Antimicrobial activity and spectrum investigation of eight broad-spectrum beta-lactam drugs: a 1997 surveillance trial in 102 medical centers in the United States. Cefepime Study Group

Anti-inflammatory studies were conducted on rats or mice using a crude hydroalcoholic extract of the aerial parts of Turnera ulmifolia and it's partitioned fractions, i.e. the aqueous, ethyl acetate and ethanolic fractions. The hydroalcoholic extract and it's fractions (aqueous and ethanolic) inhibited carrageenan-induced edema. However, only the ethanolic fraction was used in the other experiments due to it's yield. The extract also inhibited the cotton pellet granuloma and the increase of vascular permeability induced by histamine, 5-hydroxytryptamine and prostaglandin E2, but not that produced by bradykinin. The extract or the fraction did not present analgesic activity in the writhing test using acetic acid and did not reduce croton oil-induced ear edema in mice. When the ethanolic fraction and LPS were administered i.p. to Balb/C mice 72 h before blood or peritoneal fluid collection, no changes were observed in the white or total blood cell counts in the peripheral blood. On the other hand, changes were observed in both total and differential cell counts in the peritoneal exudate since all doses of the fraction reduced the number of total leukocytes (mainly lymphocytes) obtained from the peritoneal exudate. In contrast to nonsteroidal anti-inflammatory drugs, the administration of the hydroalcoholic extract or the ethanolic fraction alone did not potentiate gastric mucosal lesions induced by aspirin. The extract and the fraction inhibited the appearance of gastric lesions induced by indomethacin, ethanol and pylorus ligature, but not those induced by stress. As also observed with carbenoxolone, the ethanolic fraction increased the wall mucus in hypothermical-restraint stress-induced gastric lesions. The anti-ulcerogenic effect of the extract and of the ethanolic fraction may be related to an increase of mucosal defensive factors, such as prostaglandin and mucus. The anti-inflammatory actions of the extract and the fraction may be due to an inhibitory effect on histamine and cyclooxygenase II, but not on cyclooxygenase I, because the extract and it's fraction present both anti-inflammatory and anti-ulcerogenic effects. The major substances present in the ethanolic fraction are flavonoids which will be isolated and identified.     

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.     

Formulary review of the carbapenems: comparison of imipenem/cilastatin and meropenem

The duplicative mutation of an Ala-Val-Arg sequence at positions 208 to 210 in the loop structure of Enterobacter cloacae class C beta-lactamase caused substrate specificity extension to oxyimino beta-lactam antibiotics and this chromosomal mutation provided bacterial cells with high resistance to the beta-lactams (M. Nukaga et al, 1995, J. Biol. Chem. 270, 5729-5735). In order to confirm the universality of this phenomenon among other class C beta-lactamases, the duplicative mutation was applied to a class C beta-lactamase of Citrobacter freundii, which has 74% homology to the E. cloacae beta-lactamase amino acid sequence. The counterpart sequence to the Ala-Val-Arg of the E. cloacae enzyme in C. freundii beta-lactamase was identified to be Pro-Val-His. A Pro-Val-His sequence was inserted just after the native Pro-Val-His sequence at positions 208 to 210 in the C. freundii beta-lactamase. The resulting mutant of C. freundii beta-lactamase obtained a striking characteristic that we expected, showing substrate specificity extension to oxyimino beta-lactams. Nearly the same result was obtained with the insertion of an Ala-Val-Arg sequence after the native Pro-Val-His sequence. These results indicate that structural modification of this locus commonly induces modification of the substrate specificity to unfavorable substrates for many chromosomal class C beta-lactamases produced by gram-negative bacteria.     

