Colorectal anastomosis after laparoscopic low anterior resection with total mesorectal excision: a difficult problem made simple.

Laparoscopic anterior resection with total mesorectal excision for middle and lower third rectal cancer remains a difficult operation, in particular, in male patients with a narrow pelvis and bulky mesentery. In this type of patient, the available staplers do not allow an easy transection of the rectum close to the pelvic floor. A new approach that uses instruments (dilator, obturator, and pursestring anoscope) specifically designed for the technique of stapled hemorrhoidopexy and a common circular stapler can overcome all these issues.

Does the new TNM classification (1997) improve prognostic stratification in gastric cancer submitted to R0 surgery?

AIMS: To determine the eventual advantage of the new 1997 TNM as prognosis predictor for gastric cancer patients submitted to an R0 resection and to compare it with two other lymph-node involvement classifications, the 1990 TNM and the Okusa system. METHODS: From January 1980 to December 1995, an R0 resection was performed as primary therapy in 275 cases of gastric cancer. These operations consisted of a total or sub-total gastrectomy and of a D2 type lymph-node dissection. Tumour classification was performed according to 1990 and 1997 TNM systems, and to the Okusa lymph node classification. The statistical methods used to evaluate prognostic value were: Kaplan-Meier survival estimates; the log-rank test for univariate analysis; and Cox's model for multivariate analysis. RESULTS: The 1990 TNM showed the best stratification power in univariate analysis. In multivariate analysis, the Okusa classification was identified as the best prognostic index (P<0.01). The 1997 TNM showed worse stratification capability than the two other systems. CONCLUSIONS: In the present series, the new TNM (1997) did not improve the prognostic stratification of lymph-node involvement. An adequate and universal system for lymph-node stratification is necessary and further validation of these classifications is needed.

Chemotherapeutic activity of levofloxacin (HR 355, DR-3355) against systemic and localized infections in laboratory animals.

Ofloxacin, its optical isomers levofloxacin (HR 355, DR-3355) and D-ofloxacin (DR-3354) and ciprofloxacin were administered orally to mice and rats which had systemic and localized infections. Both levofloxacin and ciprofloxacin were equally effective in treating systemic murine infections caused by staphylococci. Enterobacteriaceae or Pseudomonas aeruginosa with ED50s ranging from 0.18 to 15.8 mg/kg and 0.42 to 16.3 mg/kg respectively and both these agents were twice as effective as ofloxacin which had an ED50 0.41 to 39.7 mg/kg. In contrast, D-ofloxacin was either inactive or exhibited only modest chemotherapeutic activity against the staphylococci and the Gram-negative organisms tested. When given to mice to treat staphylococcal abscesses and lung infections due to Klebsiella pneumoniae DT-S levofloxacin was up to four times more effective and produced a more pronounced bactericidal effect against the pathogens in vivo than the reference compounds. Despite possessing a similar, if not lesser, in-vitro activity against the infecting pathogens, levofloxacin was more effective than ofloxacin and ciprofloxacin in rats with localized infections caused by Enterobacteriaceae and P. aeruginosa.

Balhimycin, a new glycopeptide antibiotic produced by Amycolatopsis sp. Y-86,21022. Taxonomy, production, isolation and biological activity.

A new glycopeptide antibiotic, balhimycin, has been isolated from the fermentation broth of a Amycolatopsis sp. Y-86,21022. Balhimycin belongs to the vancomycin class of glycopeptides and contains a dehydrovancosamine sugar. The biological activity of balhimycin has been compared extensively with that of vancomycin against methicillin resistant staphylococci and also against anaerobes. Balhimycin is marginally superior to vancomycin in its in vitro activity against anaerobes and in its bactericidal properties.

Mersacidin, a new antibiotic from Bacillus. In vitro and in vivo antibacterial activity.

Mersacidin is a new peptide antibiotic of the proposed lantibiotic family. It is active in vitro and in vivo against Gram-positive bacteria including the methicillin-resistant Staphylococci. Its in vitro activity is less than those of vancomycin and erythromycin but it shows much higher activity in the in vivo system than can be expected from the in vitro testing results. A water soluble potassium salt has been prepared which has an activity profile similar to that of mersacidin, but has better in vivo activity against Streptococcus pyogenes than the parent compound.

RU 29 246, the active compound of the cephalosporin prodrug-ester HR 916. III. Pharmacokinetic properties and antibacterial activity in vivo.

