bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of cefuroxime in normal and impaired renal function: comparison of high-pressure liquid chromatography and microbiological assays
Authors: Bundtzen R W , Toothaker R D , Nielson O S , Madsen P O , Welling P G , Craig W A
Published: June 2012

The pharmacokinetics of cefuroxime were studied after a single dose of 750 mg was given intravenously to each of 21 male volunteers grouped according to their creatinine clearances; these clearances were 60 to 120, 20 to 59, and less than 20 ml/min per 1.73 m,2 respectively, for groups 1 (12 subjects), 2 (4 subjects), and 3 (5 subjects). Cefuroxime obeyed two-compartment model kinetics in all three groups. Initial serum levels of cefuroxime were approximately 130 microgram/ml in group 1 and 2 and 80 microgram/ml in group 3. the levels then declined rapidly for 0.5 to 1 h after injection. After that time, cefuroxime levels declined more slowly, and the elimination rate became monoexponential. The mean serum half-lives for cefuroxime in groups 2, 2, and 3 were 1.7, 2.4, and 17.6 h, respectively. Mean cefuroxime levels in serum were greater than 8 microgram/ml for 3 h in group 1, for 6 h in group 2, and for 30 h in group 3. Cumulative 24-h urinary excretion accounted for essentially 100% of the dose in group 1 and 2, and for 40% in group 3. Urine levels exceeded the minimal inhibitory concentration for susceptible organisms for more than 12 h in all groups. Cefuroxime distribution characteristics were independent of renal function. In patients with creatinine clearances less than 20 ml/min per 1.73 m2, doses of cefuroxime needs to be reduced. A microbiological disk diffusion assay and a high-pressure liquid chromatography assay for cefuroxime yielded statistically identical results, except for serum levels in uremic patients (group 3).
Antiviral activity of Win 41258-3, a pyrazole compound, against herpes simplex virus in mouse genital infection and in guinea pig skin infection
Authors: Pancic F , Steinberg B A , Diana G D , Carabateas P M , Gorman W G , Came P E
Published: June 2012

Win 41258-3 (4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazole methane sulfonate) has in vitro and in vivo activity against herpes simplex virus types 1 and 2. In cell culture, a concentration of 2 microgram/ml produced a greater than 50% inhibition of plaque formation of herpes simplex virus type 2, and 3 microgram/ml produced a 100% reduction of herpes simplex virus type 1. Win 41258-3 was effective against herpes simplex virus types 1 and 2 in mouse genital infection after intravaginal administration. Win 41258-3 was administered to mice at 4 h postinfection with solutions containing 1.25, 2.5, 5, or 10% of the compound in saturated tampons. Therapy resulted in a high survival rate (80 to 100%) of treated animals versus 20 to 30% of placebo-treated controls. Win 41258-3 was also effective in guinea pig skin infection produced by herpes simplex virus type 1. Solutions of 2.5, 5, and 10% Win 41258-3, applied to the skin starting 24 h postinfection, resulted in rapid suppression of development of herpetic vesicles and significant reduction of the virus titers in the lesion sites.
Filament formation of Fusobacterium nucleatum cells induced by mecillinam
Authors: Onoe T , Umemoto T , Sagawa H , Suginaka H
Published: June 2012

Subinhibitory concentrations of mecillinam transformed Fusobacterium nucleatum cells into a marked filament form, quite different from a spherical form demonstrated in Escherichia coli.
Effects of sodium piperacillin on platelet function in normal volunteers
Authors: Gentry L O , Jemsek J G , Natelson E A
Published: June 2012

Piperacillin is a new semisynthetic penicillin which is similar in structure to carbenicillin and ticarcillin. Since the latter antibiotics have been shown to cause abnormalities in hemostasis, we studied the effects of piperacillin on blood coagulation and platelet function. Fifteen healthy volunteers received the drug in doses of either 100, 200, or 300 mg/kg per day for a period of 7 days. Serial studies showed no abnormalities in blood coagulation in any subject. Decreased platelet aggregation responses to adenosine diphosphate, epinephrine, collagen, and achidonic acid were commonly noted, but prolongation of the bleeding time occurred in only 3 of 15 subjects after 7 days of piperacillin administration. These results suggest that although piperacillin also induces platelet dysfunction, these effects may be less than those caused by ticarcillin or carbenicillin at an equivalent dosage.
Resistance to antibiotic synergism in Streptococcus faecalis: further studies with amikacin and with a new amikacin derivative, 4'-deoxy, 6'-N-methylamikacin
Authors: Calderwood S B , Wennersten C , Moellering R C
Published: June 2012

Streptococcus faecalis strains may resist penicillin-aminoglycoside synergy by the production of plasmid-mediated aminoglycoside-modifying enzymes. One of these enzymes, aminoglycoside 3'-phosphotransferase, has been shown to have a broad range of substrate specificity, including amikacin. We have studied a derivative of amikacin, 4'-deoxy, 6'-N-methylamikacin (BB-K311), against 11 clinical blood isolates of S. faecalis. Minimal inhibitory concentrations of BB-K311 were quite similar to those of amikacin, ranging from 125 to 1,000 micrograms/ml. In assays for antibiotic synergy, penicillin and amikacin produced enhanced killing compared with the penicillin alone only against those three strains which lacked the phosphotransferase enzyme. The other eight enzyme-positive strains actually demonstrated significant antagonism between penicillin against all 11 strains, regardless of enzyme production. Analysis of substrate profiles with crude preparations of the aminoglycoside 3'-phosphotransferase enzyme confirmed that BB-K311 was a very poor substrate for modification, as expected from the synergy studies. Use of other aminoglycoside analogs confirmed the 3'-OH site of modification. These findings suggest that removing the 4'-OH group in amikacin effectively blocks 3'-phosphorylation by S. faecalis enzyme.
Isolating specific auxotrophic mutants of Mycobacterium smegmatis by using vancomycin
Authors: Woodley C L , Baldwin J N , Greenberg J
Published: June 2012

