BL-S786, a new parenteral cephalosporin. II. In vitro antimicrobial activity comparison with six related cephalosporins

BL-S786 was compared by in vitro studies with 6 other parenteral cephalosporins (cefamandole, cefazolin, cefoxitin, cephaloridine, cephalothin and cephradine). The following parameters were assessed: Comparative MICs against a wide variety of bacterial isolates, MIC/MBC comparisons and the effect of inoculum size on the MIC. BL-S786 showed the greatest antimicrobial activity against K. pneumoniae, C. diversus and Salmonella species; was equal to cefamandole against E. coli, E. agglomerans and P. mirabilis; and was second to cefamandole against Shigella, E. tarda, C. freundii, E. cloacae, E. aerogenes and the pathogenic Neisseriae. Essentially no activity against Serratia and Pseudomonas species was observed. Compared to the other cephalosporins tested BL-S786 showed poor activity against staphylococci and streptococci. For most species tested, the MBC of the various cephalosporins was the same or within one dilution of their respective MICs. However, for Enterobacter and indole-positive Proteus species, the MBC of BL-S786 and cefamandole was usually larger than or equal to 8-fold higher than the MICs. Cefoxitin, on the other hand, showed little MIC/MBC variations against indole-positive Proteus species. Inoculum size had only a small effect on the MICs against most gram-negative species--in some instances greater than 64-fold increases in MIC resulted by increasing inoculum size from 10(5) to 10(7) organisms per ml.     

Laboratory evaluation of 3-(5-tetrazolyl) penam, a new semisynthetic beta-lactam antibacterial agent with extended broad-spectrum activity

In the new agent 3-(5-tetrazolyl)penam, hereafter referred to as CP-35,587, the carboxyl function at C3 in the penicillin nucleus has been replaced with the 5-tetrazolyl moiety. Marked changes in spectrum and resistance to gram-negative beta-lactamases, particularly with regard to Klebsiella pneumoniae isolates, were conferred by this modification. The anti-Klebsiella activity clearly distinguishes the antibacterial spectrum of CP-35,587 from any known broad-spectrum penicillin. Compared to orally active cephalosporins, the spectrum advantage of CP-35,587 encompasses Enterobacter, Serratia marcescens, Citrobacter, Providencia, Haemophilus influenzae, and Streptococcus faecalis, both in vitro and in murine infections produced by many of the above-named microorganisms. Thus, CP-35,587 combines and extends the antibacterial activity of broad-spectrum penicillins and orally active cephalosporins.     

Laboratory studies with a new broad-spectrum penicillin, pirbenicillin

Pirbenicillin {6-[d-2-phenyl-2(N-4-pyridylformimidoylaminoacetamido) -acetamido]-penicillanic acid} showed broad-spectrum antibacterial activity in vitro and also in the treatment of experimental infections after parenteral administration to mice. Against Pseudomonas aeruginosa, a three- to fourfold potency advantage over carbenicillin was seen both in vitro and in vivo. The in vitro antibacterial spectrum of pirbenicillin includes Escherichia coli, Serratia, Citrobacter, and Enterobacter isolates, against which it exhibited minimal inhibitory concentration values comparable to those of carbenicillin. However, mice infected with E. coli and Serratia were protected at doses of pirbenicillin that were two to four times lower than those required of carbenicillin. Pirbenicillin was more active than carbenicillin against gram-positive bacteria, especially Streptococcus faecalis. It was less active than carbenicillin against Proteus spp. and was inactive against ampicillin-resistant E. coli strains. Pirbenicillin was bactericidal at concentrations generally equal to or only two-fold higher than the minimal inhibitory concentration. With appropriately buffered media, pirbenicillin demonstrated eight- and fourfold better minimal bactericidal concentration values towards Pseudomonas isolates than those of carbenicillin and ticarcillin, respectively.     

In vitro and in vivo antibacterial activities of TOC-50, a new parenteral cephalosporin, against Enterococcus faecalis

