Surveillance of susceptibility of clinical isolates to panipenem between 2000 and 2003

For the post-marketing surveillance of panipenem/betamipron (PAPM/BP, Carbenin), MICs of injectable beta-lactam antibacterials including PAPM against clinical isolates from 15 medical institutions all over Japan are measured yearly and the incidence rates of resistance in various species are also evaluated. In the first surveillance from June 2000 to March 2001, 1,356 isolates of 28 species were tested, 1,221 isolates of the same 28 species were tested in the second surveillance from April 2001 to March 2002, and 1,403 isolates of the same 28 species were tested in the third surveillance from April 2002 to March 2003. No remarkable changes in the activity of PAPM were observed in these surveillances spanning three years. The activity of PAPM in this study was comparable to that in the studies conducted before Carbenin was launched. This result suggests that PAPM still maintains potent activity. In these surveillances spanning three years, the incidence rates of resistance in various species were as follows (2000.6-2001.3 --> 2001.4-2002.3 --> 2002.4-2003.3): methicillin-resistant Staphylococcus aureus (39.3% --> 43.9% --> 47.3%), penicillin-intermediate Streptococcus pneumoniae (48.9% --> 44.2% --> 25.7%), penicillin-resistant S. pneumoniae (PRSP, 13.8% --> 26.3% --> 43.2%), extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (0.9% --> 0% --> 1.4%), ESBL-producing Klebsiella pneumoniae (3.4% --> 1.3% --> 3.1%), beta-lactamase-producing Haemophilus influenzae (19.2% --> 8.9% --> 42.9%), beta-lactamase-negative ampicillin-resistant H. influenzae (BLNAR, 22.1% --> 30.7% --> 33.0%), and metallo-beta-lactamase-producing Pseudomonas aeruginosa (1.0% --> 4.4% --> 1.0%). PAPM showed the most potent activity among tested drugs against PRSP, whose incidence rate increased notably. BLNAR, whose incidence rates also increased, exhibited low susceptibility to all tested drugs and metallo-beta-lactamase-producing P. aeruginosa also exhibited high resistance. The findings of this surveillance indicate that it is necessary to pay careful attention to the trends of resistant bacteria such as PRSP, BLNAR, and metallo-beta-lactamase producing strains.     

In vitro and in vivo activities of panipenem against penicillin-resistant Streptococcus pneumoniae

Efficacy of panipenem/betamipron (PAPM/BP) against experimental pneumonia caused by penicillin-resistant Streptococcus pneumoniae (PRSP: MIC of benzylpenicillin, > or = 1.56 micrograms/ml) in mice was compared with those of imipenem/cilastatin (IPM/CS), meropenem (MEPM), cefozopran (CZOP), ceftriaxone (CTRX), ampicillin (ABPC), and vancomycin (VCM). The infection was induced by inoculating a PRSP clinical isolate, 9601 (serotype 6) or 10,693 (serotype 19), into ddY male mice intranasally. Drugs were administered subcutaneously at doses of 0.4, 2, and 10 mg/kg, 18, 26, 42, and 50 hours post-infection. Viable cell counts in the lungs were determined 66 hours post-infection. PAPM/BP showed the greatest efficacy against the infections among tested drugs. MICs of PAPM against PRSP 9601 and 10,693 were both 0.125 microgram/ml, which were superior to those of IPM (0.25 and 0.5 microgram/ml, respectively), MEPM (0.5 and 1 microgram/ml, respectively), CZOP (2 and 1 microgram/ml, respectively), CTRX (both 1 microgram/ml), ABPC (both 4 micrograms/ml), and VCM (0.5 and 0.25 microgram/ml, respectively). These results suggest that the potent in vivo activity of PAPM/BP reflects the potent in vitro activity of PAPM. MICs of PAPM, IPM, MEPM, and CZOP against clinical isolates, penicillin-susceptible S. pneumoniae (PSSP: MIC of benzylpenicillin, < or = 0.05 microgram/ml), penicillin-intermediate S. pneumoniae (PISP: MIC of benzylpenicillin, 0.1-0.78 microgram/ml), and PRSP, were tested by an agar dilution method. MIC90s of the drugs against the PSSP, PISP, and PRSP were as follows: PAPM, 0.012, 0.05, and 0.39 microgram/ml; IPM, < or = 0.006, 0.1, and 0.78 microgram/ml; MEPM, 0.05, 0.39, and 1.56 micrograms/ml; and CZOP, 0.2, 0.78, and 6.25 micrograms/ml, respectively. Thus, PAPM showed the most potent activity among tested drugs against clinical isolates of PISP and PRSP.     