After inducing mutagenesis with nitrosoguanidine, we used vancomycin enrichment in isolating auxotrophic mutants of Mycobacterium smegmatis. Compared with cycloserine and penicillin G, which are also cell wall inhibitors, vancomycin, with 24 h of exposure, produced less cell lysis and a greater reduction in viable cell numbers. With vancomycin enrichment, 13 specific auxotrophs were isolated after nitrosoguanidine-induced mutation, whereas only two mutants were isolated without enrichment.
Moxalactam pharmacokinetics during hemodialysis
Authors: Aronoff G R , Sloan R S , Mong S A , Luft F C , Kleit S A
Published: June 2012

To establish dosage recommendations, moxalactam elimination kinetics were studied in six anephric patients during hemodialysis and in four anephric patients during the interdialytic period. After a single 1-g intravenous bolus injection, moxalactam elimination half-life was 18.0 plus or minus 0.6 h with a volume of distribution of 20.2 plus or minus 3.6 liters and a plasma clearance of 12.8 plus or minus 2.0 ml/min in four nondialyzed patients. Moxalactam elimination half-life was decreased to 2.7 plus or minus 0.2 h during hemodialysis in six patients. After 4 h, 48.5% of the dose was recovered in the dialysate. The maintenance dose of moxalactam should be decreased to 15% of a normal dose in patients with creatinine clearances less than 10 ml/min, and 50% of a loading dose should be given after hemodialysis.
Sequestration of the chloroquine receptor in cell-free preparations of erythrocytes infected with Plasmodium berghei
Authors: Fitch C D , Chevli R
Published: June 2012

When mouse erythrocytes infected with Plasmodium berghei were preincubated with [14C]chloroquine and then lysed by hypotonic shock, chloroquine remained bound to the resulting cell-free preparation. In an isotonic medium at pH 7.4 and 25 degrees C, chloroquine was bound to the cell-free preparation with an apparent dissociation constant of 1.8 x 10(-7) M. The bound [14C]chloroquine could be displaced by nonradioactive chloroquine, amodiaquine, quinacrine, and mefloquine, as would be predicted from knowledge of the specificity of ferriprotoporphyrin IX for antimalarial drugs. Also, as predicted, primaquine did not displace the [14C]chloroquine. The ability of these cell-free preparations to bind chloroquine with high affinity decreased rapidly with incubation at 37 degrees C and became undetectable within 1 h; at 4 degrees C the decrease occurred more slowly. This behavior of the endogenous receptor-chloroquine complex was duplicated by an exogenous ferriprotoporphyrin IX-chloroquine complex loaded into cell-free preparations of erythrocytes infected with P. berghei. These findings support the hypothesis that ferriprotoporphyrin IX is the endogenous chloroquine receptor of P. berghei and indicate that it can be sequestered rapidly in a form that is inaccessible to chloroquine.
In Vitro Susceptibility of
Gardnerella vaginalis
to High Concentrations of Sulfonamide Compounds
Authors: Jones Brian M. , Bhattacharyya Mukti N.
Published: June 2012

The excipients of triple sulfa vaginal tablets were ineffective against
Gardnerella vaginalis
in vitro. The three sulfonamides, however, were inhibitory, and minimal inhibitory concentration tests showed many strains to be susceptible to 25,000 μg of sulfacetamide per ml.
Interaction of Haemocin with
Escherichia coli
Authors: Streker R. G. , Venezia R. A. , Robertson R. G.
Published: June 2012

The bactericidal activity of haemocin, a bacteriocin produced by
Haemophilus influenzae
b, for
Escherichia coli
CR34 could be blocked by the addition of 2,4-dinitrophenol. No inhibition by 2,4-dinitrophenol of the haemocin activity on
H. influenzae
Rd strain C25 was demonstrated. The data suggest an energy-dependent step in the mode of action of haemocin on strain CR34.
Susceptibility of Multiply Antibiotic-Resistant Pneumococci to the New Beta-Lactam Drugs and Rosaramicin
Authors: Landesman Sheldon H. , Cummings Marinella , Gruarin Andrea , Bernheimer Harriet
Published: June 2012

Eight new beta-lactam antibiotics and rosaramicin were tested for their activity against penicillin-susceptible and multiply resistant pneumococci. All of the beta-lactam drugs were 50- to 150-fold less active against the drug-resistant pneumococci when compared with their activity against penicillin-susceptible pneumococci. Rosaramicin activity was similar to that of erythromycin.
Insensitivity of peptidoglycan biosynthetic reactions to beta-lactam antibiotics in a clinical isolate of Pseudomonas aeruginosa
Authors: Mirelman D , Nuchamowitz Y , Rubinstein E
Published: June 2012

