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The synthesis and biological activities of a series of new 1beta-methylcarbapenems 1a-h having heteroaromatic thioether moiety at C-5 position of pyrrolidine were described. Among these compounds, 1,2,3-thiadiazole derivative 1h showed the most potent antibacterial activity and advanced pharmacokinetics in comparison with meropenem.
The synthesis of novel 1 beta-methylcarbapenems 1a,b bearing isothiazoloethenyl moieties at C-5 position of pyrrolidine ring and their biological evaluation are described. Both compounds showed potent and well-balanced antibacterial activity as well as high stability to DHP-I. Especially, 5-isothiazole derivative 1a exhibited excellent DHP-I stability and advanced pharmacokinetics profiles, compared to 5-isoxazole derivative 2, imipenem, and meropenem.
The synthesis and in vitro antibacterial activity of a novel series of 2-alkoxymethyl-4-pyrrolidinylthio-1 beta-methyl carbapenems are described. As a result of these studies, we discovered that FR27743 (19j) containing a novel 2-fluoroethoxymethyl substituent possesses a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosa. Furthermore, FR27743 exhibited excellent stability against renal dehydropeptidase-I (DHP-I), good urinary recovery, and superior in vivo activity compared to that for Meropenem against several systemic infections.
Comamonas testosteroni, a lesser-known member of the genus, has shown little apparent capacity for causing infections in humans. We here present a case of purulent meningitis due to C. testosteroni, which occurred in a patient who had recurrent cholesteatoma. Ceftriaxone treatment was not effective in this patient even though in vitro the bacteria were susceptible to the drug. The patient responded well to meropenem therapy.
The potencies of the carbapenems; doripenem (DRPM), meropenem (MEPM) and imipenem (IPM) in preventing the emergence of carbapenem-resistant mutants were examined in Pseudomonas aeruginosa strains. The carbapenems predominantly selected carbapenem-resistant mutants or carbapenem mutants with reduced susceptibilities that were specifically resistant to carbapenems and had arisen as a result of the reduced level of expression of the outer membrane protein with a molecular weight of about 48,000 (OprD). The potency of carbapenems in preventing the growth of the mutants differed for DRPM, MEPM and IPM. The isolation frequency of the mutant was examined on agar plates containing each of the carbapenems at a concentration of 1/2 or 1/4 MIC of each carbapenem for that mutant. Mutants were not selected on agar containing DRPM at a frequency of greater than 10(-9) per cell per generation, whereas mutants of each strain were selected on agar containing MEPM or IPM at frequencies of 10(-7) to 10(-9) per cell per generation. The drug concentrations and the drug concentration range for the selective increase of carbapenem resistant mutants in the broth culture containing each carbapenem differed for each carbapenem. DRPM exhibited both the lowest drug concentration and the narrowest range of drug concentration for selection of the carbapenem-resistant mutants. The results shown in this report indicated that DRPM exhibited the greatest ability to prevent the emergence of the mutant.
The incidence of candiduria is increasing in teaching hospitals. We examined the hypothesis that this trend was correlated with the amount of departmental antibiotic consumption. In the setting of a large teaching hospital in Israel, the correlation coefficient between departmental intravenous antibiotic consumption (expressed as daily defined dose (DDD)/1000 patient-days) and the incidence of candiduria per 1000 patient-days was 0.47 (P=0.03). For broad-spectrum antibiotics, the corresponding correlation coefficient was 0.66 (P=0.001). The strongest correlation with candiduria was shown for the use of meropenem (r=0.79, P<0.001) and ceftazidime (r=0.66, P=0.001). This is the first time that departmental habits of antibiotic use have been shown to be strongly correlated with the incidence of candiduria in hospitalized patients. These results add an important new dimension to the strategy of restricting broad-spectrum antibiotics.
BACKGROUND: Diagnostic laboratories increasingly offer bacterial identification to the species level. The 17 nocardia species known to date differ in their clinical presentation, antibiotic resistance patterns and geographic distribution. The discovery of a new species with pathogenicity for humans calls for the characterization of its clinical and epidemiological properties. PATIENTS AND METHODS: Nocardia isolated from multifocal brain abscesses of an immunocompromised patient were further identified by the analysis of their cellular fatty acids and sequencing of the 16S ribosomal DNA. Quantitative antibiotic resistance testing was performed with E-tests. RESULTS: The 16S ribosomal DNA analysis showed a 99 % homology to Nocardia cyriacigeorgici. This is the first report of this species as an invasive human pathogen. N. cyriacigeorgici was found susceptible for meropenem, amikacin, ceftriaxon and cotrimoxazole. The combination of surgical drainage and antibiotic treatment for 13 months was curative. CONCLUSIONS: N. cyriacigeorgici has the potential to cause invasive infections at least in immunocompromised patients. Comparing clinical and in vitro characteristics with N. asteroides, the main causative agent of nocardial infections in Europe, we found no clinically relevant differences.
