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Flexible wearable sensors have obtained tremendous interest in various fields and conductive hydrogels are a promising candidate. Nevertheless, the insufficient mechanical properties, the low electrical conductivity and sensitivity, and the limited functional properties prevent the development of hydrogels as wearable sensors. In this study, an SFMA/BAChol/PAA/ZnCl 2 hydrogel was fabricated with high mechanical strength and versatile comprehensive properties. Specifically, the obtained hydrogel displayed excellent adhesion and mechanical stability, cryophylactic ability, stable sensitive freezing-tolerant conductivity, and feasible electrical conduction under a wide temperature range, demonstrating the high application potential as a flexible wearable sensor for movement behavior surveillance, even under harsh environments. Furthermore, the mechanical strength of the hydrogel could easily be regulated by varying the copolymer content. The molecular mechanisms of the hydrogel formation and the reversible adhesion during the wet-dry transition were proposed. The non-covalent interactions, including the electrostatic interaction, hydrogen bond interaction and hydrophobic association, and coordination interaction, were dynamically presented in the hydrogel network and hence supported the versatile comprehensive properties of the hydrogel. This study provides a strategy for designing novel hydrogels to promote the development of flexible sensors with stable sensitive freezing-tolerant conductivity.

Objective: To identify a rare α-thalassemia gene mutation in a family from south China and perform a pedigree analysis and genetic diagnosis of hemoglobin H (HbH) disease caused by this mutation., Methods: Peripheral blood samples were collected from the family members for analysis of the hematological phenotype and routine test of thalassemia genes. DNA sequencing was carried out for samples that showed genotype and phenotype inconsistency., Results: A rare α-thalassemia *92A>G gene mutation was detected within this family. The proband and his sister were confirmed to have non-deletional HbH disease with α-- SEA /α *92A>G α genotype. The proband's brother was confirmed to have an α-thalassemia trait with the genotype of -α 3.7 /α *92A>G α. The proband's father was identified as an α-thalassemia silent carrier with the genotype of αα/α *92A>G α., Conclusion: A rare α-thalassemia *92A>G gene mutation was identified for first time in south China. The description of the basic phenotypic characteristics of α-thalassemia trait and silent carrier caused by this mutation enriches the α-thalassemia gene mutation spectrum in Chinese population and helps in population screening, clinical molecular diagnosis and genetic counseling.

The objective of the present study was to construct a human chromosome 21 specific DNA library for further use in research of genetic disease. Human chromosome 21 microdissected from the peripheral blood cells were subjected to repeatedly incubation in gradient temperature bath to release DNA. The library of chromosome 21 was constructed using the DNA fragment of 100-500 bp and 500-2 000 bp recovered from the products of DOP-PCR. Florescence in situ hy-bridization (FISH) and dot blotting analyses were carried out to assess the chromosome 21 specificity of the DNA library. The results indicated that DNA of chromosome 21 was released easily after repeatedly incubation in gradient temperature bath. Recovery of DNA fragments from DOP-PCR in different size ranges improved the efficiency of cloning of large fragments. Both FISH and dot blotting analyses revealed that the DNA library constructed in this study was chromosome 21-specific. This DNA library facilitates identification and investigation of the chromosome 21 related abnormality.

The in vitro activity of levofloxacin against coagulase-negative staphylococci (CNS) was investigated. In vitro, on the basis of MIC90 values, levofloxacin was as active as ciprofloxacin, inhibiting both methicillin-sensitive and -resistant staphylococci at 0.5 microgram/ml. The frequency of one-step development of levofloxacin-resistant CNS was < 1 x 10(-9). After repeated transfer of CNS in the presence of increasing concentrations of levofloxacin or other quinolones, there were 4-fold increases in MIC50 values for both levofloxacin and ofloxacin, whereas there were 64- to 128-fold increases for ciprofloxacin, norfloxacin and enoxacin. Based on MIC50 values, the concentrations of 1 or 2 micrograms/ml are clinically relevant. The mutant strains induced by levofloxacin showed less virulence based on the LD50 value in acute systemic murine infection.

FK037, a new parenteral cephalosporin, is an oxime-type cephem antibiotic with a 1-hydroxyethyl-5-amino-pyrazole moiety at the 3 position. FK037 was evaluated for antimicrobial activity in vitro and in vivo. In vitro, FK037 was twofold or more active than ceftazidime, cefoperazone, cefotaxime, and ceftriaxone against Pseudomonas aeruginosa (MIC for 90% of the strains [MIC90] = 32 micrograms/ml), members of the family Enterobacteriaceae (MIC90 < or = 2 micrograms/ml), group A streptococci (MIC90 = 0.015 microgram/ml), and methicillin-sensitive or -resistant coagulase-negative staphylococci (MIC90 = 2 and 16 micrograms/ml, respectively). In addition, the activity of FK037 was equal to or greater than that of ceftazidime, cefotaxime, or ceftriaxone against Streptococcus pneumoniae (MIC90 = 0.12 microgram/ml) and methicillin-sensitive or -resistant Staphylococcus aureus (MIC90 = 2 and 16 micrograms/ml, respectively). FK037 was more active in vitro than cefepime (two- to fourfold) and cefpirome (twofold) against S. aureus. In murine systemic infection models, FK037 showed potent activity against P. aeruginosa, Escherichia coli, and methicillin-sensitive and methicillin-resistant S. aureus. FK037 was also efficacious in a mouse model of pyelonephritis caused by S. aureus or Klebsiella pneumoniae and in a mouse model of pneumococcal pneumonia caused by S. pneumoniae. Additional studies on this compound to assess its potential clinical utility are warranted.