The enzymatic reactions (transpeptidases/ that catalyze the attachment of newly synthesized peptidoglycan to the preexisting cell wall sacculus of both Escherichia coli and Pseudomonas aeruginosa have been shown to be very sensitive to most beta-lactam antibiotics. Biosynthetic studies carried out with a clinical isolate of P. aeruginosa resistant to carbenicillin and cefsulodin showed that the in vitro reactions were also insensitive to most beta-lactam antibiotics (up to 50 micrograms/ml) and only cefotaxime or its tetrazolyl analog, compound LY 97962, had an inhibitory effect at 0.01 microgram/ml. The pattern of beta-lactam binding proteins obtained upon exposure of intact or presonicated cells to radioactively labeled compound LY 97962 or penicillin G indicates that: (i) intact cells of the clinical isolate are 10 to 50 times less permeable to the antibiotics than is the wild-type strain X-48; (ii) beta-lactam binding proteins Ia, Ib, and III of the clinical isolate showed poor affinity for penicillin G and cefsulodin, but were similar to the wild type in their affinity for cefotaxime and compound LY 979062. The two strains also differed in several of their outer membrane components. These results suggest that the insusceptibility of this clinical isolate is due to a combination of outer membrane impermeability and intrinsic insensitivity to most of the beta-lactams on the part of the enzymes which catalyze expansion and growth of peptidoglycan.
Increase of the intestinal absorption of gentamicin and amikacin by a nonionic surfactant
Authors: Rubinstein A , Rubinstein E , Toitou E , Donbrow M
Published: June 2012

This study was concerned with the effect of Cetomacrogol (polyethylene glycol 1000 monocetyl ether), a nonionic surfactant, on the absorption of gentamicin and amikacin from the gastrointestinal tract of rats. A 200-mg dose of Cetomacrogol coadministered orally with 10 mg of gentamicin resulted in a mean peak gentamicin blood concentration of 14.1 microgram/ml, compared with 67.8 microgram/mg when the same gentamicin dose was administered intramuscularly. The area under the curve after administration of the oral mixture was 23% of that after the intramuscular dose. The rectal administration of the mixture resulted in a mean peak gentamicin blood level of 8.2 micrograms/ml, compares to 16.5 microgram/ml when the mixture was administered orally. A 50-mg dose of amikacin coadministered orally with 200 mg of Cetomacrogol resulted in a mean peak amikacin blood level of 13.3 microgram/ml, compared to 310 microgram/ml when this amikacin dose was administered intramuscularly. Cetomacrogol augments the intestinal absorption of gentamicin and amikacin in rats. If the toxicity of the combination in humans is limited, the combination may be potentially clinically useful.
beta-Lactam-resistant Pseudomonas aeruginosa with modified penicillin-binding proteins emerging during cystic fibrosis treatment
Authors: Godfrey A J , Bryan L E , Rabin H R
Published: June 2012

The emergence of beta-lactam-resistant strains of Pseudomonas aeruginosa in a cystic fibrosis patient treated with high-dose tobramycin and piperacillin was studied. Two serotypes, M and K, were present before treatment and persisted, with changes in their beta-lactam resistance spectra, during treatment. The resistance was correlated with changes in the penicillin-binding proteins (PBPs) in both serotypes. In the low-level-resistant serotype K organism, PBP-3 either was absent or had lost the ability to bind [14C]penicillin G. Tow serotypes M strains, one with low- and one with high-level resistance to several antipseudomonal beta-lactam antibiotics, were isolated at progressively later stages of therapy. Several differences were noted between the PBP patterns of the resistant M and the susceptible M strains. The affinity for [14C]penicillin G was reduced in both resistant strains. PBP bands, with the exception of PBP-6 in the most resistant M type, were barely or not detectable at a [14C]penicillin G concentration of 39 microgram/ml. The graduated decrease in affinity for [14c]penicillin G was correlated with increasing beta-lactam resistance and with an increase in the quantity of the protein corresponding to PBP-6. The emergence of the low-level-resistant strains midway through, and of the highly resistant strain in the final stages of, the reported treatment strongly suggested that the resistance resulted from mutation in those strains present before treatment selected for by the high-dose piperacillin treatment.
Comparative inhibition of influenza and parainfluenza virus replication by ribavirin in MDCK cells
Authors: Browne M J
Published: June 2012

Actinomycin D inhibited the yield of influenza virus hemagglutinin from MDCK cells infected at high multiplicity, but had little effect on the yield of parainfluenza virus hemagglutinin. In similar hemagglutinin yield experiments, ribavirin was only slightly more active (threefold) against influenza virus than against parainfluenza virus replication. In plaque inhibition experiments, ribavirin depressed influenza virus plaque formation by 50% at a concentration of approximately 3 micrograms/ml, whereas the corresponding figure for parainfluenza viruses was threefold higher. The concentration of ribavirin demonstrating anti-influenza activity was indistinguishable for that inhibiting host cell growth. It is concluded that, unlike actinomycin D, ribavirin is unlikely to have a major effect on the provision of host cell 5-germinal methylated cap structures and the subsequent priming of influenza messenger ribonucleic acid synthesis.
Pharmacokinetics of erythromycin ethylsuccinate and estolate in infants under 4 months of age
Authors: Patamasucon P , Kaojarern S , Kusmiesz H , Nelson J D
Published: June 2012

We studied the pharmacokinetics of erythromycin estolate and ethylsuccinate suspensions in infants under 4 months of age who were being treated for chlamydial infections or pertussis. We conducted our studies after the initial dose of 10 mg/kg and subsequently during steady-state treatment. The estolate preparation resulted in higher peak concentrations in sera, and its absorption and elimination half-lives were longer. Peak concentrations occurred 3 h after a dose with the estolate preparation and 1 h after a dose with the ethylsuccinate preparation. The area under the curve for the estolate preparation was about three times greater than that for the ethylsuccinate preparation. Based on these findings, we recommend that erythromycin estolate suspensions be given to young infants at 8- or 12-h intervals (30 mg/kg per day in three divided doses or 20 mg/kg per day in two divided doses) and that erythromycin ethylsuccinate is best given at 6-h intervals (40 mg/kg per day in four divided doses).
Hypersusceptibility of penicillin-treated group B streptococci to bactericidal activity of human polymorphonuclear leukocytes
Authors: Horne D , Tomasz A
Published: June 2012