Antimicrobial activity of RU-66647, a new ketolide

A new macrolide subclass called ketolides, possess a mode of action similar to the macrolide-lincosamide-streptogramin (MLS) compounds. Utilizing reference in vitro tests, the in vitro activity of RU-66647 (a ketolide) was compared to other MLS compounds against 376 Gram-positive organisms and over 400 representative strains of Gram-negative bacilli. The ketolide's spectrum was most similar to clindamycin and an earlier drug in the series (RU-64004 or RU-004) against staphylococci and streptococci. However, RU-66647 was more active than erythromycin and azithromycin against oxacillin-resistant Staphylococcus spp. and vancomycin-resistant enterococci. Ketolide activity was more potent than other MLS drugs against vancomycin-susceptible enterococci (MIC90, 0.25-4 micrograms/ml) and all streptococci (MICs, < or = 0.25 microgram/ml). Erythromycin-resistant (constitutive) strains were generally inhibited by < or = 2 micrograms RU-66647/ml (staphylococci, 31 to 36%; streptococci, 100%; enterococci, 72%). RU-66647 was active against Haemophilus influenzae (MIC90, 2 micrograms/ml), Moraxella catarrhalis (MIC90, 0.12 microgram/ml), and pathogenic Neisseria spp. (MIC90 0.5 microgram/ml). The ketolide failed to inhibit Enterobacteriaceae, nonfermentative Gram-negative bacilli, and Bacteriodes fragilis group strains. RU-66647 was observed to be a promising new compound directed toward some organisms resistant to other MLS-class drugs.     

Antimicrobial activity in the skin of the channel catfish Ictalurus punctatus: characterization of broad-spectrum histone-like antimicrobial proteins

BACKGROUND: A major reduction in the energy demand of the myocardium results from the electromechanical arrest, and cooling contributes to a lesser degree to this reduction. It is from this assumption that strategies of myocardial protection, utilizing warm blood cardioplegic induction, followed by cold cardioplegia with terminal warm reperfusion before removal of the aortic cross clamp, became established as optimal myocardial protection. Continuous normothermic perfusion 'closed the loop' by avoiding myocardial ischemia and linking warm induction and terminal reperfusion. A series of laboratory and clinical data confirmed the benefits of warm heart surgery on myocardial function and metabolism. The disadvantages of continuous warm blood cardioplegia including disturbance of the operative field, led surgeons to administer warm hyperkalaemic blood intermittently as a new cardioplegic strategy. METHODS: This review examines the laboratory and clinical data with reference to the intermittent warm blood cardioplegia, to establish its experimental basis and place in clinical practice. CONCLUSIONS: Experimental observation and clinical application have established intermittent warm blood cardioplegia as a practical, effective and cheap myocardial protection technique, particularly with reference to coronary artery surgery.     

Increased activity of a new chlorofluoroquinolone, BAY y 3118, compared with activities of ciprofloxacin, sparfloxacin, and other antimicrobial agents against anaerobic bacteria

A total of 435 clinical isolates of anaerobes were tested with a broth microdilution method to determine the activity of BAY y 3118 compared with those of other agents against anaerobic bacteria. All strains of Bacteroides capillosus, Prevotella spp., Porphyromonas spp., Fusobacterium spp., Clostridium spp., Eubacterium spp., Peptostreptococcus spp., and Veillonella parvula were susceptible (MICs of < or = 2 micrograms/ml) to BAY y 3118. Against the 315 strains of the Bacteroides fragilis group, five strains required elevated MICs (> or = 4 micrograms/ml) of BAY y 3118. Only imipenem and metronidazole were active against all anaerobes. Overall, BAY y 3118 was more active than ciprofloxacin, sparfloxacin, piperacillin, cefotaxime, and clindamycin against the test isolates.     

In vitro activity of trovafloxacin in combination with ceftazidime, meropenem, and amikacin

There are few reports on chemotherapy of non-Hodgkin's lymphoma (NHL) in patients with chronic renal failure. Two long-term hemodialysis patients were treated for NHL with modified CHOP therapy. The plasma pharmacokinetics of adriamycin (ADR) and etoposide (VP-16) were investigated in these patients. In the first case, NHL was diagnosed in a 37-year-old male (diffuse pleomorphic, T cell type, stage I E). After 4 courses of chemotherapy, he achieved complete remission. The second case, was a 56-year-old male who was admitted to our hospital with melena and abdominal pain. A diagnosis of NHL (diffuse mixed, B cell type, stage III E) was made. Complete remission was achieved with 2 courses of chemotherapy. Levels of hematological and neurological toxicity were moderately severe but tolerable. Pharmacokinetics of ADR and VP-16 in these patients were similar to those in patients with normal renal function. These results suggested that ADR and VP-16 were effective drugs for hemodialysis patients with NHL.     

