Penetration of monobactam antibiotics (aztreonam, carumonam) into human prostatic tissue

Concomitant concentrations of monobactam antibiotics were measured in plasma and in prostatic tissue obtained by transurethral resection in 25 patients, 60-120 min after dosage. A 1-gram single intravenous injection of aztreonam or carumonam yielded mean prostatic concentrations of 6.0 mg/kg in 20 patients. Five patients who received a 2-gram dose of carumonam demonstrated average prostatic levels of 10 mg/kg. These concentrations significantly exceed MIC values for most common gram-negative urinary tract pathogens.     

Antimicrobial and beta-lactamase inhibitory activities of carpetimycins A and B, new carbapenem antibiotics.

Carpetimycins A and B showed widely broad spectra and potent activity against gram-positive and gram-negative bacteria, including various species of anaerobic bacteria. The antimicrobial activity of carpetimycin A was 8 to 64 times greater than that of carpetimycin B and 4 to 128 times greater than that of cefoxitin. The inhibitory concentration of carpetimycin A required to inhibit more than 90% of clinical isolates was 0.39 micrograms/ml for Escherichia coli and klebsiella and 1.56 microgram/ml for Proteus and Staphylococcus aureus. At a concentration of 3.13 micrograms/ml, carpetimycin A inhibited almost all clinical isolates of Enterobacter and Citrobacter, which showed resistance to many clinically used beta-lactam antibiotics. Carpetimycins A and B furthermore were shown to have potent inhibitory activities against several kinds of beta-lactamases produced by beta-lactam-resistant strains; they inhibited not only penicillinase-type beta-lactamases but also cephalosporinase-type beta-lactamases, which were insensitive to clavulanic acid. In combination with beta-lactam antibiotics such as ampicillin, carbenicillin, and cefazolin, carpetimycins A and B showed synergistic activities against beta-lactam-resistant bacteria.     

Tigemonam, an oral monobactam.

Tigemonam is an orally administered monobactam. At less than or equal to 1 microgram/ml it inhibited the majority of strains of Escherichia coli, Klebsiella spp., Enterobacter aerogenes, Citrobacter diversus, Proteus spp., Providencia spp., Aeromonas hydrophila, Salmonella spp., Shigella spp., Serratia marcescens, and Yersinia enterocolitica. At less than or equal to 0.25 microgram/ml it inhibited Haemophilus spp., Neisseria spp., and Branhamella catarrhalis. It did not inhibit Pseudomonas spp. or Acinetobacter spp. Tigemonam was more active than cephalexin and amoxicillin-clavulanate and inhibited many members of the family Enterobacteriaceae resistant to trimethoprim-sulfamethoxazole and gentamicin. Some Enterobacter cloacae and Citrobacter freundii strains resistant to aminothiazole iminomethoxy cephalosporins and aztreonam were resistant to tigemonam. The MIC for 90% of hemolytic streptococci of groups A, B, and C and for Streptococcus pneumoniae was 16 micrograms/ml, but the MIC for 90% of enterococci, Listeria spp., Bacteroides spp., and viridans group streptococci was greater than 64 micrograms/ml. Tigemonam was not hydrolyzed by the common plasmid beta-lactamases such as TEM-1 and SHV-1 or by the chromosomal beta-lactamases of Enterobacter, Morganella, Pseudomonas, and Bacteroides spp. Tigemonam inhibited beta-lactamases of E. cloacae and Pseudomonas aeruginosa but did not induce beta-lactamases. The growth medium had a minimal effect on the in vitro activity of tigemonam, and there was a close agreement between the MICs and MBCs.     