Pretreatment of serotype Ib group B streptococci with benzylpenicillin, other beta-lactam antibiotics, or vancomycin increased the susceptibility of these bacteria to the bactericidal activity of a mixture of human polymorphonuclear leukocytes and normal human serum. Increased susceptibility of the bacteria to killing by phagocytes was elicited even by exposure to subinhibitory levels of the beta-lactam antibiotics. Inhibitors of protein synthesis did not induce such susceptibility. We investigated the possible biochemical basis of penicillin-induced susceptibility to phagocytosis. Penicillin treatment induced the release of substantial quantities of group B streptococcal surface components into the growth medium (lipoteichoic acid, lipid, and capsular polysaccharide). Labeling of the live streptococci with 3H-labeled penicillin was used to evaluate the effect of exposure to subinhibitory concentrations of this antibiotic on the penicillin-binding proteins. Our results suggested that beta-lactam antibiotics and components of the immune system may act in concert to eliminate invading bacteria.
Therapy of lower respiratory tract infections with moxalactam
Authors: Lentino J R , Rytel M W , Moore E
Published: June 2012

Moxalactam was evaluated in the therapy of lower respiratory tract infections in 40 patients. The most common organisms isolated were Streptococcus pneumoniae (37.2%) and Haemophilus influenzae (21.5%). Gram-negative enteric organisms were isolated from six patients. No patient was evaluated as a treatment failure; however, two patients died of unrelated causes either during therapy or in the immediate posttherapy period. We determined the comparative minimal inhibitory concentrations of moxalactam, cefamandole, and cephalothin for our aerobic clinical isolates. Susceptibilities of the anaerobic isolates were measured by the Kirby-Bauer method. All isolates were susceptible to moxalactam. Moxalactam was found to be highly effective in the therapy of lower respiratory tract infections.
Pharmacokinetics of cefoperazone in normal volunteers and subjects with renal insufficiency
Authors: Bolton W K , Scheld W M , Spyker D A , Sande M A
Published: June 2012

We examined the pharmacokinetics of the new beta-lactam agent, cefoperazone, in normal and functionally anephric dialysis subjects with normal liver function. All subjects received 3 g of cefoperazone intravenously, and serial serum and urine samples were taken thereafter for up to 36 h. The serum levels, volume of distribution (0.22 liter/kg, normal; 0.19 liter/kg; dialysis), beta half-life (2.07 h, normal; 2.03 h, dialysis), and total body clearance (96.2 ml/min, normal; 92.9 ml/ min, dialysis) were all not significantly different between the two groups. Cefoperazone may be administered without adjustment of dose for any degree of renal dysfunction to patients with normal hepatic function.
Chemoprophylaxis with cefoxitin and cephalothin in orthopedic surgery: a comparison
Authors: Rosenfeld M B , Campos J , Ratzan K R , Uredo I
Published: June 2012

Forty-eight patients who underwent elective hip or knee surgery were randomly divided into two groups. A total of 22 patients received a single 1-g preoperative bolus of cefoxitin, and 26 patients received a single 1-g preoperative dose of cephalothin. At various time intervals, serum and bone samples were taken during the operative procedure. Our data indicated that whereas serum levels of cefoxitin and cephalothin were maintained for at least 2h at levels capable of inhibiting most gram-positive cocci and many gram-negative rods, bone levels of cefoxitin rather rapid decay over a 2-h period. Moreover, in only 58% of the entire cephalothin-treated group were bone levels detectable and then only at a concentration that would inhibited gram-positive cocci. No significant morbidity was observed in either treatment group.
Inhibition of mouse LM cell replication by trifluorothymidine: role of cytosolic deoxythymidine kinase
Authors: Wigdahl B L , Parkhurst J R
Published: June 2012

The effects of trifluorothymidine (5-trifluoromethyl-2'-deoxyuridine, F3dThd) on the replication of three mouse cell lines, LM929, Ltk- (and LM929 derivative devoid of cytosolic deoxythymidine [dThd] kinase activity), and Ltk- c139 (a Ltk- derivative which expresses herpes simplex virus type 1-specified dThd kinase subsequent to biochemical transformation with ultraviolet-irradiated herpes simplex virus type 1), have been investigated. Complete inhibition of Ltk- cell growth required a 10,000-fold higher concentration of F3dThd (1.0 mM) than was required to completely inhibit LM929 and Ltk- c139 cell growth. The plating efficiency of exponentially dividing Ltk- cells after exposure to F3dThd (10 microM) for 24 h was 63% as compared to 3% for exponentially dividing LM929 cells. Stationary LM929 cells (confluent cultures held for a 6-day period in serum-reduced medium) with reduced dThd kinase specific activity and deoxyribonucleic acid biosynthesis level exhibited a plating efficiency similar to that of exponentially dividing Ltk- cells after exposure to F3Thd (1.0 mM) for 24 h. In addition, treatment of exponentially dividing LM929 and Ltk- cells with F3dThd (10 microM) for 24 h resulted in approximately an 80% and 25% reduction in deoxyribonucleic acid biosynthesis, respectively. These data indicated a requirement for cytosolic dThd kinase in the expression of F3dThd-induced cytotoxicity. F3dThd was shown to be a linear competitive inhibitor with respect to dThd for affinity-purified LM929 cytosolic dThd kinase. The Km(app) for dThd and Ki(app) for F3dThd with the cytosolic dThd kinase were 2.4 and 3.8 microM, respectively.
Murein synthesis and beta-lactam antibiotic susceptibility during rod-to-sphere transition in a pbpA(Ts) mutant of Escherichia coli
Authors: Botta G A , Buffa D
Published: June 2012