The object of the study was to compare resting pupil diameter in darkness and light, and the pupillary darkness and light reflexes between a group of young and elderly healthy subjects. Twelve young (eight men, four women; median age 19.5 years) and 14 elderly subjects (six men, eight women; median age 69 years) participated. Pupil diameter was monitored with an infra-red television pupillometer. Resting pupil size was measured in light (16 and 32 Cd m-2) and in darkness. The darkness reflex was elicited by switching off the ambient illumination (16 Cd m-2) for 1 s. The light reflex was elicited in darkness by short (200 ms) pulses of green (peak wavelength 565 nm) light at four ascending stimulus intensities (8.5 x 10(-3), 7.0 x 10(-2), 0.43 and 1.84 mW cm-2). The amplitude (mm) and maximum velocity (mm s-1) of the darkness reflex and the latency (ms), amplitude (mm), maximum constriction velocity (mm s-1) and 75% recovery time (s) of the light reflex were measured. The resting pupil diameter was found to be smaller in the elderly group at all three illumination levels (p = 0.001). The amplitude and maximum dilatation velocity of the darkness reflex were smaller for the elderly group (p = 0.001). The amplitude of the light reflex at the three highest light intensities and maximum constriction velocity at all light intensities were smaller in the elderly group (p = 0.002). Seventy-five per cent recovery time was longer in the elderly group (p = 0.02). There was no difference in the latency of the light reflex response between the two groups. The reduced pupil size, diminished darkness reflex amplitude and velocity, and prolonged recovery time of light reflex are consistent with sympathetic deficit in old age. Although the reductions in light reflex amplitude and constriction velocity in the elderly group at first sight would indicate a parasympathetic deficit in old age, they are more likely to be secondary to the grossly diminished pupil size.     

In vitro and in vivo antibacterial activities of OPC-20011, a novel parenteral broad-spectrum 2-oxaisocephem antibiotic

OPC-20011, a new parenteral 2-oxaisocephem antibiotic, has an oxygen atom at the 2- position of the cephalosporin frame. OPC-20011 had the best antibacterial activities against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae: MICs at which 90% of the isolates were inhibited were 6.25, 6.25, and 0.05 microg/ml, respectively. Its activity is due to a high affinity of the penicillin-binding protein 2' in MRSA, an affinity which was approximately 1,050 times as high as that for flomoxef. Against gram-negative bacteria, OPC-20011 also showed antibacterial activities similar to those of ceftazidime. The in vivo activities of OPC-20011 were comparable to or greater than those of reference compounds in murine models of systemic infection caused by gram-positive and -negative pathogens. OPC-20011 was up to 10 times as effective as vancomycin against MRSA infections in mice. This better in vivo efficacy is probably due to the bactericidal activity of OPC-20011, while vancomycin showed bacteriostatic activity against MRSA. OPC-20011 produced a significant decrease of viable counts in lung tissue at a dose of 2.5 mg/kg of body weight, an efficacy similar to that of ampicillin at a dose of 10 to 20 mg/kg on an experimental murine model of respiratory tract infection caused by non-ampicillin-susceptible S. pneumoniae T-0005. The better therapeutic efficacy of OPC-20011 was considered to be due to its potent antibacterial activity and low affinity for serum proteins of experimental animals (29% in mice and 6.4% in rats).     

In vitro antimicrobial activity of RU-59863, a C-7 catechol substituted cephalosporin

In this report the authors describe the characterization of a cytosolic tyrosine kinase activity (IL-6PTK) stimulated by interleukin 6 (IL-6). IL-6PTK appears 6 h after IL-6 addition and is inhibited by tyrphostin but not genistein. It is active under its phosphorylated form although it is not immunoprecipitated by antiphosphotyrosine antibodies, suggesting that autophosphorylation occurs on residues other than tyrosine. Using the ATP-binding site covalent label, 5'-p-fluorosulfonylbenzoyladenosine (FSBA), two phosphoproteins have been identified of 52 and 59 kDa respectively, that could potentially harbour IL-6PTK activity. The intracellular elevation of cAMP, which inhibits 7TD1 cell proliferation, decreases as the same time IL-6PTK activity suggesting that the cAMP-dependent kinase could act as a negative regulator of this tyrosine kinase species. Taken together the results strongly suggest that a tyrosine kinase (IL-6PTK) might be involved in the cascade of events leading to the proliferation of 7TD1 cells under IL-6 stimulation.     

A broad-spectrum microbicide with virucidal activity against sexually transmitted viruses

Sodium dodecyl sulfate (SDS), an alkyl sulfate surfactant derived from an organic alcohol, possesses surfactant properties but also denatures and unfolds both monomeric and subunit proteins. In preliminary experiments, we demonstrated that SDS is a potent inactivator of herpes simplex virus type 2 and human immunodeficiency virus type 1 at concentrations comparable to those used for the surfactant nonoxynol-9. We hypothesized that SDS might be capable of denaturing the capsid proteins of nonenveloped viruses. In this report, we demonstrate inactivation of rabbit, bovine, and human papillomaviruses after brief treatment with dilute solutions of SDS. Effective concentrations were nontoxic to rabbit skin and to split-thickness grafts of human foreskin epithelium. This is the first report of a microbicidal surfactant that will inactivate papillomaviruses. We propose that SDS is now a candidate microbicide for formulation and testing with humans.     

