Activity Of Carbapenems Research Articles

In vitro activity of doripenem and other carbapenems against contemporary Gram-negative pathogens isolated from hospitalised patients in the Asia-Pacific region: results of the COMPACT Asia-Pacific Study

The Comparative Activity of Carbapenems Testing (COMPACT) Study was designed to determine the in vitro potency of doripenem compared with imipenem and meropenem against a large number of contemporary Gram-negative pathogens from more than 100 centres across Europe and the Asia-Pacific region and to assess the reliability of Etest methodology for doripenem minimum inhibitory concentration (MIC) determination against these pathogens. Data from eight countries within the Asia-Pacific region, which collected 1612 bacterial isolates, are presented here. Etest methodology was found to be a reliable method for MIC determination. Doripenem showed in vitro activity similar to or better than meropenem and at least four-fold better than imipenem against Enterobacteriaceae. Against Pseudomonas aeruginosa, doripenem was also the most active of the three carbapenems in vitro. However, in vitro results do not necessarily correlate with clinical outcome.

Antibacterial activity of carbapenems against clinical isolates of respiratory bacterial pathogens in the northeastern region of Japan in 2007

As the increasing prevalence of resistant strains of respiratory bacterial pathogens has recently been reported, continuous monitoring of the susceptibility of clinical isolates to antibacterial agents is important. We performed a surveillance study focusing on the susceptibility of major respiratory bacterial pathogens in the northeastern region of Japan to carbapenems and control drugs. A total of 168 bacterial strains isolated from patients with respiratory tract infections in 2007 were collected and the minimum inhibitory concentration (MIC) determined. MIC data were subjected to pharmacokinetic/pharmacodynamic analysis with Monte Carlo simulation to calculate the probability of achieving the target of time above MIC with each carbapenem. All Moraxella catarrhalis, Streptococcus pneumoniae, and methicillin-sensitive Staphylococcus aureus isolates were susceptible to carbapenems. Despite the increasing prevalence of β-lactamase-nonproducing ampicillin-resistant strains, all Haemophilus influenzae isolates were susceptible to meropenem. For Pseudomonas aeruginosa, the susceptibility rates for meropenem and biapenem were 76.7%, and the highest probability of achieving pharmacodynamic target (40% of the time above MIC) was obtained with meropenem 0.5 g three times daily as a 4-h infusion (89.4%), followed by meropenem 0.5 g four times daily as a 1-h infusion (88.4%). Carbapenems have retained their position as key drugs for severe respiratory tract infections.

ChemInform Abstract: Chemistry of O-Silylated Ketene Acetals: A Stereoselective Synthesis of Optically Active Carbapenem Antibiotics, (+)-Thienamycin, and (+)- PS-5.

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The Effect of Carbapenem Antibiotics on Plasma Concentrations of Valproic Acid