The conditional morphology mutant of Escherichia coli SP45 grows as a rod at 30 degrees C and assumes a spherical shape after 90 min of incubation at 42 degrees C. The rod-to-sphere morphological transition has been found to be associated with the disappearance of penicillin-binding protein 2 (PBP-2), the progressive reduction (as much as 50%) of murein synthesis, as measured both in intact cells and ether-permeabilized bacteria, and alterations in the structure of the cell envelope, including detachment of the outer membrane from the underlying structures. The detachment was initially localized at the poles of the cells and then spread over the entire surface. Shape transition was also linked to increased susceptibility to beta-lactam antibiotics which preferentially bound to PBP-1A (cephalothin, cephaloridine) or to PBP-3 (furazlocillin, piperacillin). Treatment with beta-lactams possessing a high affinity for PBP-1A, although inducing a low degree of peptidoglycan synthesis inhibition (5 to 10%), was associated with a marked loss of cell viability and massive lysis. On the other hand, the simultaneous absence of PBP-2 and inhibition of PBP-3 causes a significant reduction of peptidoglycan synthesis, yet only slightly affected cell viability. Whereas PBP-1A inhibition during shape transition had no effect on morphology, addition of antibiotics binding to PBP-3 30 min after the temperature shift-up caused formation of elongated cells with a centrally located bulge, not observed in similarly treated cells grown at 30 degrees C. Inhibition of PBP-3 in round cells 90 min after temperature shift caused formation of giant cells, indicating complete loss of elongation ability. The different effects of the simultaneous inhibition of two PBPs, combining mutational loss with specific binding in vivo of another PBP by beta-lactams, provide new insight into the role of these proteins and the killing mechanisms of this class of antibiotics.
In Vitro Susceptibility of
Haemophilus influenzae
and
Neisseria gonorrhoeae
to Ro 13-9904 in Comparison with Other β-Lactam Antibiotics
Authors: Ng W. S. , Chau P. Y. , Arnold K.
Published: June 2012

Ro 13-9904 has high in vitro activity, as does cefotaxime, against 57
Haemophilus influenzae
and 60
Neisseria gonorrhoeae
strains, including 5 and 11 β-lactamase-producing strains in each group, respectively.
In vitro and in vivo antibacterial activity of FR-31564, a phosphonic acid antimicrobial agent
Authors: Neu H C , Kamimura T
Published: June 2012

The in vitro and in vivo activity of FR-31564 [sodium hydrogen 3-(N-hydroxyformamido)propylphosphate] against gram-positive and -negative aerobic and anaerobic bacteria was investigated and compared with that of fosfomycin, cephalexin, carbenicillin, and trimethoprim-sulfamethoxazole. The in vitro activity of FR-31564 was markedly enhanced when combined with glucose 6-phosphate or fructose 6-phosphate, but not when combined with ribose phosphate, adenosine monophosphate, or glycerol phosphate. In vitro activity of FR-31564 also was enhanced by human or horse blood, but not by human serum. The type of medium had a great effect on the minimal inhibitory concentration, with the lowest minimal inhibitory concentrations achieved on nutrient agar, 8- to 16-fold less than with Mueller-Hinton, heart infusion, or Trypticase soy agars. FR-31564 was more active than fosfomycin, cephalexin, carbenicillin, or trimethoprimsulfamethoxazole against Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Enterobacter cloacae, E. aerogenes, and Citrobacter. It was less active than fosfomycin against Serratia marcescens and Proteus mirabilis and did not inhibit gram-positive cocci or anaerobic species. FR-31564 inhibited a number of E. coli, K. pneumoniae, and some Pseudomonas aeruginosa strains resistant to the other agents. In the presence and absence of human blood FR-31564 showed bactericidal activity, and P. aeruginosa exposed to FR-31564 for 3 h showed a 6-h lag in regrowth. FR-31564 administered by the subcutaneous route was more active in protecting mice challenged with P. aeruginosa than was fosfomycin, carbenicillin, or cefoperazone. It was as active by the oral route in protecting mice challenged with E. coli as was fosfomycin, ampicillin, cephalexin, or trimethoprimsulfamethoxazole.
Gynecomastia with Ketoconazole
Authors: DeFelice Richard , Johnson David G. , Galgiani John N.
Published: June 2012

Three of forty men developed bilateral gynecomastia upon ketoconazole treatment. Symptoms abated despite continued therapy. This appears to be a direct drug effect on breast tissue.
Molecular and phenotypic characterization of penicillinase-producing Neisseria gonorrhoeae from Canadian sources
Authors: Dillon J R , Duck P , Thomas D Y
Published: June 2012

The incidence of penicillinase-producing Neisseria gonorrhoeae (PPNG) infections has increased in Canada during the past 2 years. Most of these cases were imported from abroad. The PPNG strains from these cases were characterized with respect to susceptibility to 11 antibiotics, auxotype, and plasmid content. Rosaramicin and cefuroxime proved to be the most potent of the antibiotics tested. The molecular characterization of the isolates indicated that all carried a 2.6-megadalton cryptic plasmid. Most of the PPNG isolates (87%) harbored a 4.5-megadalton penicillinase-producing plasmid, whereas only 13% harbored the 3.2-megadalton penicillinase-producing plasmid. In those cases where contact tracing was possible, the correlation linking strains of Far Eastern etiology with carriage of the 4.5-megadalton plasmid was upheld. The penicillinase-producing strains were typed auxanographically in either the proline-requiring (57%) or prototrophic groups (42%). Substrate hydrolysis profiles and analytical isoelectric focusing of crude beta-lactamase extracts of several isolates has reconfirmed that these strains elaborate a type TEM-1 enzyme. Several of the penicillinase-producing plasmids were also examined for plasmid stability.
Transferable tetracycline resistance in Clostridium difficile
Authors: Smith C J , Markowitz S M , Macrina F L
Published: June 2012

