Synthesis and anti-HIV-1 activity of N-hydroxy-N1-aminoguanidines.

The synthesis of 13 new Schiff bases of N-hydroxy-N1-aminoguanidines starting from thiosemicarbazide are reported. These new derivatives were for the first time tested against infection by the Human Immunodeficiency Virus Type 1 (HIV-1) using the human T-lymphocyte cell line. Four N-hydroxy-N1-aminoguanidines exhibited HIV-1 inhibition in the micromolar range. The most active compound, [1-(1'-chloro-2'-hydroxy-3'-methoxybenzylidene)amino]-3-hydroxy guanidine inhibited HIV-1 by 96% at 10 micrograms/ml concentration. All the derivatives exhibited substantial cytotoxicity at 320 micrograms/ml concentration. The results indicate that the activity against HIV-1 increases with increasing hydrophobicity and substituents with electron-donating properties.     

In vitro and in vivo anti-picornavirus activity of some p-benzoylphenoxypyridines

Fifteen p-benzoylphenoxypyridines were initially evaluated for their in vitro activity against rhinoviruses (RV) 1A, 2 and 64 and coxsackie virus (Cox) A21 and for their oral prophylactic and therapeutic activity in Swiss albino mice lethally challenged with Cox A21. One compound, (4-[(5-methylsulfonyl-2-pyridinyl)oxy]phenyl) phenyl methanone, was selected for additional evaluation. These studies showed the compound to possess MIC50 values of less than or equal to 5 micrograms/ml against only 6 of 20 (30.0%) RV serotypes tested. In contrast, the compound was active at concentrations of less than or equal to 5.0 micrograms/ml against 10 of 12 (83.3%) enteroviruses evaluated. In vivo studies showed the compound to significantly protect mice lethally infected with Cox A21 after a single oral dose of 37.5 mg/kg (P less than 0.02) and during a regimen of continuous oral doses of at least 4.7 mg/kg per day (P less than 0.001). Mechanism of action studies indicated that the compound inhibits picornavirus uncoating or some earlier virus-host cell-associated event. Isotopic studies show that (4-[(5-methylsulfonyl-2-pyridinyl)oxy]phenyl) phenyl methanone perturbs HeLa cell macromolecular synthesis at concentrations of as low as 3.12 micrograms/ml. This concentration is only 4-fold higher than the concentration of compound necessary to inhibit Cox A21 RNA synthesis by 90%. This narrow therapeutic ratio limits the potential clinical utility of this compound to all but the most serious picornavirus infections.     

Anti-HIV activity of dextran sulphate as determined under different experimental conditions

Dextran sulphate is a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1). Its anti-HIV-1 activity has been investigated under varying experimental conditions. MT-4 cells were infected with HIV-1 at different multiplicities of infection (MOI), and treated with either dextran sulphate, 3'-azido-2',3'-dideoxythymidine (AZT), or anti-HIV-1 serum obtained from an ARC patient. Dextran sulphate suppressed HIV-1 replication (as monitored by viral antigen expression) when the MOI was 0.01 or 0.1. It was ineffective at an MOI of 1.0. The anti-HIV-1 serum was only partially effective at an MOI of 0.01 and ineffective at an MOI of 0.1 or 1.0. AZT proved effective at all three MOIs. Co-cultures of uninfected and HIV-1-infected MT-4 cells were protected against destruction by dextran sulphate at a concentration of 10 and 100 micrograms/ml. To fully suppress viral antigen expression a concentration of 100 micrograms/ml was needed. When used at this concentration, a 1-h contact of dextran sulphate with the cells during the virus adsorption period sufficed to suppress HIV-1 antigen expression. In this sense, dextran sulphate behaved like the anti-HIV-1 serum. Dextran sulphate also behaved like OKT-4A in that they both inhibited HIV-1 attachment to the MT-4 cells, whereas OKT-4 failed to do so. However, dextran sulphate did not affect the binding of OKT-4A to the cells. The present results support the concept that dextran sulphate owes its anti-HIV-1 activity mainly to inhibition of virus binding to its target cells. The anti-HIV-1 activity of dextran sulphate is highly dependent on its sulphate content.     