Estimation of outer membrane permeability of carbapenem antibiotics to Pseudomonas aeruginosa

The outer membrane permeability of carbapenems (imipenem [IPM], panipenem [PAPM], meropenem [MEPM], and biapenem [BIPM]) and ceftazidime (CAZ) to Pseudomonas aeruginosa was determined by the Zimmermann and Rosselet method. The permeability coefficients of β-lactams tested at 50 μM concentration of substrates ranged from (0.40 ± 0.10) × 10⁻⁶ cm/s for CAZ to (2.33 ± 0.33) × 10⁻⁶ cm/s for IPM, indicating that the outer membrane permeability of carbapenems to P. aeruginosa was high in comparison with that of CAZ. In particular, IPM and BIPM showed a higher rate of penetration than MEPM and PAPM. Received: November 30, 1998 / Accepted: March 10, 1999     

Comparative in-vitro activity of carbapenem antibiotics against respiratory pathogens isolated between 1999 and 2000

We investigated the antibacterial activity of 12 antibiotics, inclusive of four carbapenems, against 167 strains of respiratory pathogens isolated between 1999 and 2000. Thirty strains of methicillin-susceptible Staphylococcus aureus (MSSA), 28 strains of methicillin-resistant S. aureus (MRSA), 11 strains of penicillin-susceptible Streptococcus pneumoniae (PSSP), 29 strains of penicillin-resistant S. pneumoniae (PRSP), 30 strains of Pseudomonas aeruginosa, 14 strains of Moraxella catarrhalis, and 25 strains of Haemophilus influenzae were examined. The minimum inhibitory concentration (MICs)_50/90 (μg/ml) of imipenem, panipenem, meropenem, and biapenem against the clinical isolates obtained between 1999 and 2000 were: 0.06/0.25, 0.12/0.25, 0.12/0.25, and 0.12/0.25, respectively, against MSSA; 16/32, 16/32, 16/32, and 8/32 against MRSA; ≦0.015/0.06, ≦0.015/0.03, 0.03/0.12, and ≦0.015/0.06 against PSSP; 0.12/0.25, 0.03/0.06, 0.25/0.5, and 0.12/0.25 against PRSP; 1/8, 2/8, 0.5/2, and 2/16 against P. aeruginosa; 0.06/0.06, 0.03/0.06, ≦0.015/0.06, and 0.06/0.12 against M. catarrhalis; and 1/4, 1/4, 0.12/0.25, and 2/4 against H. influenzae. A comparison of the antibacterial activity of the four carbapenems with that found in our previous studies showed no significant difference in the susceptibility of clinical isolates, except for a slight decrease in the susceptibility of MSSA. Carbapenems have remained effective for severe infections. The MIC data showed that imipenem and panipenem were more active than meropenem and biapenem against gram-positive bacteria, and that meropenem and biapenem were more active than imipenem and panipenem against gram-negative bacteria. As only meropenem had an MIC₉₀ below the breakpoint of pneumonia against all species except MRSA, meropenem was considered to be the most potent of the four carbapenems studied. Received: February 8, 2001 / Accepted : June 5, 2001     

Inactivation of new carbapenem antibiotics by dehydropeptidase-I from porcine and human renal cortex.

The stability of the new carbapenem antibiotics, panipenem, meropenem and LJC 10,627, against porcine and human renal dehydropeptidase-I (DHP-I) was compared with that of imipenem. The order of stability to hydrolysis by renal DHP-I was: LJC 10,627 greater than meropenem greater than panipenem greater than imipenem. After incubation of the drugs with porcine or human enzyme at 30 degrees C for 4 h, the percentages of residual activity were as follows: LJC 10,627, 73.7% and 95.6%, respectively; meropenem, 0.2% and 28.7%, respectively; panipenem, 0% and 4.3%, respectively; and imipenem, 0% and 0.1%, respectively. These results demonstrate that LJC 10,627 has extremely high stability against renal DHP-I.     

Relationship between the usage of carbapenem antibiotics and the incidence of imipenem-resistant Pseudomonas aeruginosa

Metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa isolates are resistant to almost all broadspectrum β-lactams and carbapenems. We investigated 389 P. aeruginosa isolates, collected from 29 hospitals in the Tohoku area of Japan, to determine their susceptibilities to ten antimicrobial drugs, and the rates of MBL-producing P. aeruginosa among them. Two hundred and one P. aeruginosa strains were isolated from small (group S)hospitals that had adopted imipenem as a carbapenem antibiotic, and 188 were isolated from general (group G) hospitals, which employed three or four carbapenems. MBL genes were analyzed by polymerase chain reaction (PCR) in all isolates for which the sodium mercaptoacetic acid (SMA) disk method gave positive results. The antimicrobial agents tested were imipenem, meropenem, biapenem, panipenem, piperacillin, ceftazidime, sulbactam/cefoperazone, amikacin, arbekacin, and ciprofloxacin. Sixteen (8.0%) of the 201 isolates from group S hospitals and three (1.6%) of the 188 isolates from group G hospitals were MBL-producing P. aeruginosa. In this study, the proportion of MBL-producing P. aeruginosa in group S was significantly higher than that found in group G (P < 0.01). The use of only one agent as a carbapenem antibiotic may have been one of the factors contributing to the high detection rate of MBL-producing P. aeruginosa observed in group S hospitals.     

Increase in susceptibility of Pseudomonas aeruginosa to carbapenem antibiotics in low-amino-acid media.

The in vitro susceptibility of Pseudomonas aeruginosa PAO1 to carbapenem antibiotics, such as CS-533, was influenced by various concentrations of basic amino acids, i.e., L-lysine, L-histidine, and L-arginine, in agar media. P. aeruginosa PAO1 showed higher susceptibility to carbapenems in minimal medium than it did in rich media such as Mueller-Hinton II agar. The susceptibility was decreased by the addition of a basic amino acid to the minimal medium, whereas it was influenced less by other amino acids. The susceptibility of PAO1 to cephalosporins, piperacillin, quinolones, and gentamicin was not influenced by the addition of a basic amino acid to the minimal medium. A significant change in susceptibility to carbapenems by the addition of a basic amino acid was not observed with D2 protein-deficient mutants of PAO1. Clinical isolates of P. aeruginosa also showed an increase in susceptibility in minimal medium. L-Lysine in minimal medium did not have any influence on the production of D2 protein, beta-lactamases, or penicillin-binding proteins of PAO1 or on the chemical degradation of CS-533. These results strongly indicate that the increase in susceptibility of P. aeruginosa to carbapenems relates to less competition with basic amino acids for permeation through the D2 protein channel of P. aeruginosa.     

Comparative in-vitro activity of tigemonam, a new monobactam

The in-vitro activity against Gram-negative aerobic bacterial pathogens of a new oral monobactam, tigemonam, was compared with those of amoxycillin/clavulanic acid, aztreonam, cefaclor, ceftazidime, cefuroxime, ciprofloxacin, co-trimoxazole and gentamicin, by an agar-dilution method. Tigemonam inhibited 90% of strains tested of Escherichia coli, Klebsiella spp., Proteus spp., Salmonella spp., Haemophilus influenzae and Branhamella catarrhalis at concentrations of 0.25 mg/l or below. The MIC90 for Enterobacter spp. was 16 mg/l and for Citrobacter 4 mg/l. Pseudomonas aeruginosa was resistant to tigemonam but susceptible to aztreonam. In comparison with the other oral antibiotics tested, tigemonam was generally more active. Tigemonam showed minimal inoculum dependence, between 10(2) and 10(6) cfu per spot. It is concluded that tigemonam is a candidate for clinical trials in patients with infections caused by Gram-negative aerobes other than pseudomonas and acinetobacter.     