The transfer of tetracycline resistance among strains of Clostridium difficile is described. Transfer occurred by a conjugation-like event that was insensitive to deoxyribonuclease, could not be mediated by donor culture filtrates or chloroform-treated donor cultures, and required cell-to-cell contact. Tetracycline-resistant progeny recovered from matings displayed a resistance phenotype identical to that of the donor in level of resistance, constitutive expression, and transmissibility. Although the original tetracycline-resistant donor contained 5 x 10(6)- and 22 x 10(6)-dalton plasmids, standard physical analyses of antibiotic-resistant transconjugants revealed no plasmid deoxyribonucleic acid molecules in common with the donor strain. Furthermore, tetracycline-susceptible derivatives of the original donor always possessed a plasmid complement identical to that of the resistant parental strain as determined by restriction endonuclease digestion analysis. The results indicate that the tetracycline resistance determinant(s) was not encoded by readily detectable plasmid deoxyribonucleic acid and may be chromosomally located.
pH-dependent penicillin tolerance of group B streptococci
Authors: Horne D , Tomasz A
Published: June 2012

Group B streptococci lose viability without apparent lysis during treatment with beta-lactam antibiotics and vancomycin. Rapid loss of viability was observed in early-exponential-phase cultures. Cultures in the mid-exponential growth phase exhibited various degrees of resistance to the bactericidal effect of the antibiotics, whereas their susceptibilities to the growth-inhibitory effect remained unchanged. This growth-phase-dependent tolerance was caused by the gradual increase in acidity of the cultures as the cell concentration increased. Retitration of the pH to neutrality made the formerly tolerant bacteria again fully susceptible to the killing effect of penicillin. Conversely, lowering the pH value of the medium resulted in antibiotic tolerance throughout culture growth. The penicillin-binding proteins of whole bacteria and their labeling pattern were found to be independent of culture pH. It is suggested that the mechanism of Ph-dependent tolerance is indirect and may be mediated by an autolysin. The tolerance of group B streptococci for penicillin could be clinically relevant in view of the relatively low pH values known to prevail in the natural host environments colonized by these bacteria.
Pharmacology, Safety, and efficacy of cefamandole in childhood infections
Authors: Thirumoorthi M C , Dajani A S , Vincent C V , Maurer M J
Published: June 2012

We used cefamandole in the initial treatment of 34 children (10 months to 15 years of age) with suspected bone, joint, or soft tissue infections. The minimal inhibitory concentration of organisms encountered ranged between 0.015 and 2 microgram/ml. At 1 h after intravenous infusion of 25 mg/kg, the mean serum level of cefamandole was 26.2 microgram/ml (range, 8.9 to 47.5 microgram/ml), and at 3 h the level was 1.8 microgram/ml (range, 0.6 to 4.4 microgram/ml), which is above the minimal inhibitory concentration for most of the organisms encountered. However, when the drug was given intravenously every 6 h, the mean level after a 37-mg/kg dose was 0.9 microgram/ml (range, less than 0.5 to 1.9 microgram/ml) at 4 h and, by extrapolation, would have fallen below 0.1 microgram/ml at 6 h. The mean serum half-life was 34 min. Cefamandole appeared to diffuse well into synovial fluid, with joint fluid levels between 5 and 40 microgram/ml. The drug was tolerated well. Cefamandole appears to be a reasonable alternative in the initial treatment of skeletal infections in children, but need to be administered every 4 h to maintain suprainhibitory serum levels between doses.
Standardized method for determining antimicrobial susceptibility of strains of Ureaplasma urealyticum and their response to tetracycline, erythromycin, and rosaramicin
Authors: Robertson J A , Coppola J E , Heisler O R
Published: June 2012

We describe a method for determining the minimal inhibitory concentrations (MICs) of antibiotics for Ureaplasma urealyticum which is compatible with current standard of susceptibility testing. A presumptive MIC is available after 24 h of incubation, and the definitive MIC is available at 48 h. The MICs for 9 serotype strains and 27 clinical isolates ranged from less than or equal to 0.5 to 256 microgram of tetracycline per ml, greater than or equal to 1 to 64 microgram of erythromycin per ml, and 0.031 to 4.0 microgram of rosaramicin per ml. Of an additional 555 isolates screened for their response to tetracycline, 2% required MICs of greater than 64 microgram/ml, which we believe is near the concentration at which in vivo resistance to this agent is expressed. After prolonged exposure to rosaramicin, the resistance of two of three serotype strains of U. urealyticum was increased 8- and 16-fold, but the MICs still did not exceed 1.0 microgram/ml.
Heterogeneity of action of mechanisms among antimycotic imidazoles
Authors: Sud I J , Feingold D S
Published: June 2012

The three imidazole antimycotics clotrimazole, miconazole, and ketoconazole all inhibit the demethylation of lanosterol to ergosterol, resulting in inhibition of growth of Saccharomyces cerevisiae; this is a fungistatic action. At higher concentrations clotrimazole and miconazole are fungicidal, whereas ketoconazole is not. The fungicidal action reflects direct membrane damage by the imidazoles. Evidence for this is that ketoconazole is markedly less active than the other imidazoles in its ability to allow methylene blue entry into cells and to disrupt liposome model membranes. The possible clinical significance of these findings is discussed.
New plasmid-mediated aminoglycoside adenylyltransferase of broad substrate range that adenylylates amikacin
Authors: Coombe R G , George A M
Published: June 2012