Twelve strains of Streptococcus pneumoniae were serially exposed to increasing concentrations of levofloxacin, temafloxacin, ciprofloxacin and norfloxacin for five passages. Wild-type and passaged strains were tested for susceptibility to quinolones, macrolide and penicillin G. The MIC90 data showed a 2-fold increase for levofloxacin but a 32-fold increase for ciprofloxacin, a 16-fold increase for temafloxacin and an 8-fold increase for norfloxacin. Among 16 ciprofloxacin-induced resistant strains, 14 were susceptible to levofloxacin. No cross-resistance to other antibiotics was observed.

The in vitro activity of l-ofloxacin was determined against coagulase-negative staphylococci that were induced to norfloxacin resistance. l-Ofloxacin was the most active agent tested with an MIC90 of 4 micrograms/ml compared with greater than 128, 32, and 128 micrograms/ml for norfloxacin, ciprofloxacin, and enoxacin, respectively. Rifampin-resistant, coagulase-negative staphylococci were not cross-resistant to the quinolones tested. Among the rifampin-resistant organisms tested, l-ofloxacin was also the most active agent with an MIC90 of 0.25 micrograms/ml.

The postantibiotic suppressive effect (PAE) of L-ofloxacin was studied and compared with those of ciprofloxacin and norfloxacin. The PAE of L-ofloxacin was observed against all Gram-positive organisms tested: Staphylococcus aureus, S. epidermidis, and Enterococcus faecalis. At the achievable serum concentrations L-ofloxacin showed a longer PAE than ciprofloxacin and norfloxacin. Exposure of organisms to 4 micrograms/ml of L-ofloxacin for 2 hr produced a 3.1 and 4.2 hr PAE for methicillin-sensitive and methicillin-resistant staphylococci, respectively. Against E. faecalis and S. epidermidis, the PAEs of L-ofloxacin were 1.9 and 1.6 hr, respectively.

The antibacterial activity of levofloxacin was compared with those of ofloxacin, ciprofloxacin, and other antibiotics. In general, levofloxacin was equally active or up to fourfold more active than ofloxacin against all 801 organisms tested. Levofloxacin was twofold [corrected] more active than ciprofloxacin against Streptococcus pneumoniae and 2- to 4-fold more active than ciprofloxacin against Staphylococcus aureus, Xanthomonas maltophilia, and Bacteroides fragilis. Levofloxacin was two- to eightfold more active than ciprofloxacin against coagulase-negative staphylococci and Acinetobacter spp., although these improvements in potency may not be clinically relevant. Levofloxacin inhibited 90% of streptococci when it was used at concentrations of 1 to 2 micrograms/ml. Levofloxacin was two- to fourfold less active than ciprofloxacin against most members of the family Enterobacteriaceae, such as Escherichia coli; Klebsiella pneumoniae; Citrobacter, Proteus, Providencia, Salmonella, and Yersinia spp.; and Pseudomonas aeruginosa. Both compounds were equally active against Pseudomonas cepacia. The in vitro DNA gyrase inhibitory activity of levofloxacin was as potent as that of ciprofloxacin, with a 50% inhibitory concentration of 0.65 micrograms/ml against an E. coli enzyme. In vivo, oral treatment with levofloxacin was as efficacious or more efficacious than that with ciprofloxacin in systemic as well as pyelonephritis infections in mice. Levofloxacin achieved higher concentrations in the serum and tissue of mice than did ciprofloxacin. This study presents some potential advantages of the pure L isomer of ofloxacin over ciprofloxacin and other quinolones.

The in vitro activity of saperconazole against selected isolates of dermatophytes and its in vivo efficacy in a guinea pig dermatophytic infection model using Trichophyton mentagrophytes were evaluated. Susceptibility testing was determined with an agar dilution method in three media: yeast nitrogen base agar (YNBA), brain heart infusion agar (BHIA) and Sabouraud dextrose agar (SDA). An inoculum of 1 x 10(5) CFU of T. mentagrophytes spores was placed onto the surface of these agars. Incubation was at 32 degrees C for 72 h. The MIC of saperconazole against all isolates was less than 1 microgram/ml, whereas the MIC ranged from 0.1 to > 128 micrograms/ml for fluconazole. The MIC range of saperconazole against Trichophyton species was < or = 0.002 to 0.25 micrograms/ml; against Microsporum species it was < 0.001 to 0.1 microgram/ml; and against Epidemophyton species was < or = 0.002 to 0.25 micrograms/ml. These data showed that saperconazole was the most active compound tested against these selected dermatophytes. The activities of saperconazole against T. mentagrophytes, T. rubrum and M. canis were not affected by the medium. The MICs against these organisms were < or = 0.008 micrograms/ml in SDA, YNBA or BHIA. There were 2- to 4-fold decreases in activity for fluconazole at the same conditions. In vivo, topical treatment with saperconazole at concentrations of 0.125% and 0.25% resulted in 50% and 75% microbiological cure rates, respectively, in the guinea pig topically infected with T. mentagrophytes.

The in vitro activity of saperconazole against eight candidal species (81 strains) was determined and compared with fluconazole, Sch 39304 and amphotericin B. Using brain heart infusion broth with an inoculum of 10(4) CFU/ml, the MIC ranges (micrograms/ml) of saperconazole were: less than or equal to 0.015- greater than 32 for Candida albicans, less than or equal to 0.015-16 for C. tropicalis, less than or equal to 0.015-32 for C. glabrata, less than or equal to 0.015-32 for C. parapsilosis, less than or equal to 0.015-0.12 for C. guilliermondii and less than or equal to 0.015-0.06 for C. krusei. Saperconazole was the most active agent tested against Candida species. Saperconazole and 5-fluorocytosine combinations showed synergistic interactions against Candida species, and no antagonistic interaction was demonstrated. In a rat vaginal candidiasis infection model, saperconazole and fluconazole were equipotent producing 75-100% cures at levels of 0.016-0.25%, respectively, when dosed intravaginally. After single oral dosing, saperconazole was 5-fold more potent than fluconazole with an ED50 value of 0.53 mg/kg. These data demonstrate that saperconazole is effective in a rat vaginal candidiasis infection either with a single oral dose or by intravaginal treatment.