Ceftezole, a new cephalosporin C derivative I. In vitro and in vivo antimicrobial activity

Ceftezole, a new cephalosporin antibiotic similar to cefazolin, has the following chemical structure: (6R,7R)-8-oxo-7[2-(1H-tetrazol-1-yl)acetamido]-3-[(1,3,4-thiadiazol-2-ylthio)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid. Ceftezole was found to be a broad-spectrum antibiotic, active in vitro against many species of gram-positive and gram-negative bacteria except Pseudomonas aeruginosa, Serratia marcescens and Proteus vulgaris. The activity of ceftezole against clinical isolates of Escherichia coli and Klebsiella spp. appeared to be nearly equal to that of cefazolin and higher than those of cephaloridine and cephalothin. Cross-resistance was observed between ampicillin and cephaloridine, but not between ampicillin and ceftezole, in susceptibility tests on clinical isolates of P. mirabilis. The in vitro activity was little affected by the inoculum size, the presence of human serum or the test medium. Ceftezole exhibited apparent bactericidal activity at the concentrations above the minimum inhibitory concentration (MIC) against both S. aureus and E. coli. The development in vitro of resistance by S. aureus 209p and E. coli NIHJ to ceftezole after 16 transfers was similar to or somewhat slower than that to other drugs tested. Ceftezole was relatively stable in nutrient broth and minimally degraded in the serum or tissue homogenates of rats. Ceftezole, in a single subcutaneous administration, exhibited somewhat less efficacy in mice against intraperitoneal infections with Streptococcus pyogenes, S. pneumoniae, E. coli, K. pneumoniae or P. mirabilis than either cephaloridine or cefazolin. However, ceftezole exhibited efficacy similar to that of cephaloridine or cefazolin when administered in three doses. Furthermore, ceftezole was as effective as cefazolin in the treatment of experimental abscesses in mice caused by subcutaneous inoculation with S. aureus.     

Structure of a cephalosporin synthase

Penicillins and cephalosporins are among the most widely used therapeutic agents. These antibiotics are produced from fermentation-derived materials as their chemical synthesis is not commercially viable. Unconventional steps in their biosynthesis are catalysed by Fe(II)-dependent oxidases/oxygenases; isopenicillin N synthase (IPNS) creates in one step the bicyclic nucleus of penicillins, and deacetoxycephalosporin C synthase (DAOCS) catalyses the expansion of the penicillin nucleus into the nucleus of cephalosporins. Both enzymes use dioxygen-derived ferryl intermediates in catalysis but, in contrast to IPNS, the ferryl form of DAOCS is produced by the oxidative splitting of a co-substrate, 2-oxoglutarate (alpha-ketoglutarate). This route of controlled ferryl formation and reaction is common to many mononuclear ferrous enzymes, which participate in a broader range of reactions than their well-characterized counterparts, the haem enzymes. Here we report the first crystal structure of a 2-oxoacid-dependent oxygenase. High-resolution structures for apo-DAOCS, the enzyme complexed with Fe(II), and with Fe(II) and 2-oxoglutarate, were obtained from merohedrally twinned crystals. Using a model based on these structures, we propose a mechanism for ferryl formation.     

Successful treatment of smokers with a broad-spectrum behavioral approach.

Compared a broad-spectrum treatment (aversion, contractual management, booster sessions, group contact, and support) against a control limited to 1 wk of aversive conditioning (satiation). 16 males and 18 females (mean age 31.2 yrs) served as Ss. Results indicate a dramatic treatment effect, with 76% of experimental Ss (as compared to 35% of controls) remaining abstinent at a 6-mo follow-up. These findings suggest that a clinically effective program may have been established. Further research is needed both to isolate the effective components of treatment and to assess the possible application of similar broad-spectrum approaches to large numbers of smokers in clinical settings. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Laboratory evaluation of hypercoagulable states

The number of well-characterized hereditary and acquired hypercoagulable conditions is increasing, such that in many thrombophilic patients, the laboratory can now identify a hypercoagulable condition. This review describes the currently known hypercoagulable states that predispose patients to venous, and in some instances, arterial thrombosis. For each condition, the discussion includes the incidence, magnitude of the thrombotic risk in the general population in comparison with symptomatic families, synergistic interactions among the various hypercoagulable conditions, molecular pathogenesis, and interpretation of laboratory test results. In addition, recommendations for laboratory testing are summarized.     

Laboratory issues in the detection and reporting of antibacterial resistance

The emergence of antimicrobial resistance among several common bacterial pathogens requires that clinical microbiology laboratories have the ability to promptly and accurately recognize resistance in patients' isolates. Laboratories have several options for performing routine susceptibility testing, including the broth microdilution procedure (with or without instrumentation for test reading), automated instrument systems that provide rapid results, antibiotic gradient diffusion, and disk diffusion procedures. In addition, there are definitive screening tests capable of recognizing resistance to drugs of choice among several common bacterial species based on single drug concentration tests or rapid spot tests. The likely emergence of still newer resistance mechanisms will provide a challenge to clinical microbiologists to devise accurate, yet cost-effective strategies for use in the future.     