The frequency of Streptococcus pneumoniae strains and sensitivity surveillance for several antibiotics in Gifu Prefecture

The frequency and the antibacterial sensitivity of Streptococcus pneumoniae strains isolated from 6 key hospitals (in 5 areas) and 1 otorhinolaryngology clinic in Gifu Prefecture from February to March, 1999, were investigated with several antibiotics. A total of 128 strains of Streptococcus pneumoniae were isolated throughout the study: 47 strains (36.7%) of penicillin-susceptible S. pneumoniae (PSSP), 51 strains (39.8%) of penicillin-intermediate S. pneumoniae (PISP), and 30 strains (23.4%) of penicillin-resistant S. pneumoniae (PRSP); the resistant bacteria being relatively prominent. In these hospitals, PSSP was isolated by 38.8% in all the key hospitals and by 30% in the otolaryngology clinic with almost no discernible difference. PISP was isolated by 63.3%, higher in the otolaryngology clinic and PRSP by 28.6%, higher in the key hospitals conversely. The MIC90s in PISP and PRSP were determined with the antibiotics. In result, only cefditoren (CDTR) showed favorable antibacterial activities with the MIC90 of 0.78 microgram/ml among penicillins or oral cephems. The MIC90s of carbapenems such as imipenem (IPM), meropenem (MEPM), and panipenem (PAPM) were less than 0.39 microgram/ml; particularly, PAPM showed the highest antibacterial activities. Among new quinolones such as tosufloxacin (TFLX), levofloxacin (LVFX), sparfloxacin (SPFX), and ciprofloxacin (CPFX), TFLX showed the highest antibacterial activities with the MIC90 of 0.39 microgram/ml. Other agents showed very low antibacterial activities as the MIC90s were 25 micrograms/ml in minocycline (MINO) and more than 100 micrograms/ml in clarithromycin (CAM) and clindamycin (CLDM).     

In-vitro activity of panipenem against clinical isolates in 2006

The antimicrobial activity of various antibiotics against clinical bacterial isolates recovered from patients with infectious diseases at the medical facilities in the Kanto region between March and September 2006 was evaluated. A total of 1030 clinical isolates were available for susceptibility tests: 420 aerobic Gram-positive organisms, 520 aerobic Gram-negative organisms, 30 anaerobic Gram-positive organisms and 60 anaerobic Gram-negative pathogens. Antimicrobial susceptibility data for Streptococcus pneumoniae and Haemophilus influenzae isolates from pediatric and adult patients were analyzed separately. Panipenem (PAPM), imipenem (IPM), meropenem (MEPM), biapenem (BIPM), doripenem (DRPM), cefozopran (CZOP), cefepime (CFPM), and sulbactam/cefoperazone (SBT/CPZ) were used as test antibiotics. PAPM, IPM and DRPM exhibited excellent in vitro antibacterial activities against methicillin-susceptible Staphylococcus, with all isolates exhibiting a MIC of < or =0.06 microg/mL. Against Streptococcus including penicillin-resistant S. pneumoniae, PAPM demonstrated the strongest antibacterial activity among the carbapenems with a MIC range of < or =0.06 to 0.12 microg/mL. Against Enterobacteriaceae, MEPM showed the strongest antibacterial activity, and PAPM had comparable activity to IPM. Against the extended-spectrum beta-lactamase producing Escherichia coli, Klebsiella species and Proteus species, the MICs for the cephems were high, however, those for the carbepenems were low. Against H. influenzae, PAPM had comparable activity to IPM. With respect to anaerobes, each of the carbapenems tested demonstrated almost the same strong antibacterial activity. In conclusion, 13 years has passed since PAPM was launched in 1993, PAPM still maintains potent antibacterial activity and is considered an effective antimicrobial agent for various types of infectious diseases.     

Changes in the antibacterial activity of chemotherapeutic agents (especially carbapenems) for 10 species of clinical isolates between 1994 and 1996. Surveillance group of the sensitivities of clinical isolates to antibacterial agents

During October and December of each year of from 1994 to 1996, 3,849 strains of 10 species of bacteria were isolated from clinical materials in 21 institutions nationwide. The minimum inhibitory concentrations (MICs) for these bacteria of four carbapenems (imipenem [IPM], panipenem [PAPM], meropenem [MEPM], and biapenem [BIPM]) and other representative antibacterial agents were measured to investigate annual changes in antibacterial activity. Carbapenems showed potent activity against methicillin-sensitive S. aureus (MSSA), S. pneumoniae, E. faecalis, H. influenzae, E. coli, K. pneumoniae, E. cloacae, S. marcescens, and the B. fragilis group, with the activity being stable. However, these drugs showed weak activity against methicillin-resistant S. aureus (MRSA) and P. aeruginosa. The antibacterial activity (MIC90) against the tested organisms generally remained stable. Particularly, there was annual improvement of the MIC90 values of IPM and BIPM for S. pneumoniae, as well as the values of IPM and PAPM for H. influenzae, and those of IPM, PAPM, and BIPM for S. marcescens. On the other hand, the activity of carbapenems (including IPM) against MRSA was not necessarily strong, but there was annual improvement of MIC90 values.     