The effects of ofloxacin in Salmonella typhimurium infection in mice were compared with those of ciprofloxacin, ampicillin and chloramphenicol. Oral administration of ofloxacin at 10, 50 or 100 mg/kg once per day for seven days significantly (P less than 0.02) increased survival (20.1 days at 100 mg/kg) of infected mice relative to non-treated controls (4.1 days). In addition, after oral treatment with 100 mg/kg of each of the antibiotics, ofloxacin was significantly more effective than ampicillin (9.9 days), chloramphenicol (8.4 days) or ciprofloxacin (14.9 days) in prolonging the mean survival time of these mice. A comparison of oral potencies indicates that ofloxacin is five times more potent than ciprofloxacin (oral ED50 = 13.3 mg/kg vs ciprofloxacin = 69.9 mg/kg) and over eight times more potent than either of the other two antibiotics. When the number of bacteria from livers and spleens was quantitated, only ofloxacin (25 or 100 mg/kg,po) significantly (P less than 0.02) reduced the number of viable bacteria in both of these tissues in comparison with untreated controls, and, relative to the other antibiotics, ofloxacin (100 mg/kg) caused a significantly greater reduction. Single oral dosing of 20 mg/kg of either ofloxacin or ciprofloxacin showed that ofloxacin achieves approximately a four-fold higher peak serum or liver concentration than ciprofloxacin, which may contribute to its better efficacy in this infection model. These results taken together suggest that oral ofloxacin may be of value in treating systemic salmonella infections in humans.

A cephalosporin-hydrolyzing enzyme from strains of Proteus penneri resistant to beta-lactam antibiotics was purified and characterized. The enzyme gave a single protein band on SDS-polyacrylamide gel electrophoresis with a molecular weight of 30,000. This cephalosporinase has an isoelectric point of 6.8, a pH optimum of 6.5 and a temperature optimum of 45 degrees C. The enzyme hydrolyzed cephaloridine, cephalothin, cefuroxime, and cefotaxime more rapidly than penicillins. The relative rate, with cephaloridine as 100, were: cephalothin, 50; cefuroxime, 93; cefotaxime, 48; ceftriaxone, 23; cefoperazone, 11; benzylpenicillin, 3; ampicillin, 9; and carbenicillin, less than 1. Cephamycins had low affinities for the enzyme. However, clavulanic acid and sulbactam, with high affinities for the enzyme, were inhibitors of this enzyme.

The pharmacokinetics of ceftriaxone were evaluated in eight adults after doses of 1 g administered by intravenous infusion and 1 and 0.5 g administered by intramuscular injection. Mean peak plasma concentrations were 168 micrograms/ml for 1 g given intravenously, 81 micrograms/ml for 1 g given intramuscularly, and 46 micrograms/ml for 0.5 g intramuscularly. Plasma concentrations were similar by both high pressure liquid chromatographic and microbiologic methods. The plasma half-lives were 7.6 and 8.3 hours, respectively, for the intravenous infusion and intramuscular injection. Plasma concentrations were equal for the 1 g intravenous and intramuscular routes by 2.5 hours. Plasma concentrations exceeded the minimal inhibitory concentrations (MICs) of most aerobic gram-positive and gram-negative organisms with the exception of Pseudomonas aeruginosa and Acinetobacter species for 24 hours. Urinary concentrations exceeded 100 micrograms/ml for 24 hours for the 1-g doses and for 12 hours for the 0.5-g dose. Urinary recovery of ceftriaxone within 24 hours was 40 percent for intravenous infusion and 33 and 34 percent for the intramuscular injection. A single 1-g dose daily will exceed the MICs of most staphylococcal and streptococcal species and Enterobacteriaceae for 12 to 24 hours.

The therapeutic efficacy of cefpiramide and apalcillin was evaluated and compared with that of six other antipseudomonal beta-lactam antibiotics in an experimental mouse burn infection due to Pseudomonas aeruginosa. Both cefpiramide and apalcillin were as potent as cefsulodin and more potent than carbenicillin, cefotaxime, cefoperazone, piperacillin and gentamicin in protecting the infected mice from fatal bacteraemia and in eradicating Ps. aeruginosa from the infected site.

5-Episisomicin, a semisynthetic aminoglycoside, has been shown to inhibit many members of the Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. At a concentration of 3.1 mug/ml, more than 90% of Escherichia coli, Klebsiella pneumoniae, Enterobacter, Citrobacter, indole-positive Proteus, and Providencia were inhibited. 5-Episisomicin had activity against S. aureus, E. coli, Klebsiella, Enterobacter, and Citrobacter similar to gentamicin and netilmicin. It had activity similar to amikacin and netilmicin against many gentamicin-resistant bacteria. The activity of 5-episisomicin was greatest at an alkaline pH and in medium of low magnesium content. Synergy of 5-episisomicin and carbenicillin was found to occur most often against Pseudomonas.