Antimicrobial activity of fluoroquinolones and other antibiotics on 1,116 clinical gram-positive and gram-negative isolates

A total of 1,116 clinically isolated strains belonging to Staphylococcus aureus (200), Staphylococcus epidermidis (200), Streptococcus pneumoniae (20), Escherchia coli (200), Klebsiella spp. (177), Serratia marcescens (22), Pseudomonas aeruginosa (224), Haemophilus influenzae (35) and Salmonella (38) from the Department of Infectious Diseases, La Sapienza University in Rome (Italy) were tested against three fluoroquinolones (ofloxacin, ciprofloxacin and levofloxacin) and 10 other antibiotics (augmentin, ampicillin, cefaclor, cefixime, cefotaxime, cotrimoxazole, gentamicin, minocycline, oxacillin and vancomycin). Fluoroquinolones inhibited essentially about 100% of H. influenzae, Salmonella and S. pneumoniae, more than 75% of Staphylococcus including methicillin-resistant strains, and about 90% of Enterobacteriaceae and 50% of P. aeruginosa. Minimal inhibitory concentration values ranged from < 0.015 to > 32 micrograms/ml for Klebsiella, S. aureus and epidermidis, E. coli and P. aeruginosa; from < 0.015 to 2 micrograms/ml for Salmonella; from 0.03 to 16 micrograms/ml for Serratia; from < 0.015 to 1 microgram/ml for Haemophilus; and from 0.5 to 2 micrograms/ml for S. pneumoniae. Levofloxacin and to a lesser extent ofloxacin and ciprofloxacin, generally exhibited a greater activity than the other agents against both Gram-positive and Gram-negative bacteria. Regarding the distribution of resistant strains in Italy, we found a peculiar pattern of resistance as far as E. coli and P. aeruginosa were concerned. Quality control parameters are also summarized. S. epidermidis resulted as a new emergent pathogen especially in immunocompromised patients and its level of sensitivity has been modified over the last few years. In fact, the percentage of resistant strains to antibiotics or the percentage of methicillin-resistant isolates (in our study 35%), has gradually increased. Levofloxacin and ofloxacin showed good activity against staphylococcal strains compared with the majority of other antibiotics. These results suggest that the newer quinolones are promising antimicrobial agents for various infections.     

Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents

Susceptibility of 230 penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, was tested by agar dilution, and results were compared with those of erythromycin, azithromycin, clarithromycin, roxithromycin, rokitamycin, clindamycin, pristinamycin, ciprofloxacin, sparfloxacin, trimethoprim-sulfamethoxazole, doxycycline, chloramphenicol, cefuroxime, ceftriaxone, imipenem, and vancomycin. HMR 3647 was very active against all strains tested, with MICs at which 90% of the strains were inhibited (MIC90s) of 0.03 microg/ml for erythromycin-susceptible strains (MICs, < or =0.25 microg/ml) and 0.25 microg/ml for erythromycin-resistant strains (MICs, > or =1.0 microg/ml). All other macrolides yielded MIC90s of 0.03 to 0.25 and >64.0 microg/ml for erythromycin-susceptible and -resistant strains, respectively. The MICs of clindamycin for 51 of 100 (51%) erythromycin-resistant strains were < or =0.125 microg/ml. The MICs of pristinamycin for all strains were < or =1.0 microg/ml. The MIC90s of ciprofloxacin and sparfloxacin were 4.0 and 0.5 microg/ml, respectively, and were unaffected by penicillin or erythromycin susceptibility. Vancomycin and imipenem inhibited all strains at < or =1.0 microg/ml. The MICs of cefuroxime and cefotaxime rose with those of penicillin G. The MICs of trimethoprim-sulfamethoxazole, doxycycline, and chloramphenicol were variable but were generally higher in penicillin- and erythromycin-resistant strains. HMR 3647 had the best kill kinetics of all macrolides tested against 11 erythromycin-susceptible and -resistant strains, with uniform bactericidal activity (99.9% killing) after 24 h at two times the MIC and 99% killing of all strains at two times the MIC after 12 h for all strains. Pristinamycin showed more rapid killing at 2 to 6 h, with 99.9% killing of 10 of 11 strains after 24 h at two times the MIC. Other macrolides showed significant activity, relative to the MIC, against erythromycin-susceptible strains only.     