To critically evaluate the mechanisms of the interaction between valproic acid and carbapenem antibiotics. A PubMed search (January 1971-June 2009) was performed to identify literature on the interaction between valproic acid and carbapenem antibiotics. Additional references were identified through review of bibliographies of identified articles. Data on the mechanisms of the interaction between valproic acid and carbapenem antibiotics were extracted from identified references that were published in English. Valproic acid plasma concentrations fall markedly during concomitant administration with carbapenem antibiotics due to a combination of absorption, distribution, and metabolism mechanisms. Carbapenems appear to inhibit the intestinal transporter of valproic acid, thereby reducing absorption of orally administered valproic acid. In vivo experiments in rats demonstrate a 57% reduction in absorption of orally administered valproic acid in the presence of imipenem. Follow-up studies in Caco-2 cells suggest that the inhibition probably occurs at the basolateral membrane. In addition, enterohepatic recycling of valproic acid may be diminished due to carbapenem activity against gut flora producing beta-glucuronidase. When rabbits and rats were given intravenous valproic acid-glucuronide, the glucuronide metabolite of valproic acid, 50-90% of the conversion back into valproic acid was inhibited in the presence of a carbapenem. An increase in erythrocyte distribution of valproic acid has also been observed in the presence of carbapenems. After intravenous administration of a carbapenem and valproic acid, valproic acid plasma concentrations fell in the presence of a carbapenem, yet whole blood concentrations of valproic acid did not change significantly. Follow-up studies suggest that the mechanism of this distribution shift is that multidrug resistance proteins on adenosine triphosphate-binding cassette transporters on erythrocyte membranes are inhibited by carbapenems. Thus, valproic acid is not effluxed out of the erythrocytes. Finally, carbapenems may enhance glucuronidation of valproic acid by increasing UDP-glucuronic acid levels. In rats, UDP-glucuronic acid levels increased by 1.7-fold in the presence of panipenem, which was proportionate to the increase in valproic acid-glucuronide formation. Published data demonstrate a serious and complex interaction between valproic acid and carbapenem antibiotics. Coadministration should be avoided, but if no other antibiotic therapies exist, it is imperative to monitor valproic acid concentrations more frequently. Clinicians should anticipate higher doses of valproic acid to maintain therapeutic serum concentrations during coadministration and subsequent dose reductions upon discontinuation of the carbapenem antibiotic.

Superior in vitro activity of carbapenems over anti-methicillin-resistant Staphylococcus aureus (MRSA) and some related antimicrobial agents for community-acquired MRSA but not for hospital-acquired MRSA

Eighty-eight strains of Panton-Valentine leukocidin (PVL)-positive and -negative community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and 152 strains of hospital-acquired MRSA (HA-MRSA) were examined for susceptibility to carbapenems, oxacillin, and other antimicrobial agents. CA-MRSA strains were more susceptible to carbapenems (MIC(90), 1-4 microg/ml) than HA-MRSA strains (MIC(90), 32-64 microg/ml). Among the carbapenems examined, CA-MRSA strains were most susceptible to imipenem (MIC(50), 0.12 microg/ml; MIC(90), 1 microg/ml). A similar tendency was observed with oxacillin, but less markedly (MIC(90): 32 microg/ml for CA-MRSA and > or =256 microg/ml for HA-MRSA). This difference was also observed between CA-MRSA and HA-MRSA in susceptibility levels to cephems, erythromycin, clindamycin, and levofloxacin, but not to ampicillin, vancomycin, teicoplanin, linezolid, and arbekacin. The data indicate that, in terms of MIC(50) or MIC(90) values, CA-MRSA is 64-256 times more susceptible to imipenem than HA-MRSA, and for CA-MRSA, some carbapenems, e.g., imipenem, show better in vitro activity than anti-MRSA or some related agents.

In Vitro Activity of Doripenem, a Carbapenem for the Treatment of Challenging Infections Caused by Gram-Negative Bacteria, against Recent Clinical Isolates from the United States

Doripenem, a 1beta-methylcarbapenem, is a broad-spectrum antibiotic approved for the treatment of complicated urinary tract and complicated intra-abdominal infections. An indication for hospital-acquired pneumonia including ventilator-associated pneumonia is pending. The current study examined the activity of doripenem against recent clinical isolates for the purposes of its ongoing clinical development and future longitudinal analysis. Doripenem and comparators were tested against 12,581 U.S. clinical isolates collected between 2005 and 2006 including isolates of Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pneumoniae, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter spp. MICs (microg/ml) were established by broth microdilution. By MIC(90), doripenem was comparable to imipenem and meropenem in activity against S. aureus (methicillin susceptible, 0.06; resistant, 8) and S. pneumoniae (penicillin susceptible, < or =0.015; resistant, 1). Against ceftazidime-susceptible Enterobacteriaceae, the MIC(90) of doripenem (0.12) was comparable to that of meropenem (0.12) and superior to that of imipenem (2), though susceptibility of isolates exceeded 99% for all evaluated carbapenems. The activity of doripenem was not notably altered against ceftazidime-nonsusceptible or extended-spectrum beta-lactamase screen-positive Enterobacteriaceae. Doripenem was the most potent carbapenem tested against P. aeruginosa (MIC(90)/% susceptibility [%S]: ceftazidime susceptible = 2/92%S, nonsusceptible = 16/61%S; imipenem susceptible = 1/98.5%S, nonsusceptible = 8/56%S). Against imipenem-susceptible Acinetobacter spp., doripenem (MIC(90) = 2, 89.1%S) was twice as active by MIC(90) as were imipenem and meropenem. Overall, doripenem potency was comparable to those of meropenem and imipenem against gram-positive cocci and doripenem was equal or superior in activity to meropenem and imipenem against Enterobacteriaceae, including beta-lactam-nonsusceptible isolates. Doripenem was the most active carbapenem tested against P. aeruginosa regardless of beta-lactam resistance.