Pentosan polysulfate, a sulfated oligosaccharide, is a potent and selective anti-HIV agent in vitro

Several sulfated oligo- or polysaccharides such as pentosan polysulfate, fucoidan, dextran sulfate, heparin and iota-, kappa- and lambda-carrageenans proved to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) in vitro. The most potent anti-HIV-1 activity was recorded for the oligosaccharide pentosan polysulfate, its 50% antiviral effective dose (ED50) being 0.19 microgram/ml in MT-4 cells. It inhibited HIV-1 antigen expression in HUT-78 cells at an ED50 of 0.02 microgram/ml, and complete inhibition of HIV-1 antigen expression was obtained at a concentration of 4.0 micrograms/ml. No toxicity for MT-4 cells was observed with pentosan polysulfate at a concentration of 2500 micrograms/ml. The anticoagulant activity of pentosan polysulfate was more than ten-fold lower than that of heparin (14.4 and 177 U/mg, respectively). In fact, pentosan polysulfate achieved its anti-HIV-1 activity at a concentration that is 370-fold below its anticoagulant threshold (1 U). Pentosan polysulfate inhibits virus adsorption to the cells, as was demonstrated by monitoring the association of radiolabeled HIV-1 virions with MT-4 cells.     

Fundamental and clinical studies on cefixime in pediatrics

Bacteriological, pharmacokinetic, and clinical studies of cefixime (CFIX), a newly developed oral cephalosporin, was conducted in our pediatric department as outlined below. Bacteriology The prevalent MICs of CFIX by microbiological species, compared with those of the reference drugs, were detailed below. Against 16 strains of S. aureus, the MICs averaged 6.25 micrograms/ml, and were found to be nearly the same as the MICs of amoxicillin (AMPC) but higher than those of cephalexin (CEX) and cefaclor (CCL). For 4 strains of S. pyogenes, the MICs averaged 0.05 microgram/ml, and were higher than the MICs of AMPC but lower than those of CEX and CCL. Mean MICs of CFIX against other clinical isolates were lower than those of CEX, CCL, or AMPC; E. coli (20 strains), 3.13 micrograms/ml; K. pneumoniae (9), 0.10 microgram/ml; P. mirabilis (16), 0.025 microgram/ml; P. vulgaris (5), 0.10 microgram/ml; H. influenzae (11), 0.05 microgram/ml; and S. typhimurium (4), 0.10 microgram/ml. The MICs of CFIX against 10 strains of P. aeruginosa were distributed at and above 25 micrograms/ml, a range much lower than greater than or equal to 100 micrograms/ml for CEX, CCL, or AMPC. Pharmacokinetics The serum concentrations and urinary recovery were studied in 3 children ranging from age 7 to 13. They were given CFIX on empty stomach in 2 different single doses of 3 and 6 mg/kg in a cross-over design. Average serum CFIX concentrations were dose-dependent, as evidenced by the respective peak concentrations of 1.70 microgram/ml for a 3 mg/kg dosage and 2.72 micrograms/ml for 6 mg/kg, which were attained 4 hours after the administration of the drug. The average half-lives of CFIX in the serum were 3.09 hours and 3.11 hours, respectively, and the 12-hour serum concentrations were 0.32 microgram/ml and 0.77 microgram/ml, respectively, for the 2 different dose levels. The average 12-hour urinary recovery was 25.2% and 22.3%, respectively. Clinical study Clinical effectiveness, bacteriological effectiveness, and side effects were studied in 27 children with infection including 4 patients with acute pharyngitis, 13 with acute purulent tonsillitis, 5 with acute pneumonia, 3 with urinary tract infection, and 1 each with acute rhinitis and acute bronchitis. One child with acute pneumonia (Mycoplasma pneumonia) was excluded from the study. The therapeutic effectiveness was "excellent" in 21, "good" in 3, "fair" in 1, and "poor" in 1, with an effectiveness rate of 92.3%.(ABSTRACT TRUNCATED AT 400 WORDS)     