Neonatal Escherichia coli meningitis is a serious disease with high mortality and poor outcome. Ventriculitis, brain abscess and subdural empyema are frequent, with no homogeneous recommendations available for these complications. The case of a newborn infant who developed sepsis and meningitis caused by E. coli is presented. During intravenous treatment with ampicillin, cefotaxime and gentamycin in recommended doses, the patient developed severe subdural abscesses detected on MRI. After consequent antibiotic therapy over 2 months with fosfomycin, amikacin and meropenem the patient improved clinically and the abscesses regressed and disappeared without neurosurgical intervention. At the age of 6.5 months the infant is healthy and well developed. The conservative treatment of subdural abscesses complicating neonatal Escherichia coli meningitis without neurosurgical intervention is possible. The treatment of the individual case should be discussed between pediatrician and neurosurgeon.
We evaluated effects of medium composition, including basic amino acid content and pH, on susceptibility to carbapenems such as imipenem, panipenem and meropenem, in clinical isolates of Pseudomonas aeruginosa. Susceptibility to carbapenems was reduced by basic amino acids in the medium, while susceptibilities to ceftazidime and aztreonam were not. Among carbapenems, susceptibility to panipenem was most sharply reduced by addition of basic amino acids to 1:16 Mueller-Hinton agar (MHA). In 174 of 175 clinical isolates, MICs for carbapenems were affected to different degrees by medium composition. One isolate, in which MICs for carbapenems did not differ between MHA and 1:16 MHA, showed reduced production of porin (OprD). Our results suggest that susceptibility to individual carbapenems, especially panipenem, is difficult to evaluate based on MICs for other carbapenems determined on MHA. For a better prediction of antibiotic efficacy, it may be important to evaluate the susceptibility for each carbapenem individually.
In 2003 a Bacteroides fragilis blood culture isolate (K2-28) was recovered from a 61-y-old male with severe general atherosclerosis during treatment with meropenem. K2-28 was shown to possess a functional metallo-beta-lactamase with a reduction in imipenem MIC from 256 to 3 mg/l in the presence of EDTA using the MBL E-test strip. PCR results were for positive for the cfiA gene. Analysis of the cfiA from K2-28 revealed it was 100% identical to previously described cfiA-1 genes. Analysis of the upstream region of cfiA revealed a novel insertion sequence (IS) element, being most similar (94% identity) to IS612 recently described from Japan designating the element within the IS4 family. The element possessed a perfect terminal inverted repeat sequence at the distal ends of the IS element and provided a putative promoter for transcription of the cfiA gene. The distance between the hybrid promoter and the cfiA start codon was 158 base pairs and inserted into a different DNA sequence upstream of cfiA to that previously reported. The -10 promoter region was most similar to that of IS613 (100%) and the -35 promoter region to IS612 (100%), demonstrating the plasticity of these genetic regions.
A case of acute generalized exanthematous pustulosis (AGEP) is presented. The case is notable for the recurrent episodes of AGEP, caused by three beta-lactam antibiotics (piperacillin, ceftazidime, and meropenem) in septicemic patient. The case represents the first report of the reaction developing in response to these three antibiotics. The report is also notable for the spontaneous resolution of the rash in all the three episodes.
Administration of empirical antibiotic therapy is now standard practice in the management of febrile neutropenia, but there has been considerable debate about the selection of an efficacious empirical antimicrobial regimen over the past 2 decades. A variety of approaches, including both monotherapeutic and multidrug regimens, have been demonstrated to be effective, although no one regimen has been proven to be superior to another. Changes in the epidemiology of infectious organisms and the growing emergence of highly drug-resistant strains make it necessary to continually reevaluate the therapeutic options. Fortunately, the number of therapeutic options has also been broadening as new antimicrobial agents, including third-generation cephalosporins and carbapenem antibiotics such as imipenem and meropenem, become available. Optimal management is directed by the findings of a clinical evaluation of the patient as well as an awareness of institutional patterns of infection and susceptibility of likely infecting organisms.
In a rabbit Escherichia coli meningitis model, endotoxin liberation and concentrations of leukocytes, tumor necrosis factor (TNF), and lactate were compared after a single intravenous dose of cefotaxime, cefpirome, meropenem, chloramphenicol, or gentamicin. These antibiotics caused a 2- to 10-fold increase in cerebrospinal fluid concentrations of free (filterable) endotoxin within 2 h of starting treatment. By contrast, free endotoxin concentrations increased almost 100-fold in untreated animals 4 h later as bacteria continued to multiply. An initial enhancement of inflammation in the central nervous system occurred in all treatment groups compared with untreated controls. No significant differences were observed between treatment groups except for lower TNF concentrations in chloramphenicol-treated animals. Antibiotic therapy in E. coli meningitis, irrespective of the agent used, may result in an increase in free endotoxin and enhancement of inflammation, but the amount of endotoxin liberated is considerably smaller than that shed by untreated bacteria.