1-N HAPA gentamicin B is a new aminoglycoside active against most Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. Among 504 clinical isolates at a concentration of 12.5 microgram/ml all Staph. aureus, Escherichia coli, Klebsiella, Enterobacter, Proteus rettgeri, Providencia and 78% of Pseudomonas, 86% of Proteus morganii were inhibited. Like other aminoglycosides, the activity was greatest at an alkaline ph and reduced by high cations concentrations. 1-N HAPA gentamicin B was equal in activity to amikacin against both gentamicin-sensitive and resistant isolates. It inhibited bacteria containing many of the aminoglycoside inactivating enzymes. When combined with carbenicillin it inhibited in a synergistic manner many Gram-negative bacteria, particularly Pseudomonas and Serratia.

The in vitro activity of (6R,7R)-7-{[carboxy(4-hydroxyphenyl)acetyl]amino}-7-methoxy-3-[[(1-methyl -1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-oxa-1-azabicyclo-[4.2.0]oct-2-ene -2-carboxylic acid was tested against isolates of gram-positive and negative bacteria and compared with those of cephalothin, cefuroxime, cefamandole, cefoxitin, cefotaxime, and carbenicillin. The compound was less active than the other compounds when tested against Staphylococcus aureus and Staphylococcus epidermidis. It had equal or slightly less activity than did cefotaxime when tested against members of the Enterobacteriaceae, but was 8- to 32-fold more active than the other cephalosporins against the Enterobacteriaceae, inhibiting most isolates at concentrations less than 0.5 mug/ml. The compound was twofold more active than cefotaxime and cefoxitin against Bacteroides, and it was twofold more active than cefotaxime and fourfold more active than carbenicillin against Pseudomonas aeruginosa. In vitro activity did not correlate with either the presence or type of beta-lactamase in either Enterobacteriaceae or Pseudomonas. The compound showed minimal synergy when combined with aminoglycosides or carbenicillin.

The in vitro activity of HR 756, 7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoximino)acetamido] cephalosporanic acid, was investigated against 659 isolates. HR 756 inhibited Neisseria and Haemophilus species at concentrations similar to those needed with ampicillin. It inhibited beta-lactamase-producing N. gonorrhoeae and H. influenzae. HR 756 was the most active compound tested against members of the Enterobacteriaceae, inhibiting most isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, Enterobacter, and Shigella at concentrations of less than 0.1 mug/ml. It was twice as active as carbenicillin against Pseudomonas aeruginosa and inhibited Bacteroides fragilis as well as cefoxitin. HR 756 killed E. coli, Staphylococcus aureus, and P. aeruginosa at rates similar to other beta-lactam antibiotics.

The in vitro activity of cefaclor against 556 clinical isolates of gram-positive and gram-negative bacteria was compared with that of other cephalosporins. Cefaclor had activity similar to that of cephalexin against gram-positive bacteria. It showed greater activity against Haemophilus strains than did cephalexin and inhibited beta-lactamase-producing Haemophilus isolates. Cefaclor was more active than cephalexin or cephalothin against Escherichia coli, Salmonella, and Shigella isolates but did not act against Serratia, Acinetobacter, indole-positive Proteus, or Bacteroides isolates. Cefaclor was resistant to type III (TEM) beta-lactamases but was destroyed by type I beta-lactamases and, to a lesser degree, by type IV and type V beta-lactamases.

The in vitro activity of ceftriaxone (Ro 13-9904), a parenteral cephalosporin, was compared with that of other beta-lactam antibiotics. the compound was less active against Staphylococcus aureus and Staphylococcus epidermidis than was cephalothin or cefamandole, but it was comparable to cefoxitin, cefotaxime, and moxalactam in inhibiting most isolates of S. aureus at 3.1 microgram/ml. Ro 13-9904 inhibited Streptococcus pyogenes and Streptococcus pneumoniae at concentrations below 0.25 microgram/ml, but Streptococcus faecalis required concentrations above 25 microgram/ml. Neisseria gonorrhoeae and Haemophilus influenzae were inhibited at concentrations similar to those of cefotaxime, less than 0.1 microgram/ml. Ro 13-9904 was as active as cefotaxime and moxalactam against most Enterobacteriaceae and was the most active agent tested against Proteus, inhibiting all strains tested at 0.006 microgram/ml. Ro 13-9904 was slightly less active than moxalactam or cefoxitin against Bacteroides fragilis, requiring more than 100 microgram/ml to inhibit 90% of isolates, and it was less active than cefoperazone against Pseudomonas aeruginosa. Presence of serum, alteration of pH, and use of various media did not change the inhibitory levels. Bactericidal concentrations were similar to inhibitory levels. Ro 13-9904 was stable to most plasmid-mediated beta-lactamases, but was hydrolyzed by some Enterobacter, Proteus, and Bacteroides beta-lactamases of chromosomal origin.

SCE-129 [3-4-carbamoyl-1-pyridiniomethyl-7beta- (d-alpha-sulfophenylacetamido)-ceph-3-em-4-carboxylate] is a cephalosporin that inhibits Pseudomonas aeruginosa and Staphylococcus aureus. SCE-129 is tenfold more active than carbenicillin in inhibiting P. aeruginosa. SCE-129 has poor activity against Enterobacteriaceae compared with other cephalosporins and is 16-fold less active than the cephalosporins against streptococci. The activity of SCE-129 does not correlate with beta-lactamase stability, although SCE-129 is resistant to hydrolysis by gram-positive and gram-negative bacteria. The compound does not inhibit the hydrolysis of other cephalosporins. Although SCE-129 acts synergistically with gentamicin to inhibit some Pseudomonas, this cannot be predicted based on knowledge of resistance to one or more compounds.