In vitro studies with Bay V 3522, a new oral cephalosporin

The in vitro activities of Bay v 3522, cefaclor, cephalexin, cefuroxime, cefixime, amoxicillin/clavulanate (2:1) and reference penicillins were compared against 314 clinical isolates of Gram-positive and Gram-negative bacteria and nine strains of Escherichia coli that differed in their outer membrane proteins in agar dilution tests with an inoculum of 10(4) cfu/spot. The beta-lactamase stabilities of the cephalosporins were also evaluated by spectrophotometric assay using 21 different beta-lactamases. Bay v 3522 was the most potent cephalosporin overall against Gram-positive pathogens, but slightly less active than amoxicillin/clavulanate. In addition to being highly active against streptococci (MIC90 = 0.25 micrograms/ml) and methicillin-susceptible staphylococci (MIC90 = 1.0 micrograms/ml), Bay v 3522 was markedly more active than the other cephalosporins against Enterococcus faecalis (MIC90 = 4 micrograms/ml). Bay v 3522 was less potent against Gram-negative pathogens, especially nosocomial isolates of Escherichia coli and Klebsiella pneumoniae (MIC90 greater than 64 micrograms/ml), but was active against Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and beta-lactamase-negative Neisseria gonorrhoeae (MIC90 = 1.0 micrograms/ml0. Hydrolysis of Bay v 3522 by most beta-lactamases examined was significantly less than that observed for cephalothin and cefaclor; similar to that observed with cephalexin; and less than that observed with cefixime and cefuroxime. None of the beta-lactamases examined hydrolysed Bay v 3522 at a rate greater than 20 nmol/min/mg. The in vitro potency of Bay v 3522 against Gram-positive and fastidious Gram-negative pathogens and its resistance to hydrolysis by beta-lactamases produced by them support further investigation of this cephalosporin as a new oral therapeutic agent.     

Inhibitory effect of triterpenes from Crataegus pinatifida on HIV-I protease.

The methanol extracts of the leaves of Crataegus pinnatifida showed potent inhibitory activities against HIV-1 protease at a concentration of 100 micrograms/ml. The subsequent fractionation and isolation of the extract gave two active compounds. Their structures were identified as uvaol (1) and ursolic acid (2) by spectral data. These active compounds inhibit HIV-1 protease with IC50 values of 5.5 and 8.0 microM, respectively.     

Antiviral activity of uridine 5'-diphosphate glucose analogues against some enveloped viruses in cell culture

Twenty five analogues of uridine 5'-diphosphate glucose were screened against herpes simplex type 2, vaccinia virus, Sindbis virus and African swine fever virus. After screening, the compound 5'-[[[[(2",3",4",6"-tetra-O-benzoyl-alpha-D- glucopyranosyl)oxi]carbonyl]amino]sulfonyl]uridine (2), the synthesis of which has been reported (Camarasa et al., J. Med. Chem. 28, 40-46, 1985), was selected for further study. This compound showed in vitro activity against all viruses tested. The replication of herpes virus type 2 and African swine fever virus was completely inhibited at 100 micrograms/ml and 150 micrograms/ml respectively; vaccinia virus and Sindbis virus were inhibited to a lesser extent. The compound may inhibit several steps in the viral replication process.     

Pharmacokinetic, bacteriological and clinical studies of cefuzonam in the field of obstetrics and gynecology

To study the transfer of cefuzonam (CZON, L-105) into female genital organs, concentrations of the compound in pelvic dead space exudate were measured in cases of radical hysterectomy due to cervical cancer and analyzed by the two-compartment model. When CZON 1 g was drip-infused intravenously, the concentration in the cubital vein blood was 46.95 micrograms/ml at 1 hour after the start of infusion. Concentrations in the pelvic dead space exudate reached the peak of 11.29 micrograms/ml at 2.44 hours after the start, were higher than 4 micrograms/ml after 8 hours and were higher than 1.7 micrograms/ml after 12 hours. The area under the concentration-time curve in the pelvic dead space exudate was 77.85 micrograms X hr/ml. From these results CZON was considered to be effective when administered at 1 g against infections of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and haemophilus influenzae, but increased dose levels seemed necessary against infections of Staphylococcus epidermidis and Bacteroides fragilis. In 3 cases of obstetric and gynecological infections the efficacy of CZON was good in 2 cases and unknown in the other case.     

In vitro and in vivo antidermatophytic activity of saperconazole, a new fluorinated triazole.

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 mannose-specific plant lectins from Cymbidium hybrid and Epipactis helleborine and the (N-acetylglucosamine)n-specific plant lectin from Urtica dioica are potent and selective inhibitors of human immunodeficiency virus and cytomegalovirus replication in vitro.