Safety and pharmacokinetics of CS-834, a new oral carbapenem antibiotic, in healthy volunteers

CS-834, (+)-[pivaloyloxymethyl (4R,5S,6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(R)-5-oxopyrroli din-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate], is an ester-type oral carbapenem prodrug, and an active metabolite is R-95867, which has antibacterial activity. CS-834 was administered orally to healthy male volunteers at single doses of 50, 100, 200, and 400 mg and at a multiple dose of 150 mg three times a day for 7 days to investigate its safety and pharmacokinetic profiles. Other studies were conducted to examine the effect of food intake on the bioavailability of CS-834 and also the effect of the coadministration of probenecid on the pharmacokinetics of CS-834. In the fasting state, the concentration of R-95867 in plasma reached maximum levels from 1.1 to 1.7 h after the oral administration of CS-834, followed by a monoexponential decrease. The maximum concentrations of R-95867 in serum (C[max]s) after the administration of CS-834 at doses of 50, 100, 200, and 400 mg were 0.51, 0.97, 1.59, and 2.51 microg/ml, respectively. The half-lives (t1/2s) were almost constant, approximately 0.7 h. The areas under the concentration-time curves (AUCs) were proportional to the doses, ranging from 50 to 400 mg x h/ml. The cumulative recoveries in urine were approximately 30 to 35% until 24 h after drug administration. The C(max), AUC, t1/2, and recovery in urine were not affected by food intake. Probenecid coadministration prolonged the t1/2, and it increased the C(max) and AUC for R-95867 by approximately 1.5- and 2.1-fold, respectively. The multiple-dose study showed no change in the pharmacokinetics from those for the single doses and no drug accumulation in the body. A mild transient soft stool was observed in one volunteer in the study with a single dose of 400 mg. In the multiple-dose study, mild transient soft stools were observed in six volunteers, one volunteer had mild transient diarrhea, and one volunteer had elevated serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase levels (1.4- and 2.8-fold compared with the upper limits of normal, respectively). There were no other abnormal findings for objective symptoms or laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis.     

In vitro and in vivo antibacterial activities of ER-35786, a new antipseudomonal carbapenem

ER-35786 is a new parenteral 1 beta-methyl carbapenem with a broad antibacterial spectrum and a potent antipseudomonal activity. It showed high in vitro activity, comparable to those of meropenem and a new carbapenem, BO-2727, against methicillin-susceptible Staphylococcus aureus and streptococci, with MICs at which 90% of strains tested are inhibited (MIC90S) of < or = 0.39 microgram/ml. Against methicillin-resistant S. aureus, ER-35786 was the most active among the compounds tested, yet its MIC90 was 12.5 micrograms/ml. Against members of the family Enterobacteriaceae, Moraxella catarrhalis, and Haemophilus influenzae, ER-35786 inhibited 90% of strains tested at a concentration of < or = 1.56 micrograms/ml. The MIC90 of ER-35786 for Pseudomonas aeruginosa was 3.13 micrograms/ml, and the compound was more active than meropenem. In addition, the activity of ER-35786 against imipenem-, meropenem-, cefclidin-, or ceftazidime-resistant P. aeruginosa was equal to or higher than that of the most active reference compound. The in vivo activity of ER-35786 was consistent with this in vitro activity. The in vivo activity of ER-35786 was highest for systemic infection models with methicillin-resistant S. aureus and beta-lactam-resistant P. aeruginosa strains. In acute pneumonia caused by P. aeruginosa, ER-35786 produced a greater reduction in the viable cell count in the lungs than did imipenem-cilastatin or meropenem.     

Pharmacokinetics of a new carbapenem, DA-1131, after intravenous administration to rats with uranyl nitrate-induced acute renal failure

Because the physiological changes that occur in patients with acute renal failure could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous administration of the drug (50 mg/kg of body weight) to control rats and rats with uranyl nitrate-induced acute renal failure (U-ARF rats). The impaired kidney function was observed in U-ARF rats on the basis of physiological parameters observed by microscopy of the kidney and obtained by chemical analysis of the plasma. After a 1-min intravenous infusion of DA-1131, the concentrations in plasma and the total area under the plasma concentration-time curve from time zero to time infinity increased significantly in U-ARF rats compared with those in control rats (13,000 versus 4,400 microg x min/ml). This was due to the significantly slower total body clearance (CL) of DA-1131 (3.84 versus 11.4 ml/min/kg) from U-ARF rats than from control rats. The significantly slower CL of DA-1131 from U-ARF rats was due to both significantly slower renal clearance (0.000635 versus 4.95 ml/min/kg because of a significant decrease in the 8-h urinary excretion of unchanged DA-1131 [1.54 versus 43.8% of the intravenous dose] due to impaired kidney function, as proved by the significant decrease in creatinine clearance [0.0159 versus 4.29 ml/min/kg]) and significantly slower nonrenal clearance (3.80 versus 6.34 ml/min/kg because of a significant decrease in the metabolism of DA-1131 in the kidney) in U-ARF rats. The amounts of DA-1131 recovered from all tissues studied (except the kidneys) were significantly higher for U-ARF rats than for control rats; however, the ratios of the amount in tissue to the concentration in plasma (except those for the kidney, small intestine, and spleen) were not significantly different between the two groups of rats, indicating that the affinity of DA-1131 for rat tissues was not changed considerably in U-ARF rats.     