The in vitro activity of ceftizoxime was compared with that of other beta-lactam antibiotics against 538 isolates. Ceftizoxime was the most active agent tested against Escherichia coli and Klebsiella, inhibiting 80% at 0.025 microgram/ml. It was more active than cefotaxime against Enterobacter cloacae and E. aerogenes. Ceftizoxime was more active than cefoxitin, cefotaxime, cefoperazone, and carbenicillin against Proteus mirabilis and indole-positive Proteus. It inhibited 97% of multiresistant Serratia isolates at 12.5 microgram/ml, whereas cefotaxime inhibited only 19%. Ceftizoxime was less active than cefotaxime and cefoperazone against Pseudomonas aeruginosa, but was more active than carbenicillin. It was more active than cefotaxime and cefoxitin against Bacteroides. It was not appreciably destroyed by beta-lactamases of Staphylococcus aureus, Enterobacteriaceae, or Pseudomonas.

The therapeutic efficacy of cefpiramide and ciprofloxacin alone and in combination was investigated and compared with that of ticarcillin plus tobramycin against pseudomonal infections in mice made neutropenic by administration of cyclosphosphamide. Therapy with cefpiramide plus ciprofloxacin was significantly more effective than that by either antibiotic alone. These results were consistent with in-vitro synergistic effects. At a higher dose of ciprofloxacin (4 mg/kg) plus cefpiramide (50 mg/kg), the combination therapy protected all neutropenic mice from fatal bacteraemia, and was more protective than ticarcillin (200 mg/kg) plus tobramycin (1 mg/kg). The peak serum concentration of cefpiramide in infected neutropenic mice was 51 mg/l when they were given 50 mg/kg subcutaneously. Ciprofloxacin attained a peak serum concentration of 1.2 mg/l and a serum half-life of 34 min.

Beta-lactam-inactivating activity has been found in all sero-groups of Legionella pneumophila. The beta-lactamase activity could be detected in intact cells and released by ethylenediaminetetraacetic acid treatment, indicating that it is located in the periplasmic space. The enzyme acted primarily as a cephalosporinase hydrolyzing cefamandole, cephalothin, cephaloridine, and also penicillin G and ampicillin. Cefoxitin and cefuroxime were not hydrolyzed. Clavulanic acid and CP-45,899, beta-lactamase inhibitors, prevented the hydrolysis of cephalosporins and penicillins. The beta-lactamase activity appears to be different from that found in Enterobacteriaceae and Pseudomonas.

Clavulanic acid, Z-(2R,5R)-3-(beta-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo-[3,2,0] heptane-2-carboxylic acid, has been shown to be an effective inhibitor of the beta-lactamases of the Richmond types II, III, IV, and V. Inhibition is a time-dependent reaction and is irreversible. Clavulanic acid had poor antibacterial activity against Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa, with minimal inhibitory levels greater than 25 mug/ml. It did inhibit the majority of Neisseria gonorrhoeae at 0.1 mug/ml and Haemophilus influenzae at 6.3 mug/ml. Clavulanic acid acted synergistically with penicillins and cephalosporins to inhibit beta-lactamase-producing S. aureus and Enterobacteriaceae. Clavulanic acid combined with ampicillin inhibited beta-lactamase-producing N. gonorrhoeae, H. influenzae, Escherichia coli, Salmonella typhi, and Shigella sonnei.

The kinetics of cefotaxime, a cephalosporin with an unusually broad antibacterial spectrum, were examined in humans after intravenous bolus injection, intravenous infusion every 6 hr for 14 days, and intramuscular injection every 8 hr for 10 days. Mean peak serum level after bolus injection of 500 mg was 37.9 microgram/ml; after 1 gm, 102.4 microgram/ml; and after 2 gm, 214.1 microgram/ml. The half-life (t1/2) was 1 hr for the 3 doses. Total serum clearance was the same for all doses. Overall excretion was 50% to 60%; part of the drug was excreted as the desacetyl derivative. After multiple intravenous infusion the elimination rate constants and t1/2 were the same on days 1 and 15. Assayable levels were present on all days 5 min before injection of a dose. Multiple intramuscular injections of 500 mg produced serum levels of 9.2 to 11.9 microgram/ml. The t1/2 was 0.93 hr. Mean serum levels at 8 hr ranged from 0.08 to 0.55 microgram/ml. Serum levels produced by intravenous infusion or intramuscular injection were inhibitory for most (90%) aerobic gram-positive and gram-negative organisms susceptible to cefotaxime.

Clavulanic acid and a penicillanic acid sulfone, when combined individually with piperacillin, synergistically inhibited various Enterobacteriaceae, Staphylococcus aureus, and Bacteroides fragilis. Clavulanic acid and piperacillin synergistically inhibited 91 of 170 (55%) isolates tested. Synergy was most often found against piperacillin-resistant bacteria: 65 of 69 isolates (94%). Although the penicillanic acid sulfone acted synergistically with piperacillin, inhibiting 62 of 170 strains (33%), the concentration of clavulanic acid required for synergy generally was less than that of penicillanic acid sulfone. Combination of piperacillin and cefotaxime, an inhibitor of type 1 beta-lactamases, rarely was synergistic and was antagonistic for several species. The combination of piperacillin with potent beta-lactamase inhibitors made piperacillin active against those isolates of Escherichia coli and Klebsiella and Bacteroides species, as well as selected other species, that are resistant to piperacillin by virtue of their production of beta-lactamases.

