary-phase inoculum, 24-h tube incubation, and minimization of antibiotic carry-over. These studies suggested a need for the establishment of a standardized reference for the determination of tolerance.
Clinical evaluation of moxalactam
Authors: Mathisen G E , Meyer R D , Thompson J M , Finegold S M
Published: June 2012

Moxalactam was administered intravenously or intramuscularly or both in doses of 1 to 12 g/day to 45 patients with clinically significant infections (17 soft tissue or bone, 9 pleuropulmonary, 9 septicemic, 6 urinary tract, and 4 intraabdominal infections). Mean 0.5-h postinfusion levels were 105 micrograms/ml for a 4.0-g dose, 44.7 micrograms/ml for a 2.0-g dose, and 18 micrograms/ml for a 1.0-g dose. We identified 28 isolates of Enterobacteriaceae, 10 Pseudomonas aeruginosa isolates, 9 Staphylococcus aureus isolates, and 15 anaerobic bacterial isolates. A total of 15 patients were clinically cured, 8 patients improved, 13 patients improved initially but suffered subsequent relapses or superinfections, and 10 patients failed therapy. Toxicity was generally minimal (reversible eosinophilia, and mild liver function abnormalities, and elevated prothrombin time). The selection or emergence of resistant organisms in 17 patients during treatment (particularly Pseudomonas, enterococci, and Candida) was a disturbing feature of therapy. Our results were generally favorable, considering the complicated underlying medical problems of this group of patients.
Naphthyridinomycin, a DNA-reactive antibiotic
Authors: Zmijewski M J , Miller-Hatch K , Goebel M
Published: June 2012

Naphthyridinomycin is a novel quinone antibiotic that is produced in liquid shake cultures by Streptomyces lusitanus. Fermentation studies have shown that this antibiotic is produced maximally after 96 h of cell growth. L-[methyl-3H]methionine efficiently labels naphthyridinomycin when it is added to a fermentation mixture 24 h before culture is harvested. Unlabeled and radioactively labeled naphthyridinomycin were used to determine the mechanism of action of this unique antibiotic. Naphthyridinomycin inhibited bacterial growth primarily by inhibiting DNA synthesis. The structural similarity between naphthyridinomycin and the saframycins suggested that naphthyridinomycin might inhibit DNA synthesis by binding to the template. In vitro studies with radiolabeled naphthyridinomycin indicated that this antibiotic does specifically bind to calf thymus DNA. The binding reaction was enhanced by adding sulfhydryl-containing compounds; dithiothreitol was the best activating agent. DNA-naphthyridinomycin complexes were a poor substrate for enzymes that catalyze DNA-directed DNA and RNA syntheses. These results showed that naphthyridinomycin is similar to the saframycins in its reactivity toward DNA and suggested that the mechanism by which naphthyridinomycin inhibits DNA synthesis is through its ability to bind specifically to the DNA template of the cell.
Penetration of the outer membrane of Pseudomonas aeruginosa by synergistic combinations of beta-lactam and aminoglycoside antibiotics
Authors: Scudamore R A , Goldner M
Published: June 2012

The mechanism of the synergistic action of carbenicillin-gentamicin and moxalactam-tobramycin combinations against Pseudomonas aeruginosa ATCC 9027 was investigated. Disruption of the outer membrane penetration barrier by EDTA treatment enhanced the activity of both combinations against the cells during growth for 100 min in exponential phase. However, there was no loss of the synergistic activity of the antibiotics as a result of this treatment. A procedure involving minimal inhibitory concentration testing in the presence of rifampin did not detect any destabilization of the outer membrane barrier by any of the four drugs over an 18-h period. The combined evidence indicates that beta-lactamaminoglycoside synergy is not mediated by the outer membrane of this organism.
In vitro effects of mycophenolic acid and allopurinol against Leishmania tropica in human macrophages
Authors: Berman J D , Webster H K
Published: June 2012