Cyslabdan, a New Potentiator of Imipenem Activity against Methicillin-resistant Staphylococcus aureus, Produced by Streptomyces sp. K04-0144

Cyslabdan produced by Streptomyces sp. K04-0144 was found to potentiate imipenem activity against methicillin-resistant Staphylococcus aureus (MRSA). The MIC value of imipenem against MRSA was reduced from 16 to 0.015 microg/ml in combination with cyslabdan. Study on anti-MRSA activity of other typical antibiotics in combination with cyslabdan showed that the potentiating activity was limited to beta-lactam antibiotics. Furthermore, among beta-lactam antibiotics, the activity of carbapenems was most remarkably potentiated by cyslabdan.

In Vitro Activities of Doripenem and Six Comparator Drugs against 423 Aerobic and Anaerobic Bacterial Isolates from Infected Diabetic Foot Wounds

Against 182 anaerobe and 241 aerobe strains obtained from diabetic foot infections, doripenem was the most active carbapenem against Pseudomonas aeruginosa (MIC(90), 2 microg/ml), more active than imipenem against Proteus mirabilis, and ertapenem was more active against Escherichia coli and Klebsiella spp. The MIC(50) and MIC(90) values were < or =0.125 microg/ml for methicillin-sensitive Staphylococcus aureus and all streptococci and 0.25/1 for Bacteroides fragilis.

Comparative in vitro activities of carbapenem antimicrobial agents against 264 penicillin-resistant Streptococcus pneumoniae isolates from Korea

We compared in vitro activities of carbapenems against 264 penicillin-resistant Streptococcus pneumoniae (PRSP) isolates. The MIC 50/MIC 90 (μg/mL) values of imipenem, meropenem, ertapenem, and panipenem were 1/1, 0.25/0.25, 0.25/0.5, and 0.125/0.25, respectively. The susceptibility rates to imipenem, meropenem, and ertapenem were 0%, 85.2%, and 99.6%, respectively. Compared with imipenem and meropenem, ertapenem and panipenem had better in vitro activities against PRSP.

Antibacterial activity of carbapenems against clinically isolated respiratory bacterial pathogens in Japan between 2005 and 2006

The current status of the susceptibility of the main respiratory bacterial pathogens was evaluated by analysing the antibacterial activity of 21 drugs, including four carbapenems, against five species of the pathogens isolated between January 2005 and January 2006. A total of 157 strains were studied. Carbapenems inhibited the growth of all of the tested strains of Moraxella catarrhalis, Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus strains at concentrations that were below the breakpoints set by the Japanese Society of Chemotherapy (2 and 1 μg/mL for pneumonia and chronic respiratory tract infection, respectively). However, the majority of methicillin-resistant Staphylococcus aureus strains were resistant to carbapenems. Meropenem, but not the other carbapenems, inhibited the growth of all of the tested strains of Haemophilus influenzae isolates, including β-lactamase-non-producing ampicillin-resistant strains, at concentrations of ≤1 μg/mL. The MIC 50 and MIC 90 of meropenem , 0.25 and 4 μg/mL, against Pseudomonas aeruginosa were the lowest of the carbapenems. By comparing these results with our previous data, it was found that there was no increase in resistance to carbapenems in any of the species tested. Thus, it can be stated that carbapenems have retained their position as key drugs for severe respiratory tract infections.