A series of four mannose(Man)-, three N-acetylglucosamine (GlcNAc)n-, ten N-acetylgalactosamine/galactose(GalNAc/Gal)-, one 5-acetylneuraminic acid (alpha-2,3-Gal/GalNAc)- and one 5-acetylneuroaminic acid(alpha-2,6-Gal/Gal-NAc)-specific plant agglutinins were evaluated for their antiviral activity in vitro. the mannose-specific lectins from the orchid species Cymbidium hybrid (CA), Epipactis helleborine (EHA) and Listera ovata (LOA) were highly inhibitory to human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in MT-4, and showed a marked anti-human cytomegalovirus (CMV), respiratory syncytial virus (RSV) and influenza A virus activity in HEL, HeLa and MDCK cells, respectively. The 50% effective concentration (EC50) of CA and EHA for HIV ranged from 0.04 to 0.08 micrograms/ml, that is about 3 orders of magnitude below their toxicity threshold (50% inhibitory concentration for MT-4 cell growth: 54 to 60 micrograms/ml). Also, the (GlcNAc)n-specific lectin from Urtica dioica (UDA) was inhibitory to HIV-1-, HIV-2-, CMV-, RSV- and influenza A virus-induced cytopathicity at an EC50 ranging from 0.3 to 9 micrograms/ml. The GalNAc/Gal-, alpha-2,3-Gal/GalNAc- or alpha-2,6-Gal/GalNAc-specific lectins were not inhibitory to HIV or CMV at non-toxic concentrations. CA, EHA and UDA proved to be potent inhibitors of syncytium formation between persistently HIV-1- and HIV-2-infected HUT-78 cells and CD4+ Molt/4 (clone 8) cells (EC50: 0.2-2 micrograms/ml). Unlike dextran sulfate, the plant lectins CA, EHA and UDA did not interfere with HIV-1 adsorption to MT-4 cells and RSV- and influenza A virus adsorption to HeLa and MDCK cells, respectively. They presumably interact at the level of virion fusion with the target cell.     

Action of pregnane compounds from Mandevilla illustris against contractions induced by kinins and other oxytocics in the rat isolated uterus.

1. The effects of 5 pregnane compounds isolated from the rhizomes of Mandevilla illustris were examined against bradykinin (BK), Lysyl-bradykinin (L-BK), acetylcholine (ACh) and oxytocin (Ot)-induced contractions in the isolated uteri of the rat. 2. Compounds MI 15 and MI 18 (5-40 micrograms/ml) caused a parallel and concentration-dependent rightward displacement of BK and L-BK concentration-response curves. Compound MI 21 (2.5-10 micrograms/ml) also produced a concentration-dependent displacement to the right of the BK concentration-response curve, but reduced its maximal response. Schild analysis of these data were linear (r close to 1) and furnished the following PA2 values (as G/ml): 6.0, 5.1 and 5.9, respectively. However, the slopes were significantly higher than unity. Compounds MI 25 and MI 27 (10-40 micrograms/ml) caused little or even no effect against BK and ACh responses. 3. In addition, compounds MI 18 and MI 21 (10-40 micrograms/ml) also antagonized in a concentration-dependent manner L-BK concentration-response curves. Schild plot were linear (r close to 1) and yielded the nominal pA2 values (as G/ml) of 5.0 and 5.8, respectively, but the slopes were significantly different from one. 4. Like the results obtained previously with the crude extract from M. illustris, the purified compounds from the rhizome of this plant were not selective towards kinin action since at the same range concentrations they markedly interfered with both the sensitivities and the maximal responses caused by ACh and Ot in this preparation.     

Fundamental and clinical studies on aztreonam in the pediatric field

Fundamental and clinical studies on aztreonam (AZT), a new monobactam antibiotic, were performed in the pediatric field. The MICs of AZT were assessed against the clinically isolated strains in the pediatric infections. AZT showed an excellent antibacterial activity against Gram-negative bacteria, i.e., against E. coli (20 strains), K. pneumoniae (9), P. mirabilis (16), P. vulgaris (5), P. aeruginosa (10), S. typhimurium (4) and H. influenzae (11); the MICs of AZT against the above strains were less than 0.39 microgram/ml, 0.10 microgram/ml, 0.024 microgram/ml, 0.024 microgram/ml, 6.25 micrograms/ml, 0.10 microgram/ml and 0.10 microgram/ml, respectively. However, antibacterial activity of AZT against Gram-positive bacteria was inferior to that against Gram-negative bacteria, i.e., against the strains of S. aureus (16) and S. pyogenes (4), those MICs were more than 400 micrograms/ml and 3.13 micrograms/ml, respectively. Serum concentrations and urinary excretion of AZT were measured in 2 children aged 7 and 11 years after a single intravenous injection at the dose of 20 mg/kg. The mean serum concentration of AZT followed by the injection 62.5 micrograms/ml at 1/4 hour, 28.5 micrograms/ml at 1/2 hour, 16.5 micrograms/ml at 1 hour, 12.0 micrograms/ml at 2 hours, 3.6 micrograms/ml at 4 hours and 1.1 micrograms/ml at 6 hours, respectively. The mean half-life (beta-phase) was 1.24 hours. The mean urinary concentrations after the injection were 5,000 micrograms/ml in 0-2 hours, 1,650 micrograms/ml in 2-4 hours and 611 micrograms/ml in 4-6 hours and the mean urinary recovery rate up to 6 hours was 61.2%. These results in our studies were considered to be comparable with those reported in adults. In our clinical studies, AZT was administered to a total of 14 cases, i.e., acute pneumonia (4 cases), acute pyelonephritis (4), acute enteritis (5) and acute sppurative cholangitis (1). Clinical effect of AZT was excellent or good in 13 cases except fair in 1 case with acute enteritis and the efficacy rate (excellent and good) was 92.9%. With regard to bacteriological effect, all the strains of H. influenzae (3), E. coli (2), P. mirabilis (1) and P. vulgaris (1) were eradicated, but, S. typhimurium (4) was not eradicated. Neither side effect nor abnormal laboratory findings were observed during the study.     