The same aminoglycoside 2"-adenylyltransferase was isolated from four gram-negative species which were among a random group of gentamicin-resistant isolates from the same hospital. The enzyme was partially purified from a crude extract which also contained a second modifying enzyme identified as APH(3')-I. The substrate range of the new aminoglycoside 2"-adenylyltransferase included the newer aminoglycosides sisomicin and amikacin, but showed much-reduced activity against gentamicins C2 and Cla. The pH optimum was 7.8 to 8.0 for every substrate, and the molecular weight of the enzyme molecule was estimated at approximately 29,000. Genetic experiments clearly established that both enzymes were expressed by a conjugative plasmid.
Clinical evaluation of moxalactam
Authors: Livingston W K , Elliott A M , Dismukes W E , Avent C K , Cobbs C G
Published: June 2012

We investigated the clinical efficacy of moxalactam for treatment of a variety of infectious disorders in 50 patients (38 males and 12 females). Patient ages ranged from 8 days to 98 years, with a median of 66 years. Infectious disorders were confirmed by isolation of etiological bacteria in all patients. Thirty-eight patients had gram-negative bacillary disease, nine had pneumococcal infection, and three had disorders caused by staphylococci or streptococci. Twenty-three patients had pneumonia, 17 had bacteremic diseases other than pneumonia, and 10 had miscellaneous infectious diseases. The overall efficacy of moxalactam was excellent. Forty-eight patients were cured by clinical criteria, and 45 were cured by bacteriological criteria. A total of 19 adverse reactions were associated with the use of moxalactam in 18 patients, but none were severe and only one necessitated discontinuation of treatment. Moxalactam promises to be an important addition to our therapeutic armamentarium, especially for therapy of gram-negative bacillary infections.
Inhibition of aminoglycoside activity in heparin
Authors: Nilsson L , Maller R , Anséhn S
Published: June 2012

Measurements of aminoglycosides by an agar disk diffusion assay are inhibited by heparin in a dose-dependent way. When assayed by a homogeneous immunoassay, this was only evident for tobramycin. This indicates that specimens for aminoglycoside measurement should not be obtained in heparinized tubes. When heparin is used clinically as an anticoagulant, the amount in blood does not reach levels that affect the aminoglycoside activity.
Susceptibility of pneumococci to 14 beta-lactam agents: comparison of strains resistant, intermediate-resistant, and susceptible to penicillin
Authors: Ward J I , Moellering R C
Published: June 2012

To measure the susceptibility of penicillin-resistant pneumococci to newer beta-lactam agents, we evaluated 54 selected strains recovered from patients with bacteremia or meningitis. Three groups of pneumococci were tested: penicillin-susceptible strains, strains with intermediate penicillin resistance, and penicillin-resistant strains. Minimal inhibitory concentrations of benzyl penicillin, oxacillin, cephalothin, cefamandole, cefoxitin, moxalactam (LY127935), cefotaxime (HR756), piperacillin, pirbenicillin, N-formimidoyl thienamycin (MK0787), cefoperazone (T1551), mezlocillin, azlocillin, and mecillinam were determined. For all groups of pneumococci tested, cefotaxime, and particularly thienamycin, had the greatest activity. Piperacillin, mezlocillin, and azlocillin had activity similar to that of benzyl penicillin. Cefoperazone had less activity than penicillin against strains with penicillin minimal inhibitory concentrations of less than 1 microgram/ml but greater activity than penicillin against strains with greater resistance. Oxacillin, cephalothin, cefamandole, and pirbenicillin all had less activity for each group of pneumococci tested; moxalactam, cefoxitin, and mecillinam had the least activity. The relative differences in susceptibility to penicillin of each group of pneumococci tested were similar for each of the beta-lactam agents tested. The clinical effectiveness of cefotaxime and thienamycin for therapy of disease due to penicillin-resistant pneumococci needs further evaluation, and of particular interest will be the levels of these drugs which can be achieved in cerebrospinal fluid.
Comparative in vitro study in new cephalosporins
Authors: Bodey G P , Fainstein V , Hinkle A M
Published: June 2012

Three new cephalosporins, ceftazidime, ceftizoxime, and cefotiam, were evaluated in vitro against clinical isolates, and their activities were compared with those of other cephalosporins, mezlocillin, and tobramycin. All three new cephalosporins were very active against gram-positive cocci (except enterococci), but mezlocillin was more active against Streptococcus ssp. Cefotiam and cefamandole were the most active antibiotics against Streptococcus aureus. Ceftazidime had broad-spectrum activity against all gram-negative bacilli tested, except Enterobacter spp. Ceftizoxime was active against all, except Enterobacter spp. and Pseudomonas aeruginosa. Although cefotiam was quite active against Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, it was inactive against indole-positive Proteus spp., Serratia spp, and P. aeruginosa. The in vitro activity suggests that ceftazidime should prove useful as a broad-spectrum antibiotic, in those settings in which the most likely pathogens are gram-negative bacilli.
Biliary excretion of moxalactam
Authors: Martinez O V , Levi J U , Livingstone A , Malinin T I , Zeppa R , Hutson D , Einhorn N
Published: June 2012

The biliary excretion of moxalactam was studied in 11 postsurgery patients who had indwelling T-tubes inserted in their common bile ducts. Peak levels of moxalactam in the bile reached mean levels of 33.7 +/- 11.1 and 173.7 +/- 67.0 micrograms/ml 2 h after intravenous administration of a single 500- or 2,000-mg dose, respectively. In 5 of the 10 patients given the 2,000-mg dose, peak moxalactam concentrations in the bile were 2 to 12 times higher than simultaneous serum levels, but considerable variation in the biliary excretion of moxalactam was observed among the individual patients.
Beta-lactam susceptibility of Neisseria gonorrhoeae isolates from pelvic inflammatory disease
Authors: Pinon G , Quentin R , Laudat P , Vargues R
Published: June 2012