The pharmacokinetics of the broad spectrum cephem RU 29 246 and its prodrug-ester HR 916 B were investigated in mice, rats and dogs and compared to those of cefpodoxime proxetil, cefuroxime axetil and cefixime. HR 916 B is well absorbed following oral administration and efficiently converted to the antibacterially active form. In mice, mean peak blood levels of 31.1 micrograms/ml of the parent compound were recorded within 20 minutes after oral administration of a single dose equivalent to 40 mg/kg RU 29 246. The bioavailability calculated on the basis of the areas under the concentration-time curves (AUC) and the urinary recoveries was about 90%. In rats, peak blood levels of 14.5 micrograms/ml were obtained 1 hour after an oral 20 mg/kg dose. The bioavailability was calculated as 70%. In dogs, 40% of an oral 10 mg/kg dose was recovered in the urine within 24 hours. Cmax was 15.9 micrograms/ml at 4.6 hours. Mean elimination half-lives of RU 29 246 were 0.35, 0.5 and 2.1 hours in mice, rats and dogs, respectively. After an oral HR 916 B dose equivalent to 50 mg/kg of RU 29 246, tissue concentrations at 0.5 hour ranged between 0.8 micrograms/g in brain and 95.7 micrograms/g in murine kidneys. These values of HR 916 B are similar to, or distinctly higher than, those of the reference compounds. Of the oral cephalosporins tested, HR 916 B had the most balanced antibacterial spectrum. With ED50s of between 0.9 and 11.5 mg/kg against staphylococci, its activity was similar to that of the additional reference compound cefaclor and higher than that of cefuroxime. Cefixime and cefpodoxime proxetil displayed low antistaphylococcal activity or were inactive. In septicemias with Enterobacteriaceae, cefixime and cefpodoxime proxetil were more potent than HR 916 B and cefaclor. Cefuroxime axetil was inactive against most of these infections. HR 916 B was also highly effective against murine lung infections caused by Klebsiella pneumoniae DT-S or Streptococcus pneumoniae 1147.

Antibacterial activity in vitro of cefpirome against clinical isolates causing sexually transmitted diseases.

The in-vitro activity of cefpirome was compared with other antibiotics against organisms causing sexually transmitted diseases (STD). The excellent activity of cefpirome against Neisseria gonorrhoeae (MIC90 1.0 mg/L), Haemophilus ducreyi (MIC90 0.5 mg/L), and Gardnerella vaginalis (MIC90 1.0 mg/L) suggests that this agent might be useful in the empirical treatment of a variety of venereal diseases.

Pharmacokinetics of cefpirome administered intravenously or intramuscularly to rats and dogs.

The pharmacokinetic profile of cefpirome was evaluated in rats and dogs after a single intravenous or intramuscular dose. A two-compartment open model was used for the calculation of the pharmacokinetic parameters for both routes of administration. The elimination half-lives after intravenous and intramuscular administration of 20 mg/kg cefpirome did not differ significantly and ranged from 0.4 h in rats to 1.1 h in dogs. Cefpirome was mainly excreted via the kidneys. After iv or im dosing of the compound, between 80% (dogs) and 90% (rats) was recovered in urine within 24 h. The bioavailability of cefpirome in rats and dogs after both routes of administration was almost identical when calculated either by the AUC or the urinary recovery rates.

The in-vitro antibacterial activity of a combination of cefpirome or cefoperazone with vancomycin against enterococci and Staphylococcus aureus.

Cefpirome, cefoperazone and ceftazidime were tested for their in-vitro activity against Enterococcus faecalis and methicillin-resistant Staphylococcus aureus (MRSA) isolates. Cefpirome was the most active cephalosporin followed by cefoperazone. Ceftazidime had only very limited activity against these strains. In experiments with cefpirome/vancomycin and cefoperazone/vancomycin combinations, synergy was detected against most MRSA strains and some enterococci. Antagonism did not occur.

RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. I. Antibacterial activity in vitro.