Immunology of the monobactam aztreonam

To assess the immunological cross-reactivity of the monobactam antibiotic aztreonam (AZ), rabbits were immunized with protein conjugates of benzylpenicillin, cephalothin (CEPH), and AZ. The resulting antibenzylpenicilloyl (BPO) and anti-CEPH rabbit antibodies showed negligible cross-reactivity with AZ conjugated to human serum albumin (AZ-HSA), whereas anti-AZ showed negligible cross-reactivity with BPO-HSA and CEPH-HSA. Unlike benzylpenicillin and CEPH, unconjugated AZ was as effective as AZ conjugated to epsilon aminocaproic acid (AZ-EACA) in inhibiting the binding of homologous antibody. Studies with various analogs of AZ confirmed that immunoglobulin G (IgG) anti-AZ was entirely side-chain specific. The inhibition of the binding of human IgE anti-penicilloyl to BPO-HSA was studied in the presence of AZ-EACA, BPO-formyl lysine, and CEPH-EACA. Whereas CEPH-EACA displayed 3% cross-reactivity with BPO-lysine, AZ-EACA showed little or no cross-reactivity (much less than 0.9%). To assess the immunogenicity of AZ in humans, IgE and IgG antibodies were measured in sera from 36 healthy male volunteers receiving 0.5 or 1 g intravenously or intramuscularly every 8 h for 7 days. None of the subjects had detectable preexisting IgE reactive with AZ or demonstrated an IgE response to antibiotic administration. Four subjects gave evidence for naturally occurring IgG cross-reactive with AZ, but only one subject demonstrated a rise in IgG levels after exposure to AZ. This anti-AZ IgG did not cross-react with BPO or CEPH conjugates of bovine thyroglobulin and was completely side-chain specific. These studies suggest that AZ displays very low immunological cross-reactivity with other beta-lactam antibiotics and may be only weakly immunogenic in humans.     

Aztreonam: the first monobactam

There are several areas in which the use of aztreonam seems logical. Infections caused by organisms sensitive to aztreonam that are known to be multiresistant to other agents can be treated directly with aztreonam in single, directed therapy, thus making the use of more toxic agents unnecessary. In types of infection in which both gram positive and gram negative bacteria are present, aztreonam can replace the usual aminoglycoside component of the therapeutic regimen. In settings of mixed infections suspected of being caused by drug-resistant strains of Enterobacteriaceae and/or P. aeruginosa, aztreonam can be combined with an agent active against gram positive organisms or with one active against anaerobes. Aztreonam has proven to be effective, safe therapy for serious and life-threatening infections caused by multiresistant aerobic gram negative bacteria. It should be used in combination with drugs that inhibit gram positive species if the etiology of the infection is not known, particularly in the immunocompromised, neutropenic patient. Doses of 1 g every 8 to 12 hours will be adequate for treatment of infections caused by most Enterobacteriaceae. Whether 2 g doses every 8 hours would be preferred for treatment of systemic Pseudomonas infections remains to be determined. Urinary infections caused by gram negative bacteria can be treated with 500 mg administered IM once or twice daily. The dosage of aztreonam should be adjusted in patients with renal failure. Clearly, aztreonam is a useful addition to the antimicrobial agents available to the physician.     

In vitro activity of azthreonam, a monobactam antibiotic.

We studied the activity of azthreonam (SQ 26,776), a novel monocyclic beta-lactam compound, against a variety of clinical isolates. It was more potent than moxalactam, cefoperazone, cefamandole, cefoxitin, ticarcillin, tobramycin, or amikacin against strains of Klebsiella spp., Serratia spp., and the Proteus group. It was highly effective against Escherichia coli and strains of Salmonella spp. The median minimal inhibitory concentration for all species of Enterobacteriaceae was less than or equal to 2 micrograms/ml. Azthreonam was moderately active against Pseudomonas aeruginosa, including tobramycin-resistant strains, and against Pseudomonas cepacia (median minimal inhibitory concentration, 16 to 32 micrograms/ml), but was weakly active against Pseudomonas maltophilia and strains of Acinetobacter spp. and Achromobacter spp. The drug showed little activity against Staphylococcus aureus, enterococci, and anaerobic bacteria, including Bacteroides fragilis, Clostridium spp., and gram-positive cocci. Like moxalactam and cefoperazone, azthreonam exhibited a considerable inoculum effect with strains of Enterobacter spp. and Pseudomonas spp. Combination with clavulanic acid did not increase the activity of azthreonam against S. aureus but was synergistic for 5 of 15 strains of B. fragilis. Azthreonam is about 50% bound to human serum protein. The selective range of activity of this compound could be of clinical benefit.     

