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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.

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.

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.

The activity of the aminothiazolyliminomethoxy cephalosporin cefodizime (HR 221) was compared to that of cefotaxime, cefuroxime and cefazolin in experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. Cefodizime exhibited high and long-acting levels in the blood and lung homogenates of infected mice; the blood and tissue concentrations obtained with the other cephalosporins tested were low by comparison. In the treatment of experimental Klebsiella pneumonia, cefodizime was superior to cefotaxime and cefuroxime. Counts of the number of viable bacteria present in the infected tissue showed that cefodizime exerted a more marked bactericidal effect than cefotaxime or cefuroxime. Hardly any therapeutic activity was seen with cefazolin.

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.

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.

The chemotherapeutic efficacy of cefpirome (HR 810), a new polar aminothiazolylcephalosporin and that of ceftazidime, cefotaxime, cefoperazone, latamoxef and cefodizime were examined against experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. When compared in terms of MIC values against the infecting organism and the pharmacokinetic pattern, cefpirome showed equal activity and a similar pharmacokinetic behavior to ceftazidime and cefotaxime in mice. Trials to assess the bactericidal activity in vivo, however, showed that cefpirome displayed a more marked bactericidal effect in pneumonic mice than the other cephalosporins tested. Only cefodizime, a cephalosporin with extremely high and prolonged blood and tissue levels in experimental animals exerted chemotherapeutic effects similar to cefpirome. After cefpirome or cefodizime medication (50 mg/kg), the viable counts in the lungs of experimental animals fell steadily to 1/10,000 of the pretreatment level and, in contrast to the reference compounds, no regrowth of the challenge organisms could be observed with both drugs. Moreover, with ED50s ranging from 1.1 to 59.1 mg/kg in treatment studies, cefpirome as well as cefodizime were two to ten times more effective than ceftazidime and cefotaxime, whereas cefoperazone and latamoxef were considerably less effective.

The pharmacokinetic properties of cefodizime, a new aminothiazolyliminomethoxycephalosporin, were studied in laboratory animals and compared with the pharmacokinetics of another long-acting cephalosporin, ceftriaxone. Both cephalosporin derivatives showed high affinity (33-99%) for serum proteins. High and prolonged blood respectively serum levels of the antibiotics were achieved following subcutaneous and intravenous injection into mice, rats, rabbits, dogs and monkeys. Cefodizime elimination half-lives ranged from 1.17 hours in mice to 3.53 hours in rabbits compared to ceftriaxone half-lives ranging from 0.73 hour in mice to 7.31 hours in rabbits. The antibiotics were well distributed in the body and penetrated into tissues and body fluids to a high degree. Particularly high and prolonged levels were detected in the lungs, liver and kidneys of the experimental animals. Large amounts, approximately 35-55% of the given dose, were recovered in the urine of rabbits and dogs, while the recovery rate in the bile of rabbits was only 0.57% for cefodizime and 1.08% for ceftriaxone.

Cefodizime possesses a broad antibacterial spectrum including staphylococci, streptococci and Enterobacteriaceae. Neisseria gonorrhoeae and Haemophilus influenzae are also highly susceptible to cefodizime. Because of its beta-lactamase stability cefodizime is active against bacterial strains producing especially plasmid-coded enzymes. The MICs of cefodizime are slightly higher than those of cefotaxime, but with most Gram-negative bacteria they are lower than those of cefazolin, cefotiam and piperacillin. The in vitro activity of cefodizime is not dependent on inoculum size, or on the pH and composition of the test medium. Cefodizime did not induce in vitro resistance of Staphylococcus aureus or Escherichia coli. Because of its binding properties to PBPs 1A/B and 3, cefodizime leads to filamentation of Gram-negative rods and, at only slightly higher concentrations, to bacteriolysis.

The new penem antibiotic HRE 664 displays potent antibacterial activity in vitro against a broad spectrum of clinically relevant bacterial strains including Gram-negative and Gram-positive aerobes and anaerobes. With an MIC 90% of 0.43 micrograms/ml, it is also active against methicillin-resistant staphylococci. HRE 664 is extremely stable against beta-lactamases, it binds preferentially to the penicillin-binding proteins 2, 3, 5 and 6 of Escherichia coli.