The carbapenems differ from the penicillins (penams) in having an unsaturated bond between C2 and C3 and a carbon atom replacing sulphur at position 1 of the thiazolidine ring. The various carbapenems differ primarily in the configuration of the side chains at C2 and C6. Carbapenems include the thienamycins, olivanic acids, carpetimycins, asparenomycins, pluracidomycins, and other natural and semi-synthetic compounds. Carbapenems vary in their stability and resistance to beta-lactamases, ability to inhibit and to induce beta-lactamases, and in-vitro spectra of activity. Many are highly unstable in solution. Some are degraded by mammalian dehydropeptidases in vivo. The hydroxyethyl side chain in the alpha or trans-configuration at C6 in thienamycin provides striking resistance to beta-lactamases, but this compound is highly unstable in concentrated solution and the solid state. The N-formimidoyl derivative of thienamycin (imipenem) is more stable in solution and has broad-spectrum activity against aerobic and anaerobic bacteria. However, imipenem is not stable to renal dehydropeptidases and its degradation products are nephrotoxic in certain animals. It is thus administered with the dehydropeptidase inhibitor cilastatin. High serum levels of imipenem (especially in patients with renal failure and central nervous system disease) have been associated with seizures. The drug is therefore not appropriate for meningitis. Meropenem is a new carbapenem which has the same side chain as imipenem at C6. Its unique side chain at C2 assures a broad spectrum of activity which includes Pseudomonas aeruginosa and other aerobic and anaerobic organisms. Only Ps. (Xanthomonas) maltophilia is generally resistant. This species is resistant also to imipenem.(ABSTRACT TRUNCATED AT 250 WORDS)
We assessed the antimicrobial susceptibilities of 59 penicillin-intermediate or penicillin-resistant pneumococci. All strains were susceptible to vancomycin and rifampicin. The frequency of strains with decreased susceptibility to cefotaxime, chloramphenicol, imipenem and meropenem was 15, 31, 47 and 49% respectively. The high percentage of penicillin-intermediate or penicillin-resistant Streptococcus pneumoniae with decreased susceptibility to third-generation cephalosporins, chloramphenicol and carbapenems limits the therapeutic options for the treatment of invasive pneumococcal infections and particularly of meningitis.
In order to assess the current level of resistance to widely used antipseudomonal antibiotics in clinical isolates of Pseudomonas aeruginosa, a national survey was undertaken. Fifteen hospitals throughout Italy participated in the study. The University of Catania tested the antibiotic susceptibility of 1005 consecutive clinically significant P. aeruginosa collected from March to June 1995. Lack of susceptibility, according to NCCLS breakpoints, was at the following rates: meropenem, 9.1%; imipenem, 19.3%; ceftazidime, 13.4%; carbenicillin, 27.3%; piperacillin, 12%; ticarcillin/clavulanic acid, 22.8%; amikacin, 10.6%; and ciprofloxacin, 31.9%. About half of the isolates (44.4%) were not susceptible to at least one of the antibiotics tested.
Three carbapenem-resistant Acinetobacter baumannii isolates were collected at a hospital in Buenos Aires, Argentina. Isoelectric focusing revealed multiple beta-lactamases, with two of the isolates showing identical profiles. A pI 6.9 carbapenemase with a molecular weight of 30 kDa was purified from one of these two isolates. The enzyme was predominantly a penicillinase, with its highest Vmax for oxacillin but highest Vmax/Km for benzylpenicillin. First-generation cephalosporins and imipenem were weaker substrates than penicillins, and oxyimino-aminothiazolyl cephalosporins were essentially stable. Meropenem-hydrolysing activity was not detected, despite resistance. The carbapenemase was inhibited by clavulanic acid and tazobactam, but not by EDTA. These kinetics place the enzyme into functional group 2; as an oxacillinase it could be placed in sub-group 2d or, as a zinc-independent carbapenemase, in sub-group 2f.
The carbapenemase gene (cfiA) was detected in 12 (6.9%) out of 175 clinical isolates of Bacteroides fragilis from Nottingham, three times the frequency reported from France. Only one gene copy was present in all cases. Eleven (6.3%) of the cfiA-positive isolates were susceptible to imipenem or meropenem (MIC < 8 mg/L); strains of this type have the potential to convert to high-level resistance. One isolate (0.6%) displayed resistance to both carbapenem antibiotics and was associated with specific carbapenemase activity six times that of the sensitive isolates.