Gonococci isolated in France from urethral and endocervical cultures in 12 women with pelvic inflammatory disease were similar, in their susceptibility to six beta-lactam antibiotics as determined by an agar dilution procedure, to isolates from patients with uncomplicated anogenital infections (83 patients). These data contrast with earlier study done in the United States.
Immunological properties of beta-lactamases that hydrolyze cefuroxime and cefotaxime
Authors: Hirai K , Sato K , Matsubara N , Katsumata R , Inoue M , Mitsuhashi S
Published: June 2012

Antiserum against purified beta-lactamase from Proteus vulgaris GN7919 cross-reacted with beta-lactamases produced by strains of Pseudomonas cepacia in a neutralization test. Anti-P. cepacia beta-lactamase serum, however, did not show any cross-reactions with P. vulgaris beta-lactamases. Each of these enzymes can hydrolyze cefuroxime and cefotaxime.
Comparative in vitro activity of Mk-0366 and other selected oral antimicrobial agents against Neisseria gonorrhoeae
Authors: Khan M Y , Siddiqui Y , Gruninger R P
Published: June 2012

The in vitro activity of a new ora antimicrobial agent, Mk-0366 (AM-715), was compared with those of rosoxacin, ampicillin, erythromycin, and tetracycline against Neisseria gonorrhoeae. Mk-0366 was as active as rosoxacin and more active than the other three antimicrobial agents. It inhibited all isolates, regardless of beta-lactamase activity, at a concentration of 0.03 micrograms/ml.
Sodium polyanethol sulfonate inactivation of aminoglycosides
Authors: Krogstad D J , Murray P R , Granich G G , Niles A C , Ladenson J H , Davis J E
Published: June 2012

Sodium polyanethol sulfonate and another polyanion (dextran sulfate) both inhibited aminoglycoside activity in vitro. This effect was not produced by an otherwise similar neutral carbohydrate (dextran) or by neutral detergents (Brij-35, Triton X-100) but was antagonized by an anion-exchange resin (Dowex 1X8-50). We conclude that the inactivation of aminoglycosides by sodium polyanethol sulfonate results from its polyanionic nature and is unrelated to its detergent properties.
Activity of trifluorothymidine against cytomegalovirus
Authors: Wingard J R , Stuart R K , Saral R , Burns W H
Published: June 2012

Trifluorothymidine (TFT) was tested for antiviral activity against mouse cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) in one-step replication assays. The TFT concentration required to reduce virus yield by 50% (ID50) was 0.22 microM for MCMV and 0.012 microM for HCMV. The antiviral activity of TFT against MCMV was reversed by addition of equimolar thymidine, and no antiviral activity was demonstrable in a host cell line lacking thymidine kinase. Thus, TFT's anti-MCMV activity is dependent on a host cell TK since this herpesvirus lacks thymidine kinase. A continuous subcutaneous infusion of TFT achieving a serum concentration of 1 microM failed to protect mice from lethal MCMV infection, perhaps because serum levels of thymidine were comparable to the drug level. Comparison of the ID50 against HCMV and the ID50 against human bone marrow progenitor cells resulted in an in vitro therapeutic ratio of 108, suggesting that TFT might offer some promise as a clinically useful anti-HCMV agent.
6 beta-Iodopenicillanic acid (UI-38,006), a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactam compounds: initial bacteriological characterization
Authors: Moore B A , Brammer K W
Published: June 2012

UK-38,006, 6 beta-iodopenicillanic acid, was shown to be a potent inhibitor of beta-lactamase enzymes. It potentiated the antibacterial action of ampicillin in vitro against beta-lactamase-producing strains of Staphylococcus aureus, Haemophilus influenzae, Bacteroides fragilis. Neisseria gonorrhoeae, and many Enterobacteriaceae. This ability to synergize with ampicillin was also demonstrated in vivo after oral administration of UK-38,006 to experimentally infected mice. UK-38,006 was also shown to synergize in vitro with other penicillins and cephalosporins against beta-lactamase-producing strains of Escherichia coli, Proteus mirabilis, and Klebsiella species.
Penicillin and tetracycline resistance plasmids in Staphylococcus epidermidis
Authors: Totten P A , Vidal L , Baldwin J N
Published: June 2012

The genetic nature of penicillin (Pc) and tetracycline (Tc) resistance plasmids in Staphylococcus epidermidis were studied and compared with those in S. aureus. Of 10 S. epidermidis strains transduced for penicillin resistance, we could isolate Pc plasmids from only 3. One of these plasmids also encoded for cadmium resistance and another encoded for resistance to ethidium bromide, traits also associated with S. aureus Pc plasmids. Endonuclease fingerprinting of the Pc plasmids from the two species revealed extensive heterogeneity. Two S. epidermidis strains were also transduced for tetracycline resistance. Both harbored plasmids indistinguishable from S. aureus Tc plasmids as judged by endonuclease fingerprinting. These data suggest that genetic exchange between S. aureus and S. epidermidis occurs in vivo.
Conjugal transfer of an R-plasmid in Pasteurella multocida
Authors: Hirsh D C , Martin L D , Rhoades K R
Published: June 2012

A strain of Pasteurella multocida isolated from turkeys during an outbreak of septicemic disease (fowl cholera) was shown to possess the ability to transfer streptomycin and sulphadiazine resistance to P. multocida and to Escherichia coli by conjugation. The genes necessary for the transfer of the resistance genes appeared to be associated with a plasmid of molecular weight 28.5 x 10(6). The resistance genes were shown to be associated with a second plasmid of molecular weight 7.2 x 10(6).