Clinical studies on cefprozil granules in pediatric skin soft tissues infections]

Cefprozil (CFPZ), a newly developed cephalosporin in fine granular form, was administered to pediatric patients with skin and soft tissue infections. MICs were determined for 6 drugs including CFPZ, cephalexin (CEX), cefaclor (CCL), ampicillin (ABPC), methicillin (DMPPC), cloxacillin (MCIPC) against 53 clinical isolates of Staphylococcus aureus from these patients. An inoculum size of 10(6) CFU/ml was used in the MIC-determinations. CFPZ was given to 73 patients with ages ranging from 6 months to 10 years and 8 months and 71 cases were evaluable for clinical effects as follows; impetigo (65), Staphylococcal scalded skin syndrome (1), furuncle (1), subcutaneous abscess (3), and periproctal abscess (1). To study clinical efficacy, bacteriological effects and safety of this drug, a mean dose of 8.4 mg/kg with 3-4 daily dosages (57 cases of t.i.d. and 14 cases of q.i.d.) was administered for an average of 6 days. The results obtained are summarized as follows. 1. With regard to the 53 isolates of S. aureus, MICs of CFPZ against 52 strains (98.1%) ranged from 0.78 to 3.13 micrograms/ml. 45 strains (84.9%) were inhibited at 0.78 micrograms/ml. MIC90 of CFPZ was 1.56 micrograms/ml, but MIC against 1 strain of Methicillin-resistant S. aureus (MRSA) was 100 micrograms/ml. The MIC90 of CEX and CCL were 6.25 micrograms/ml and MIC of CEX and CCL against 1 MRSA strain were 200 and 100 micrograms/ml, respectively. The MIC90 of ABPC, DMPPC and MCIPC were 6.25, 3.13 and 0.39 micrograms/ml, respectively. CFPZ showed the second highest activity after MCIPC against S. aureus. 2. CFPZ showed very good clinical responses and clinical effects in 71 patients all of whom judged by doctors in charge as having "good" or better responses. 3. For impetigo patients, the evaluable cases by score 3, 5 and 7 days after administration of the drug were 52, 39 and 20 patients, respectively. The efficacy rates on these days were 90.4, 100 and 100%, respectively. The efficacy rate at a daily dose of 30.1-45.0 mg/kg on day 3 was 17.2% higher than that at 22.5-30.0 mg/kg, and the "excellent" response rate of 30.1-45.0 mg/kg group was 45.3% greater. Because of these results, it is expected that good clinical effects can be obtained at a daily dose of 22.5-30.0 mg/kg of CFPZ, but better responses can be expected at 30.1-45.0 mg/kg in 3-4 divided doses given for 5 days. 4. Bacteriological effects of CFPZ were determined against 60 strains of S. aureus.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sch 37137, a novel antifungal compound produced by a Micromonospora sp. Taxonomy, fermentation, isolation, structure and biological properties

A new antifungal compound, Sch 37137, was isolated from the cultured broth of a Micromonospora sp., SCC 1792. Sch 37137 is structurally related to A 19009, a dipeptide previously discovered from a Streptomyces sp. The compound was weakly active against species of Candida and dermatophytes (mean MICs greater than or equal to 128 micrograms/ml) in Sabouraud dextrose, yeast-nitrogen and modified Eagles minimum essential media; however activity against Candida sp. (mean MICs greater than or equal to 12 micrograms/ml) and dermatophytes (mean MICs greater than or equal to 0.8 microgram/ml) significantly improved in MA medium.     