Antimicrobial activity of 12 broad-spectrum agents tested against 270 nosocomial blood stream infection isolates caused by non-enteric gram-negative bacilli: occurrence of resistance, molecular epidemiology, and screening for metallo-enzymes

From March 1989 to March 1993, six athletic patients were treated in our institution by thrombolytic therapy for acute effort axillary-subclavian vein thrombosis in thoracic outlet syndrome. Mean age of these patients was 20 (range 14 to 27). An in situ infusion with urokinase (2,500 U/kg/h) and Heparin (100 U/kg/12 hours) was given during 64 hours (Range 14 to 72). Phlebography showed a complete reperfusion in three cases (the treatment began within an average period of 5.6 days), partial reperfusion in two cases (the treatment began within an average period of 8.5 days). In one case there was no reperfusion on phlebography: treatment began within an average period of 15 days. For this patient, a venous axillo-jugular bypass graft was performed. In all cases, there was no bleeding complication. A trans-axillary first rib resection was done three months later. Mean follow up was 31 months (range: two to 51 months). All patients recovered their previous physical status. Echo-Doppler exam showed normal subclavian vein flow in four cases, partial occlusion in one case and a total occlusion of the subclavian vein flow in one case. In this last case, the thrombolytic therapy failed to restore the permeability of the subclavian vein. Bypassgraft was patent. Axillary-subclavian vein thrombosis seen within a period of seven days should be treated by local thrombolytic therapy using urokinase and heparin.     

Comparative in vitro killing activities of meropenem, imipenem, ceftriaxone, and ceftriaxone plus vancomycin at clinically achievable cerebrospinal fluid concentrations against penicillin-resistant Streptococcus pneumoniae isolates from children with meningitis

The activities of meropenem, imipenem, ceftriaxone, and vancomycin were evaluated against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae strains. Meropenem, imipenem, ceftriaxone, and vancomycin MICs at which 90% of the isolates are inhibited were 0.5, 0.25, 1, and 0.25 microg/ml, respectively. Against penicillin-resistant strains, the best killing activity at cerebrospinal fluid concentrations was obtained with imipenem and ceftriaxone-vancomycin. However, while the killing activity of imipenem was significantly greater than that of meropenem, no significant difference was observed between the activities of meropenem and ceftriaxone-vancomycin.     

Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone

Compound LB20304 is a fluoronaphthyridone carboxylic acid with a novel pyrrolidine substituent. This drug was compared with ciprofloxacin, levofloxacin, ofloxacin, and trovafloxacin against over 800 pathogens, most from blood stream infections, by National Committee for Clinical Laboratory Standards reference methods. LB20304 was the most active agent against gram-positive species including strains observed to be resistant to other fluoroquinolones and glycopeptides. The potency of LB20304 (MIC50, 0.03 micrograms/ml) against the Enterobacteriaceae was exceeded only by that of ciprofloxacin (0.015 micrograms/ml). It has limited activity against gram-negative anaerobes.     

Rapid increase of pneumococcal resistance to beta-lactam and other antibiotics in isolates from the respiratory tract (Nagasaki, Japan: 1975-1994)

The susceptibility of 101 pneumococcal isolates from the respiratory tract during 1991-1994 was examined and compared with the susceptibility of isolates over the period of 1975-1990. A rapid increase of resistance was seen not only to penicillin but also other antimicrobial agents. During 1991-1994, 38% of all the isolates were resistant to penicillin. The rates of resistance during this period were 16-23% for three newer cephalosporins, 18% for imipenem, 69% for tetracycline, 31% for erythromycin, 20% for chloramphenicol and 9% for clindamycin. The use of antibiotics within one month prior to pneumococcal isolation was correlated with penicillin resistance (P < 0.05). Serotyping of the isolates by antiserum revealed differences in predominant types between penicillin-resistant (19F, 23F,4) and -susceptible isolates (15, 4, 11A). Our data suggests that anti-pneumococcal antibiotics should be carefully chosen on the basis of susceptibility tests.