The activity of azlocillin and mezlocillin, new semisynthetic ureido penicillins, was investigated and compared with that of other known beta-lactam antibiotics. At a concentration of 25 mug/ml, azlocillin inhibited 74% of Enterobacter, 97% of Proteus mirabilis, 64% of Citrobacter, 91% of Pseudomonas aeruginosa, and 82% of Bacteroides strains tested. Mezlocillin inhibited 86% of Shigella, 96% of Enterobacter, 80% of indole-positive Proteus, 88% of Bacteroides, and 63% of Pseudomonas strains tested. Azlocillin was more active against Pseudomonas than was ticarcillin, carbenicillin, or mezlocillin. Mezlocillin was more active than carbenicillin and ampicillin against Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Acinetobacter, Serratia, and Bacteroides. Azlocillin and mezlocillin were less active than cefazolin against beta-lactamase-producing E. coli and Klebsiella strains but more active than cefazolin against Enterobacter, indole-positive Proteus, Acinetobacter, Citrobacter, and Serratia strains. Both compounds showed activity equivalent to that of cefoxitin against Bacteroides isolates. Both agents were destroyed by many of the beta-lactamases from gram-negative organisms.

Netilmicin (Sch 20569) is an ethyl derivative of gentamicin C(1a) that is active against most Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus isolates. Among 342 clinical isolates tested, all staphylococci; 92% of Escherichia coli, 93% of Klebsiella pneumoniae, and 92% of Enterobacter were inhibited by 0.8 mug or less of netilmicin per ml, but only 78% of P. aeruginosa were inhibited by 3.1 mug or less per ml. Most clinical isolates of enterococci, Serratia marcescens, and Providencia were not inhibited by 3.1 mug of netilmicin per ml. Like other aminoglycosides, the netilmicin in vitro activity was markedly influenced by the growth medium used, with activity decreased by sodium, calcium, and magnesium. Netilmicin was more active at alkaline pH. Addition of magnesium to Pseudomonas or Serratia pretreated with netilmicin produced inhibition of killing. Netilmicin was more active than gentamicin, sisomicin, tobramycin, or amikacin against E. coli and K. pneumoniae. Netilmicin inhibited growth of all gentamicin-resistant isolates of Klebsiella and Citrobacter tested, but only 73% of E. coli; Pseudomonas and Providencia were resistant to netilmicin. Most Serratia (95%) and indole-positive Proteus (83%) isolates were resistant to netilmicin but were inhibited by amikacin.

The in vitro activity of cefuroxime, a cephalosporin antibiotic, was investigated against 604 isolates and compared with the activity of other beta-lactam compounds. Cefuroxime had activity comparable to that of other cephalosporins, including cefamandole and cefoxitin, against streptococcal and staphylococcal species; most streptococci were inhibited by 0.1 mug or less per ml, and staphylococci were inhibited by 1.6 mug or less per ml. Enterococci were relatively resistant. Cefuroxime inhibited beta-lactamase-producing Neisseria gonorrhoeae and Haemophilus influenzae. Cefuroxime had excellent activity against members of the Enterobacteriaceae; 83% of beta-lactamase-producing Escherichea coli, 100% of Salmonella, 100% of Klebsiella, 90% of Proteus mirabilis, 95% of Citrobacter, 56% of Enterobacter, and 58% of Shigella were inhibited by 12.5 mug/ml. Cefuroxime had activity comparable to that of cefamandole and cefoxitin; it inhibited isolates of E. coli and Klebsiella resistant to cefamandole and inhibited Enterobacter and Citrobacter resistant to cefoxitin. Many isolates of Serratia, some indole-positive strains of Proteus, and Bacteroides fragilis were resistant to cefuroxime. Resistance of cefuroxime to hydrolysis by beta-lactamases played a major role in its activity against both gram-positive and gram-negative organisms.

The in vitro activity of piperacillin, a new semisynthetic piperazine penicillin derivative, was evaluated against 626 clinical isolates and compared with the activity of other beta-lactam antibiotics. At a concentration of 0.1 microgram/ml, piperacillin inhibited all streptococci except enterococci. Non-beta-lactamase-producing staphylococci were inhibited by 1.6 microgram or less per ml. Both beta-lactamase- and non-beta-lactamase-producing Haemophilus were inhibited by 0.1 microgram/ml. Piperacillin inhibited non-beta-lactamase-producing Escherichia coli, Salmonella, and Shigella at a concentration of 6.3 micrograms/ml, but 20% of strains of these species containing type III beta-lactamase were not inhibited by 100 micrograms/ml. Piperacillin at 25 micrograms/ml, inhibited 83% of Citrobacter, 58% of Klebsiella, 88% of Enterobacter, and 50% of indole-positive Proteus, Acinetobacter, and Providencia. At 25 micrograms/ml, piperacillin inhibited 95% of Pseudomonas aeruginosa and 78% of Bacteroides fragilis. The minimal inhibitory concentration of piperacillin against Pseudomonas was affected by increasing the inoculum size and by pH. Minimum bactericidal concentrations against Pseudomonas and Serratia often were eightfold greater than the minimum inhibitory concentrations. Piperacillin was equal in activity to ampicillin against enterococci. It was more active than carbenicillin against E. coli, Klebsiella, Enterobacter, and Bacteroides. It was the most active penicillin against Pseudomonas and inhibited many strains of Pseudomonas for which the MICs of carbenicillin were above 200 micrograms/ml. Piperacillin was hydrolyzed by many different beta-lactamases. Synergistic activity of piperacillin was demonstrated when it was combined with amikacin, gentamicin, and cefazolin against P. aeruginosa and members of the Enterobacteriaceae. No antagonism was observed when piperacillin was combined with aminoglycosides; however, antagonism was observed rarely against E. coli when piperacillin was combined with cefazolin.