The aminothiazolyl-cephalosporin RU 29 246 is the active metabolite of the prodrug-pivaloyl-oxyethyl-ester HR 916. RU 29 246 in vitro activity includes a wide range of clinically relevant bacterial pathogens. Against methicillin-sensitive Staphylococci RU 29 246 (MIC90 of 0.25 approximately 2 micrograms/ml) was clearly more active than cefaclor, cefuroxime, cefpodoxime, cefixime and ceftibuten, but slightly less active than cefdinir. RU 29 246 inhibited hemolytic Streptococci of the serogroups A, B, C and G as well as penicillin-sensitive Streptococcus pneumoniae at concentrations similar to cefdinir, cefpodoxime and cefuroxime (MIC90 less than or equal to 0.13 micrograms/ml), but less than the other oral cephalosporins investigated (cefixime, cefaclor and ceftibuten). MIC90s of RU 29 246 against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Salmonella spp., Shigella spp., Proteus mirabilis and Haemophilus influenzae were less than or equal to 0.5 micrograms/ml. Only RU 29 246 and cefdinir demonstrated moderate activity against Acinetobacter baumannii (MIC90 greater than or equal to 4 micrograms/ml). Most strains of Pseudomonas spp., Serratia marcescens, Enterobacter spp., Hafnia alvei and Bacteroides spp. were resistant to RU 29 246. RU 29 246 killed Escherichia coli and Staphylococcus aureus at a rate of 99% to 99.9% at concentrations of two times MIC. The pH value of the medium (range 5.5 to 8.5) and the inoculum size (range 10(5) to 10(7) cfu/ml) had no or only low influence on the antibacterial activity of RU 29 246. RU 29 246 is a broad spectrum cephalosporin including in its activity both Gram-positive and Gram-negative pathogens and therefore--depending on the bioavailability of its prodrug--looks promising as to its therapeutic perspective.

RU 29 246, the active compound of the cephalosporin-prodrug-ester HR 916. II. Stability to beta-lactamases and affinity for penicillin-binding proteins.

The aminothiazolyl-cephalosporin RU 29 246, the active metabolite of the prodrug-ester HR 916, is active against strains producing the widespread plasmid-encoded TEM-1, TEM-2 and SHV-1 beta-lactamases. Except for TEM-7 the activity of RU 29 246 against strains producing extended broad spectrum beta-lactamases (TEM-3, TEM-5, TEM-6, SHV-2, SHV-4, SHV-5, CMY-1, CTX-M), however, is low. Relative hydrolysis rates of RU 29 246 are comparable with those of cefpodoxime, the active metabolite of CS-807, and are extremely low for the TEM-1 and SHV-1 beta-lactamases. The compound demonstrates remarkable inhibitory activity against the chromosomal beta-lactamase of Enterobacter cloacae P99. In the presence of 1.7 microM this enzyme loses 50% of its activity. At concentrations of 0.43, 0.003 and 0.01 micrograms/ml the compound binds preferentially to the penicillin-binding protein (PBP) 3 of Escherichia coli K12, to the PBPs 2x and 3 of Streptococcus pneumoniae R6 and to PBP 1 of Staphylococcus aureus SG 511, respectively.

Influence of cefodizime on the reagibility of human leukocytes.

Cefodizime was evaluated for its effect on a number of parameters of leukocyte function in humans. Four healthy volunteers received 2 g i.v. b.i.d. for seven days. Leukocyte activity was measured before, during and after treatment. Using opsonized zymosan as a stimulant, no effect on the respiratory burst of granulocytes was observed. It was found, however, that the lymphocytes in three of the four subjects showed significantly more marked proliferation rates in the mixed lymphocyte reaction after administration of cefodizime than at baseline. The stimulation indices subsequently returned to normal. This pilot study therefore demonstrated that cefodizime has biological response modifying properties in healthy humans.

Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 111V), a new broad-spectrum cephalosporin.

Cefquinome is a new injectable aminothiazolyl cephalosporin derivative. It is stable against chromosomally and plasmid-encoded beta-lactamases and has a broad antibacterial spectrum. Staphylococcus aureus, streptococci, Pseudomonas aeruginosa, and members of the family Enterobacteriaceae (Escherichia coli, Salmonella spp., Klebsiella spp., Enterobacter spp., Citrobacter spp., and Serratia marcescens) are inhibited at low concentrations. Cefquinome is also active against many strains of methicillin-resistant staphylococci and enterococci. Its in vitro activity against gram-negative anaerobes is very limited. The high in vitro activity of cefquinome is reflected by its high in vivo efficacy against experimental septicemia due to different gram-positive and gram-negative bacteria. We studied the pharmacokinetic properties of cefquinome in mice, dogs, pigs, and calves. After single parenteral administrations, cefquinome displayed high peak levels, declining with half-lives of about 0.5, 0.9, 1.2, and 1.3 h, respectively. The areas under the concentration-time curve determined for dogs and mice showed linear correlations to the given doses. In dogs the urinary recovery was more than 70% within 24 h of dosing.