The possibility that purine inhibitors or analogs might be effective antileishmanial agents led to the determination of the antileishmanial activity of mycophenolic acid and allopurinol in vitro. The drugs were tested against Leishmania tropica amastigotes (mammalian forms) within human macrophages, a model in which achievable serum concentrations of antileishmanial agents currently in use eliminate approximately 90% of the parasites. Mycophenolic acid, an inhibitor of guanosine nucleotide synthesis from inosinic acid, was shown here to inhibit guanosine nucleotide synthesis in L. tropica promastigotes (insect forms). When tested against L. tropica amastigotes within macrophages, mycophenolic acid eliminated 50% of the parasites at achievable peak human serum levels (20 micrograms/ml) and 40% of the parasites at trough serum levels (1 to 10 micrograms/ml). This demonstrates that an inhibitor of guanosine nucleotide synthesis is partially effective against L. tropica in vitro. The purine analog allopurinol was also tested and was found to eliminate 50% of L. tropica amastigotes in this model. Because mycophenolic acid and allopurinol are partially, but not completely, effective antileishmanial agents in this in vitro model, their in vivo utility remains to be determined by clinical trials.
Clinical and pharmacokinetic evaluation of parenteral moxalactam in infants and children
Authors: Keyserling H , Feldman W E , Moffitt S , Manning N , Hollins M
Published: June 2012

Thirty-four infants and children ranging in age from 2.5 to 180 months (mean, 40 months) were treated with parenteral moxalactam (150 mg/kg per day) for suspected or proved bacterial infections outside the central nervous system. Six patients infected with Haemophilus influenzae b, nine infected with Staphylococcus aureus, three infected with Streptococcus pneumoniae, one infected with Streptococcus pyogenes, one infected with Enterobacter aerogenes, one infected with Fusobacterium nucleotum, and one infected with Staphylococcus epidermidis, microaerophilic streptococcus, and Propionibacterium sp. were clinically and bacteriologically cured. One patient with polymicrobial pansinusitis did not respond to moxalactam. No patients developed meningitis. All of the isolates tested were inhibited by less than or equal to 5 micrograms of moxalactam per ml, except for one Staphylococcus epidermidis isolate which was resistant to greater than 20 micrograms/ml. Five patients had transient neutropenia which resolved after the drug was discontinued. The mean peak serum level was 106 micrograms/ml at 15 min after a 50-mg/kg dose. The mean elimination half-life was 91.2 min. These data indicate that this dosage of moxalactam is a safe and effective treatment for bacterial infections outside the central nervous system.
Effects of Common Analgesics on the In Vitro Suppression of Lymphocyte Mitogen Responses by Cephalosporins
Authors: Schuelke Guy S. , Chaperon Edward A. , Sanders W. Eugene
Published: June 2012

Acetaminophen and indomethacin either did not alter or partially reversed the inhibition of lymphocyte mitogenic responses by cephalosporins. Aspirin at concentrations of ≥100 μg/ml in cultures containing cephalosporins reduced the response below the level with either drug alone.
Effects of sublethal concentrations of antimicrobial agents on the hemagglutination, adhesion, and ultrastructure of pyelonephritogenic Escherichia coli strains
Authors: Väisänen V , Lounatmaa K , Korhonen T K
Published: June 2012

The effects of trimethoprim, sulfadiazine, sulfamethoxazole, and sulfathiazole on the hemagglutination and adhesion by three Escherichia coli strains were studied. The strains were isolated from the urine of patients with acute pyelonephritis and carried P antigen-recognizing fimbriae (P fimbriae). At antimicrobial concentrations of 12.5 to 50% of the minimal inhibitory concentration, the ability of the bacteria to agglutinate human erythrocytes and to adhere to human buccal cells was markedly reduced. This reduction corresponded to a decrease in the number of P fimbriae per cell, suggesting that the antimicrobial agents decreased adhesion and hemagglutination by interfering with the formation of fimbriae. No major changes were observed in the outer membrane protein pattern of trimethoprim-treated cells, whereas freeze-fracture electron micrographs showed deorganization of both the cytoplasmic and outer membranes in bacteria opposed to sublethal concentrations of trimethoprim.