Orally Active Carbapenem Antibiotics I. Antibacterial and Pharmacokinetic Potential of 2‐Phenyl and 2‐Thienylcarbapenems.

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Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

We discovered an orally active carbapenem, L-084, through pharmacokinetic studies on various prodrug esters of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-l-methyl-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-1-carbapen-2-em-3-carboxylic acid (LJC11,036). L-084 showed a strong antimicrobial activity against Gram-positive and Gram-negative bacteria and exhibited the highest intestinal absorption among synthesized prodrugs of LJC11,036.

Redefining penems

The antimicrobial class of penems has the potential to address most of the relevant resistance issues associated with β-lactam antibiotics because of their exceptionally broad spectrum of antibacterial activity and their intrinsic stability against hydrolytic attack by many β-lactamases including ESBL and AmpC enzymes. The subclass of carbapenems covers the spectrum of hospital pathogens whereas the subclass of penems covers community pathogens. The only currently available penem, faropenem, has a low propensity for resistance development, β-lactamase induction and selection of carbapenem-resistant Pseudomonas aeruginosa. This makes it attractive for the treatment of community-acquired infections and for step-down or sequential therapy following carbapenem treatment without jeopardizing the activity of carbapenems or the entire β-lactam class in the hospital environment.

In vitro activities of three carbapenems against recent bacterial isolates from severely ill patients at Swedish hospitals

To study the in vitro activity of imipenem, meropenem and ertapenem against common pathogens isolated from patients in intensive care, haematology and dialysis/nephrology units at 7 Swedish university hospitals, a total of 788 isolates were collected during 2002-2003. The distribution of the isolates was as follows: Escherichia coli (n = 140), Klebsiella spp. (n = 132), Proteus spp. (n = 97), Enterobacter spp. (n = 113), Pseudomonas aeruginosa (n = 126), Acinetobacter spp. (n = 53) and Enterococcus faecalis (n = 127). The susceptibility to the 3 carbapenems was determined by E-test, and the MICs were interpreted according to SRGA criteria. All 3 carbapenems were highly active against Enterobacteriaceae. The overall susceptibility to imipenem, meropenem and ertapenem was 90%, 98% and 93%, respectively. Against Enterobacteriaceae, Enterobacter spp. excluded, ertapenem had an equal or lower MIC(90) than meropenem. Apart from being the most active carbapenem against Enterobacteriaceae, meropenem was also the most active carbapenem against P. aeruginosa, whereas imipenem was the most active drug against Acinetobacter spp. The carbapenems are still potent antibiotics. With the introduction of ertapenem, and an expected increase in the carbapenem consumption due to an increased prevalence of strains with extended-spectrum beta-lactamases, continuous surveillance of carbapenem resistance appears to be warranted, with special attention to P. aeruginosa, Enterobacter and Proteus spp.

A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084

An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1beta-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.

Orally Active Carbapenem Antibiotics I

In order to design orally active carbapenem antibiotics effective against beta-lactam-resistant pathogens, such as penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), a series of novel 2-phenylcarbapenems and some 2-thienyl derivatives were synthesized and tested for antibacterial activities. These compounds were highly active against PRSP, BLNAR, and major Gram-positive and Gram-negative bacteria that cause community-acquired infections. Their pivaloyloxymethylester-type prodrug exhibited good oral absorption in mice, suggesting that this series of carbapenems were promising as a prototype of novel orally active beta-lactams.