Evaluation of the antimicrobial activity of carbapenem and cephem antibiotics againstPseudomonas aeruginosa isolated from hospitalized patients

Pseudomonas aeruginosa is an opportunistic pathogen that infects compromised hosts. It is therefore important to clarify the bactericidal activity of antimicrobial agents against this bacterium. We evaluated the antimicrobial potency of several antibiotics againstP. aeruginosa by measuring the MIC and the minimum bactericidal concentration (MBC). Imipenem, panipenem meropenem, ceftazidime, cefpirome, cefepime, and cefozopran were the antibiotics evaluated. The 40 strains ofP. aeruginosa used in this analysis were isolated from the sputum of 40 patients. The MIC was determined by the microbroth dilution method. Afterwards, we determined the MBC, which is the lowest concentration of antibiotic at which all bacteria in the diluted culture are killed. The MIC and MBC of meropenem was determined to be 2 to 8 times lower and 2 to 4 times lower, respectively, than those of other carbapenem antibiotics tested. The MIC and MBC of cefozopran were determined to be 2 to 16 times lower and 4 to 16 times lower, respectively, than those of other cephem antibiotics tested. Meropenem and cefozopran show the greatest bactericidal activity againstP. aeruginosa among the, carbapenem and cephem antibiotics tested. Meropenem would be one of the best selections for treatment of pyocyanic infections in immunocompromised patients, because it also provides a postantibiotic effect againstP. aeruginosa.     

Comparative in vitro activity of carbapenem antibiotics against respiratory pathogens isolated in recent years

We investigated the antibacterial activity of 12 antibiotics, including 4 carbapenems, against 200 strains of respiratory pathogens isolated in 1997, and compared the results with those obtained in 1993. The strains examined were 38 strains of methicillin-susceptible Staphylococcus aureus (MSSA), 32 strains of methicillin-resistant S. aureus (MRSA), 22 strains of penicillin-susceptible Streptococcus pneumoniae (PSSP), 10 strains of penicillin-resistant S. pneumoniae (PRSP), 53 strains of Pseudomonas aeruginosa, 19 strains of Moraxella catarrhalis, and 26 strains of Haemophilus influenzae. In 1993, 100 strains were examined. The minimal inhibitory concentration data of the present study showed that imipenem and panipenem were more active than the other agents against gram-positive bacteria, and that meropenem and biapenem were more active than the other agents against gram-negative bacteria. By comparing these results with those obtained in 1993, it was found that increase of resistance to carbapenem antibiotics was not observed against all the strains tested in this study. Thus, it can be stated that carbapenem antibiotics retain their position as the drug of first choice for severe infections. Received: January 4, 1999 / Accepted: May 26, 1999     

Cefadroxil, a New Broad-Spectrum Cephalosporin

Cefadroxil is a new semisynthetic cephalosporin with a broad antibacterial spectrum and a high chemotherapeutic potential when administered orally. The inhibitory activity of this compound was similar to that of cephalexin and cephradine when tested against 602 clinical isolates on Mueller-Hinton medium. In the oral treatment of experimental infections of mice, cefadroxil was more effective than cephalexin against Streptococcus pyogenes, and comparably effective against Streptococcus pneumoniae, Staphylococcus aureus, and several gram-negative species. Administered orally to mice, at doses ranging from 25 to 100 mg/kg, cefadroxil attained peak concentrations in the blood similar to those of cephalexin. At a dose of 200 mg/kg, however, higher peak levels were noted with cefadroxil than with cephalexin. In regard to other properties which were investigated, the behavior of cefadroxil compared favorably to that of cephalexin.     

In-vitro activity of new carbapenem antibiotics: comparative studies with meropenem, L-627 and imipenem against pathogenic Nocardia spp.

MICs of two new carbapenems, meropenem and L-627, and imipenem were determined against 98 strains of the Nocardia asteroides group (i.e. N. asteroides sensu stricto, Nocardia farcinica and Nocardia nova), 46 strains of Nocardia brasiliensis and 17 strains of Nocardia otitidiscaviarum. Meropenem and L-627 were less active against the N. asteroides group than imipenem. Among the three species of the N. asteroides group, N. nova was the most sensitive to all the carbapenems. Meropenem was more active than imipenem against both N. brasiliensis and N. otitidiscaviarum with MIC50 values of 28.3-53.3 mg/L. L-627 was less active than meropenem.