Comparative chemotherapeutic activity of cefpirome and imipenem in experimental infections.

In systemic and local infections, the therapeutic efficacy of cefpirome was compared to that of imipenem and cefotaxime. Murine septicemia induced with methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains responded well to cefpirome and imipenem therapy, the ED50 values ranged from 0.8 to 28.40 mg/kg and 0.5 to 15.58 mg/kg, respectively. The carbapenem also displayed high efficacy against Enterococci and was more potent than cefpirome. Cefotaxime, however, exhibited lower activity or proved to be inactive against these strains. With ED50 values of 0.03 to 31.33 mg/kg, cefpirome was the most active of the three antibiotics in protecting mice challenged with Enterobacteriaceae. The corresponding ED50 values of imipenem and cefotaxime ranged from 0.72 to 70.95 mg/kg and 0.06 to 66.30 mg/kg, respectively. Despite distinctly lower in vitro activity against the infecting organism, cefpirome showed efficacy similar to imipenem in the treatment of subcutaneous S. aureus abscesses in mice. It was more effective than imipenem and cefotaxime against experimental Klebsiella pneumonia in mice and the Escherichia coli infected granuloma pouch in rats.

Synthesis and structure-activity relationships in the cefpirome series. III. 7 Alpha-methoxy and 7 alpha-formamido analogues of cefpirome.

7 alpha-Methoxy and 7 alpha-formamido derivatives of cefpirome (HR 810) have been synthesized and tested in comparison with cefpirome and some analogues 1 against aerobic and anaerobic bacteria. Cefpirome and analogues 1 have good activity against Gram-positive and only limited activity against Gram-negative anaerobic bacteria. 7 alpha-Methoxy derivatives 2 show only a slight improvement of activity against Gram-negative anaerobes and are less active against all aerobes. Introduction of the 7 alpha-formamido group (compounds 3) results in an overall loss of activity towards both aerobic and anaerobic bacteria.

The in vitro activity of the combination of cefotaxime and HRE 664.

Cefotaxime (CTX) and HRE 664 (a novel penem antibiotic) possess complementary in vitro properties. Differences can be observed in their antibacterial spectra, their beta-lactamase stability and -inhibition, and their affinity to penicillin-binding proteins. These differences suggested that combinations of the cephalosporin and the penem antibiotic would be advantageous and should be studied. The fractional inhibitory concentration values of checkerboard studies confirmed that CTX and HRE 664 act synergistically against various Gram-positive and Gram-negative bacteria. Fixed combinations containing 80% CTX and 20% HRE 664 possess broader antibacterial spectra and in certain cases higher antibacterial activities than each of the components alone. The combinations had improved activity against Staphylococci including methicillin-resistant strains, beta-lactamase producing strains of Enterobacter sp. and Bacteroides fragilis. The combination as well as the single antibiotics had only limited activity against Pseudomonas aeruginosa.

HRE 664, a new parenteral penem. II. Evaluation of the pharmacokinetic behavior and the chemotherapeutic activity in animals.

The pharmacokinetic and chemotherapeutic properties of the new penem antibiotic HRE 664 (Fig. 1) were evaluated in experimental animals. High and sustained blood and serum levels were achieved following parenteral injection in mice, rats, dogs and monkeys. Half-lives ranged from 27 to 40 minutes in the various species tested. The antibiotic was well distributed in the rodents and penetrated well into tissues and body fluids. At 30 minutes after subcutaneous administration to mice (50 mg/kg), concentrations of between 12.4 and 35.9 micrograms/g were measured in the lungs, liver, heart and kidneys, that is 33 approximately 95% of the corresponding level in murine blood (37.7 micrograms/ml). In experimentally induced infections in mice, HRE 664 displayed good chemotherapeutic activity particularly against septicemias caused by methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains and on abscess formation induced by Bacteroides fragilis. Most of the cephalosporins and other beta-lactam antibiotics exhibited low efficacy against these strains of bacteria.