Influence of inoculum size of Staphylococcus aureus and Pseudomonas aeruginosa on in vitro activities and in vivo efficacy of fluoroquinolones and carbapenems

We investigated the effect of inoculum size on MIC, bactericidal activity and the post-antibiotic effect (PAE) of carbapenems (imipenem, panipenem and meropenem) and injectable quinolones (pazufloxacin and ciprofloxacin) against Staphylococcus aureus and Pseudomonas aeruginosa, and also the relationship between in vivo systemic infection by changing the inoculum size injected in mice. Increasing the bacterial inoculum (10(5)-10(8) cfu/mL) had no significant effect on the MIC of any of the tested antimicrobial agents. With the standard inocula (10(6) cfu/mL) of both test strains, all the antimicrobial agents showed bactericidal activity; however, increasing the inoculum size to >10(8) cfu/mL resulted in a reduction in bactericidal activity of all the antimicrobial agents against S. aureus Smith. In contrast, increasing the inoculum size of P. aeruginosa exerted only a minimal influence on the bactericidal activity of fluoroquinolones, but resulted in a reduction in the bactericidal activity of carbapenems. With the standard inoculum size of S. aureus Smith, pre-incubation with fluoroquinolones and carbapenems, except for meropenem, was sufficient to produce PAEs. When the inoculum was increased, the duration of the PAEs of these antimicrobial agents was reduced; however, those of fluoroquinolones were longer than carbapenems. Inoculum size had a greater influence on the in vivo efficacy of carbapenems than that of fluoroquinolones. Our results suggest that decreased bactericidal activity, or the in vitro PAE of carbapenems and fluoroquinolones, is related to the reduced in vivo protective effect against infection caused by high inoculum with S. aureus or P. aeruginosa.

A1.13 Comparative study of In Vitro activity of carbapenems and other β-lactams against Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa and enterobacteriaceae isolated from blood

A1.13 Comparative study of In Vitro activity of carbapenems and other β-lactams against Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa and enterobacteriaceae isolated from blood

Microbiological assay for the determination of meropenem in pharmaceutical dosage form

Meropenem is a highly active carbapenem antibiotic used in the treatment of a wide range of serious infections. The present work reports a microbiological assay, applying the cylinder-plate method, for the determination of meropenem in powder for injection. The validation method yielded good results and included linearity, precision, accuracy and specificity. The assay is based on the inhibitory effect of meropenem upon the strain of Micrococcus luteus ATCC 9341 used as the test microorganism. The results of assay were treated statistically by analysis of variance (ANOVA) and were found to be linear ( r = 0.9999) in the range of 1.5–6.0 μg ml −1, precise (intra-assay: R.S.D. = 0.29; inter-assay: R.S.D. = 0.94) and accurate. A preliminary stability study of meropenem was performed to show that the microbiological assay is specific for the determination of meropenem in the presence of its degradation products. The degraded samples were also analysed by the HPLC method. The proposed method allows the quantitation of meropenem in pharmaceutical dosage form and can be used for the drug analysis in routine quality control.

Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats.

The Ministry of Health and Welfare, Japan banned coadministration of carbapenems, such as panipenem/betamipron (PAPM), meropenem (MEPM), and valproic acid (VPA) because clinical reports have indicated that the coadministration caused seizures in epileptic patients due to lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM, MEPM, and doripenem [S-4661; (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-caboxylic acid monohydrate], a newly synthesized carbapenem. In vitro experiments using monkey liver slices suggested that the apparent synthetic rate of VPA glucuronide (VPA-G) increased in the presence of carbapenems. However, no such increase was observed in the experiment using monkey liver microsomes. Although no increase of uridine 5'-diphosphate D-glucuronic acid was found in monkey liver slices in the presence of carbapenems, potent inhibitory activity of carbapenems for the hydrolysis of VPA-G was found in monkey and rat liver homogenate. In vivo hydrolysis of VPA-G was clearly shown by the existence of VPA in plasma after dosing of VPA-G to rats, and its inhibition by carbapenems was also clearly shown by the negligible levels of VPA in rat plasma after coadministration of carbapenems and VPA-G. These results clearly indicate one of the important causes of drug interaction as follows: carbapenems would inhibit the hydrolytic enzyme, which is involved in the hydrolysis of VPA-G to VPA, resulting in a decrease of plasma concentration of VPA.