Antimicrobial activity of clavines

The antimicrobial activity of two clavine-type ergot alkaloids (agroclavine, festuclavine), and 16 derivatives against four human pathogenic bacteria and Candida albicans was determined. It is shown that all ergolines tested with one exception exhibit antibacterial properties against one to four bacteria species. The most active compounds are 6-allyl-6-norfestuclavine (minimal inhibitory concentration (MIC) 30 micrograms/ml against Staphylococcus aureus), 1-propyl-6-norfestuclavine (MIC 60 micrograms/ml against Escherichia coli), 6-cyano-6-norfestuclavine (MIC 250 micrograms/ml against Pseudomonas aeruginosa), and 1-methyl-agroclavine (MIC 200 micrograms/ml against Proteus vulgaris). 1-Allyl-6-norfestuclavine and 1-propyl-6-norfestuclavine showed a broad action spectrum: the growth of all four bacteria species and of Candida albicans was inhibited. The most effective antifungal compounds are 1-propyl-6-norfestuclavine and 6-cyano-6-norfestuclavine (MIC 250 micrograms/ml). Three alkaloids of different structure (codeine, emetine, quinine) are inactive up to 500 micrograms/ml against the bacteria species and C. albicans. The acute toxicity (mouse) is remarkably diminished by the modifications of the natural clavines.     

Basic and clinical evaluation of sulbactam/cefoperazone in the field of pediatrics

Sulbactam (SBT) in a novel beta-lactamase inhibitor from Pfizer and combined with cefoperazone (CPZ) ina 1:1 ratio (SBT/CPZ). Fundamental and clinical studies on SBT/CPZ were executed. The antibacterial activity of SBT/CPZ was compared with those of SBT, CPZ and CEZ against clinical isolates of S. aureus and E. coli which were not susceptible to CEZ. SBT alone did not show any activity against S. aureus, MICs against all strains were over than 100 micrograms/ml on the inoculations of undiluted and 100-fold diluted specimen. CPZ showed MICs over than 100 micrograms/ml against approximately 70% of the isolates on the undiluted inoculation, and on the 100-fold diluted inoculation, the MIC50 and MIC70 were 12.5 micrograms/ml and 100 micrograms/ml, respectively. SBT/CPZ showed better activity than CPZ by 2-8 folds against the strains highly resistant to CPZ; the MIC50 on the undiluted inoculation was 50 micrograms/ml. Against E. coli, the characteristic of SBT/CPZ was shown more clearly. The MICs of CPZ were over than 100 micrograms/ml against approximately 70% of the isolates on the undiluted inoculation, but SBT/CPZ showed MIC50 at 25 micrograms/ml. On the 100-fold diluted inoculation, SBT/CPZ was 4 approximately 8-fold superior than CPZ against strains on which MICs of CPZ were over than 12.5 micrograms/ml. Serum levels were determined by a bolus intravenous injection and by intravenous drip infusion of 10, 20, 40 mg/kg of SBT/CPZ. When administered by a bolus injection, the peak level was seen at 30 minutes in most patients: 8.7, 14.7 or 27.0 micrograms/ml of SBT and 30.1, 42.5 or 76.4 micrograms/ml of CPZ were detected with the 3 different doses. These levels were dose-dependent, and decreased slowly to 0.3, 0.3 or 0.3 micrograms/ml of SBT and 2.9, 2.8 or 3.3 micrograms/ml of CPZ at 6 hours after administration. Half-lives were 1.39, 1.20 or 0.98 hour for SBT and 1.77, 1.59 or 1.42 hours for CPZ. The same 3 doses were given by intravenous drip infusion. The peak levels obtained at the end of infusion (1 hour after initiation of infusion) were 15.3, 14.4 or 43.2 micrograms/ml for SBT and 33.4, 38.2 or 104.2 micrograms/ml for CPZ, respectively. The levels were somewhat low in 20 mg/kg group. After the end of infusion, these levels decreased fairly rapidly, and after 6 hours almost the same levels of 0.4, 0.5 or 0.3 micrograms/ml for SBT and 1.4, 3.9 or 3.3 micrograms/ml for CPZ were detected.(ABSTRACT TRUNCATED AT 400 WORDS)