In vitro antibacterial activity of cefoperazone-sulbactam

This study was conducted to evaluate the antibacterial activity of CPZ-SBT in 1,146 clinical isolates and compared with that of CPZ and other antimicrobial agents. CPZ-SBT has much better antibacterial activity than CPZ against B-lactamase producing organisms. Of the 834 gram negative organisms tested, 165 were CPZ resistant, but 94 (57.0%) of them were still susceptible to CPZ-SBT, CPZ-SBT broadens the antibacterial spectrum of CPZ, it has good activity against Acinetobacter spp and B fragilis. Compared with other antimicrobial agents tested, CPZ-SBT is as active as ceftazidime, amikacin and ciprofloxacin against Enterobacteriaceae, P aeruginosa and Acinetobacter spp, but slightly less active than imipenem. It is as active as imipenem, timentin and metronidazole against B fragilis and other anaerobes. The results show that CPZ-SBT is a new member of the broad spectrum antimicrobial agents. It may become a promising agent for the treatment of severe infections caused by cefoperazone-resistant Gram negative bacilli including P aeruginosa.     

Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin

A group of 34 penicillin-allergic patients was studied to determine skin test reactivity to the different penicillins involved in inducing the allergic reaction and the cross-reactivity with side-chain-related and side-chain-unrelated cephalosporins. All the subjects selected for the study had to be skin test positive to at least one of the following determinants: benzyl-penicilloyl-polylysine (BPO-PLL), minor-determinant mixture (MDM), amoxicillin (AX), or ampicillin (AMP), or to possess in vitro IgE to the following conjugates: benzyl-penicilloyl-human-serum albumin (BPO-HSA), ampicilloyl-human-serum albumin (AMP-HSA), and amoxicilloyl-human-serum albumin (AX-HSA). Cephalexin (CE) and ceftazidime (CEF) were used to assess cross-reactivity. If skin tests to any of these compounds were positive, the patient was considered to be allergic; if negative, a challenge test was performed. Sixteen patients (47%) were skin test positive to BPO and/or MDM, and nine (26%) exclusively to AX and/or AMP. In three cases (8%), the RAST was positive although the skin test was negative; one to BPO-HSA and two to AX-HSA and AMP-HSA. Six patients (17%) needed to be challenged with the penicillin involved to establish the diagnosis. In five patients (14%), the skin tests were positive to CE and in none to CEF. In all the others, the skin tests were negative to both cephalosporins, and the patients tolerated the drugs when challenged. These results indicate the relevance of side-chain-specific minor determinants in betalactams allergy and provide support for the role of this chemical structure in the evaluation of cross-reactivity between penicillins and cephalosporins.     

In vitro antibacterial activity of a new fluoroquinolone, fleroxacin, against hospital bacteria and regression curve

Minimal inhibitory concentrations (MICs) of fleroxacin (FLE) were determined by agar dilution for 1261 bacterial strains isolated in 1992 in 4 university hospitals; in addition, antibiograms by agar diffusion were performed with 5 micrograms disks. Activity of FLE against nalidixic acid (NAL) susceptible (S) Enterobacteriaceae was close to that of other fluoroquinolones (FQ) (MIC 50 and 90: 0.12-0.25 micrograms/ml); like for other FQ, this activity was reduced against NAL intermediate and resistant (R) Enterobacteriaceae (4-32). MICs of FLE against P. aeruginosa were between 1 and 128 (8-128). FLE had also a good activity against NAL-S A. baumannii (0.12-0.5) but this activity is reduced against NAL-R Acinetobacter (64-128). FLE was highly active against Haemophilus (0.06-0.12), Gonococci (0.03-0.25), Meningococci (0.016-0.03) and B. catarrhalis (0.12-0.25). FLE showed activity close to the currently available FQ against methicillin susceptible Staphylococci (0.25-1); the resistant strains (32- > 128) are usually methicillin resistant. FLE is less effective against Enterococci (4-128), Streptococci (8-16) and Pneumococci (4-8). The coefficient correlation of the regression curve is 0.93; for MIC breakpoints of 1 and 4 micrograms/ml, zone diameter breakpoints should be 20 and 15 mm.     

Structure and activity of cathelicidin antibacterial proteins

The Laser-Shield II (Xomed-Treace, Jacksonville, FL) endotracheal tube is equipped with methylene blue crystals to aid in the prompt detection of tube cuff rupture. As the tube cuff is being inflated with saline, the crystals are supposed to dissolve fully in the saline, forming a solution that is readily visible in the event of cuff rupture. We describe a case of occlusion of the pilot balloon tube caused by undissolved methylene blue crystals, a situation that made it impossible to deflate the Laser-Shield II tube cuff. Our experience may aid in future modification of endotracheal tube design.