The pharmacokinetics of cefotaxime after intramuscular injection and intravenous infusion were determined. The mean peak serum level after the 500-mg intramuscular dose was 11.7 micrograms/ml, and it was 20.5 micrograms/ml after a 1,000-mg dose. The serum half-life was 1.2 and 1.3 h, respectively for the two doses. The apparent fractional volumes of distribution of 32 and 37 liters were not significantly different for the two doses, and the fractional serum clearance was approximately 315 ml/min per 1.73 m2 for both doses. The mean peak serum level after 1,000 mg administered by intravenous infusion over 30 min was 41.1 micrograms/ml. The half-life was 1.13 h, apparent volume of distribution was 33 liters, serum clearance 341 ml/min per 1.73 m2, and renal clearance was 130 ml/min per 1.73 m2. The pharmacology of cefotaxime is similar to the pharmacology of other cephalosporin antibiotics, but the low inhibitory levels which it has against gram-positive and gram-negative bacteria suggest that lower dosage regimens should be possible.

The pharmacokinetic characteristics of delta 2-89 tPA, characterized by the deletion of the first 89 amino acids at the NH2-terminus of tPA, were evaluated and compared to those of recombinant tPA (rtPA). When they were administered intravenously to mice, a biexponential disposition curve was observed for both tPAs. The plasma half-lives of lambda 1 and lambda 2 phases of delta 2-89 tPA were 15 minutes and 180 minutes which are significantly higher than those of rtPA. A zymogram of mouse plasma taken at various time intervals showed that delta 2-89 tPA retained fibrinolytic activity up to 30 minutes, whereas rtPA could be detected only up to 5 minutes after injection. Autoradiography revealed that most of 125I-delta 2-89 tPA was associated with plasma protein complex.

The synergistic activities of netilmicin, gentamicin and amikacin combined with carbenicillin, ticarcillin, azlocillin and mezlocillin were investigated against 32 Serratia marcescens isolates. Synergy could be demonstrated by killing curve technique, isobologram plots as susceptibility data with any of the aminoglycosides and penicillins combinations. No antagonism was shown with any of the combinations. The majority of the isolates were resistant to the aminoglycosides and penicillins. Combination of either ureido-penicillin or carbenicillin with gentamicin or netilmicin did not reduce the MIC values to levels achievable in serum but did reduce the MIC levels of both agents to those achievable in urine. The combination of ureido-penicillins or carbenicillin and ticarcillin with amikacin reduced the inhibitory levels of all isolates to levels achievable in both serum and urine.

The combination of netilmicin (Sch 20569) with carbenicillin, cefazolin, chloramphenicol, and clindamycin was evaluated by in vitro tests against 91 clinical isolates of Pseudomonas, Klebsiella, and Escherichia coli. Combinations were considered to show synergy if there was a fourfold or greater reduction in minimal inhibitory concentration values of both antibiotics when combined. Synergy of netilmicin with carbenicillin could be demonstrated against 21 of 46 Pseudomonas isolates. Comparison of the synergy of carbenicillin with netilmicin or gentamicin showed that netilmicin was less active than gentamicin against Pseudomonas aeruginosa. However, at therapeutic concentrations of the antibiotics, significant differences were not observed. Synergy of netilmicin and cefazolin was demonstrated against only 1 of 21 Klebsiella strains tested, but partial synergy was found for 12 of 20 isolates. Synergy and antagonism were uncommon with the netilmicin-chloramphenicol and netilmicin-clindamycin combinations against E. coli and Pseudomonas.

The antibacterial activity of cefamandole against 445 clinical isolates was investigated and compared with the activity of other known cephalosporins (cephalothin, cephaloridine, cephalexin, and cefazolin) and of two penicillins (ampicillin and carbenicillin). Cefamandole was the most active antibiotic against isolates of Citrobacter, Enterobacter, and Shigella, and its activity against Staphylococcus aureus, Bacteroides, and some members of the Enterobacteriaceae was comparable to that of the other antibiotics tested. The stability of cefamandole with respect to beta-lactamase was investigated and compared with that of cephalothin, cefazolin, and cephalexin. Cefamandole was stable with respect to the beta-lactamases of Enterobacter and some other members of the Enterobacteriaceae. No significant correlation was found between the antibacterial activity and the beta-lactamase stability of cefamandole, except with Enterobacter. The synergistic activity of cefamandole combined with gentamicin or amikacin was demonstrated by killing-curve techniques, isobolograms, and susceptibility data. Although 12%--46% of the isolates were synergistically inhibited by either combination, antagonism was not observed. No correlation between the hydrolysis of cefamandole by beta-lactamase and the synergistic activity of cefamandole combined with amikacin was demonstrated.

The pharmacokinetics of moxalactam, a new beta-lactam antibiotic with an unusually broad spectrum of activity, were studied in normal volunteers and compared with the pharmacokinetics of cefazolin. After a 1,000-mg intramuscular injection of moxalactam, a mean peak serum level of 49 +/- 10 micrograms/ml was achieved at 30 to 60 min which was equivalent to the level achieved with 0.5 g of cefazolin. Serum levels of 4.57 +/- 0.63 micrograms/ml, above the inhibitory levels for most organisms, were present at 8 h. The half-life of moxalactam was 2.3 h. After a 30-min intravenous infusion of 1 g, the serum level of moxalactam was 60 +/- 18.8 micrograms/ml. This compares with a serum level of 70 micrograms/ml obtained with an infusion of 0.5 g of cefazolin. At 6 h, 3.59 +/- 0.68 microgram/ml of moxalactam was present. The half-life of moxalactam was 2.3 h, similar to that of cefazolin. By 1 h after administration, serum levels of moxalactam were higher after intramuscular administration than after intravenous delivery. Urinary recovery of the drug was 76% after intramuscular injection and 74% after intravenous infusion, with the majority of the drug having been excreted in the first 4 h after administration. Urinary recovery of cefazolin was 85%. The pharmacokinetics of moxalactam are similar to those of cefazolin.

In vitro activity of BL-S786, a new parenterally semisynthetic cephalosporin, was investigated against 570 bacterial isolates. BL-S786 inhibited most Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Salmonella. It inhibited some Enterobacter and indole-positive Proteus, but it was less active against these later species than was cefamandole, cefuroxime, or cefoxitin. It was not active against Serratia marcescens, Pseudomonas aeruginosa, or Bacteroides fragilis. BL-S786 was the least active new cephalosporin tested against staphylococci and was less active than cephalothin against streptococcal species. The activity of BL-S786 was not altered by the type of assay medium nor by 50% serum. The size of the test inoculum altered the minimal inhibitory and bactericidal concentrations for inhibition of some organisms, particularly those with Richmond type I beta-lactamases. BL-S786 was not hydrolyzed by the R-factor-mediated, Richmond type III beta-lactamase, but it was hydrolyzed by type I beta-lactamases.

The kinetic parameters of netilmicin were studied in normal human subjects. In the intravenous study a steady-state was obtained in 4 subjects by the constant infusion of 2 mg/kg of netilmicin during the first hour followed by 0.5 mg/kg/hr for each of three successive hours. Creatinine clearance was greater than the simultaneous serum and renal clearance of netilmicin. In the intramuscular study 6 subjects received a single injection of 1 mg/kg of netilmicin followed by the same dose of gentamicin 1 wk later. A mean peak serum levels of 3.9 microgram/ml was found for both antibiotics, but the mean serum half-life of netilmicin was shorter than that of gentamicin. Doubling the intramuscular dose of netilmicin approximately doubled the peak serum level. In both studies 75% to 90% of the netilmicin was recovered in the urine within the first 24 hr. Netilmicin appears to be primarily excreted by glomerular filtration. The apparent volume of distribution was similar to that reported for other related aminoglycosides. Netilmicin and gentamicin have similar kinetic parameters. There were wide individual differences among normal subjects with both drugs.

The pharmacokinetic properties of hPA(B), characterized by the insertion of a urokinase kringle coding region before the double kringle of tPA plus the complete tPA coding region, were investigated and compared to those of melanoma tPA (mtPA). Mean peak plasma concentrations at the end of infusion were 4.7 micrograms/ml for hPA(B) and 4.6 micrograms/ml for mtPA. The pharmacokinetics of both hPA(B) and mtPA showed a biexponential disappearance from plasma which is consistent with a two-compartment model of t 1/2 (lambda 1) = 2 minutes, t 1/2 (lambda 2) = 58 minutes for hPA(B), and t 1/2 (lambda 1) = 2.2 minutes, t 1/2 (lambda 2) = 61 minutes for mtPA. However, this very fast decaying lambda 1 phase of mtPA lasted five times longer than that of hPA(B) which resulted in very low concentrations of mtPA. Thus, hPA(B) exhibited larger AUC, slower clearance rate, and smaller volume of distribution (P less than 0.01) than those of mtPA. The fibrinolytic activity of hPA(B) in rabbit plasma as determined by zymography lasted up to 120 minutes after the end of infusion as compared to that of 2 minutes for mtPA. This indicates that mtPA, despite its t 1/2 (lambda 2) being similar to that of hPA(B), is no longer at physiologically meaningful concentrations at the start of the lambda 2 phase.

The efficacy of rifampicin in treating a Bacteroides fragilis infection was investigated and compared to clindamycin and metronidazole in an experimental model of intra-abdominal abscess in mice. Rifampicin, when given subcutaneously, showed activity superior to that of clindamycin in reducing the incidence of abscess formation as well as the number of Bacteroides organisms recovered from the abscess, and rifampicin was comparable in efficacy to metronidazole when given orally at the same dose level. The comparative pharmacokinetic properties of rifampicin and clindamycin demonstrated that the peak serum and abscess levels reached with rifampicin were significantly higher than those of clindamycin. The half-life of rifampicin in serum and in the abscess was longer than that of clindamycin.

Experimental intra-abdominal abscesses were produced in mice by intraperitoneal injections of Bacteroides fragilis and Escherichia coli. The therapeutic efficacy of ciprofloxacin was investigated in this mixed intra-abdominal abscess model and was compared with that of rifampicin. Treatment with ciprofloxacin at 0.2 to 20 mg/kg or rifampicin at 20 mg/kg prevented all mice from death, as compared to the 60% mortality rate observed in the vehicle-treated controls. Rifampicin concentrations at 10 and 20 mg/kg were effective in preventing abscess formation and eradicated bacterial abscess. Ciprofloxacin at all the levels tested neither reduced the incidence of abscess nor eradicated Bact. fragilis from abscesses. However, ciprofloxacin at levels of 20, 10, 5, and 1 mg/kg reduced significantly the number of E. coli cells in the abscess. The peak serum level of ciprofloxacin at the oral dose of 20 mg/kg was 0.43 mg/l which was well above the MIC values for E. coli but not for Bact. fragilis.

The stability to beta-lactamase hydrolysis of HR 756, a new cephalosporin antibiotic, was compared to the beta-lactamase stability of cefoxitin and cefuroxime. HR 756, cefoxitin, and cefuroxime were not hydrolyzed by Richmond type I, III, IV, and V beta-lactamases. Antibacterial activity of HR 756 correlated well with resistance to beta-lactamase hydrolysis except against Pseudomonas aeruginosa. HR 756, cefoxitin, and cefuroxime inhibited type I beta-lactamases, but not type III, IV, or V enzymes. HR 756 was the most active inhibitor.