Bactericidal activity of biapenem against various bacteria

The bactericidal activity of biapenem (BIPM), a new carbapenem agent, against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia marcescens was compared with those of imipenem (IPM), panipenem (PAPM), meropenem (MEPM) and ceftazidime (CAZ). The bactericidal activity of BIPM against S. aureus was equal to those of IPM, PAPM and MEPM. Against E. coli and K. pneumoniae, BIPM showed higher bactericidal activity than IPM and PAPM. Against P. aeruginosa, BIPM showed excellent bactericidal activity campared with IPM. The killing speeds of BIPM and IPM were obviously the most rapid among four carbapenems. BIPM showed a strong bactericidal activity against 5 species of bacteria including P. aeruginosa.     

Efficacy of injectable carbapenems for respiratory infections caused by Streptococcus pneumoniae and Haemophilus influenzae with Monte Carlo simulation

Streptococcus pneumoniae and Haemophilus influenzae are two major pathogens for respiratory tract infections, and those infections might cause critically ill patients. We performed the analysis with Monte Carlo Simulation for 253 strains of S. pneumoniae and 309 strains of H. influenzae isolated in the Gifu prefecture in 2002 and 2003. As for the pneumococcal infection in patient with good immunological response, good clinical effect might be obtained by panipenem/betamipron (PAPM/BP) 500 mg, imipenem/cilastatin (IPM/CS) 500 mg, meropenem (MEPM) 500 mg and biapenem (BIPM) 300 mg, b.i.d., while for immunocompromised hosts or infections by penicillin-resistant Streptococcus pneumoniae (PRSP), PAPM/BP, 500 mg, b.i.d., or IPM/CS 500 mg, MEPM 500 mg, t.i.d. or BIPM 600 mg, b.i.d. would be recommended. As for the infections caused by H. influenzae, in patient with good immunological response, good clinical effect might be obtained by MEPM 500 mg, b.i.d or PAPM/BP 1000 mg, b.i.d., while for immunocompromised hosts, MEPM 500 mg, t.i.d. would be recommended. Monte Carlo Simulation would be one of the useful tools for appropriate antimicrobial chemotherapy also against respiratory infections.     

Antimicrobial activities of meropenem against clinically isolated strains in 1997

In order to evaluate antimicrobial activity of meropenem (MEPM), minimum inhibitory concentrations (MICs) of MEPM and control drugs were determined against clinical isolates in 1997. The results were as follows; 1. Antimicrobial activities of MEPM against Gram-positive bacteria were stronger than those of cephems (CEPs) and were approximately equal to those of imipenem (IPM) and panipenem (PAPM). 2. Carbapenems showed strong antimicrobial activities against Enterobacteriaceae, Glucose non-fermentative Gram-negative rods and Bacteroides fragilis group that were multiple drug resistant including the third generation CEPs. Antimicrobial activities of MEPM against these organisms were stronger than those of IPM and PAPM. By comparing antimicrobial activities of MEPM against Gram-negative bacteria in 1997 with those obtained in 1993, increase of resistance was not observed. 3. MIC-ranges of MEPM were low against the resistant strains of Pseudomonas aeruginosa to IPM and PAPM. It was considered that these resistant strains were not expressing oprD products (D2 porin protein), forming main outer membrane porin channels of carbapenems and basic amino acids.     

Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa isolated in major hospitals in Nagano prefecture

We determined the minimum inhibitory concentration (MIC) of various antimicrobial agents against 140 strains of Streptococcus pneumoniae, 131 strains of Haemophilus influenzae and 178 strains of Pseudomonas aeruginosa isolated from respiratory organs in 28 affiliated hospitals in Nagano prefecture between December 2002 and February 2003. The results of this report were as followed: 1. All 140 strains of S. pneumoniae were classified into 3 groups; penicillin-susceptible S. pneumoniae (PSSP) (47.1%), penicillin-intermediate S. pneumoniae (PISP) (43.6%) and penicillin-resistant S. pneumoniae (PRSP) (9.3%). 2. Carbapenems and glycopeptide (vancomycin) had highly potent antimicrobial activity against PISP and PRSP like PSSP. However, some of PISP or PRSP isolates were resistant to cephalosporins and a fluoroquinolone (levofloxacin). 3. All 131 strains ofH. Influenzae were also classified into three groups; ampicillin sensitive H. influenzae (73.3%), beta-lactamase producing ampicillin resistant H. influenzae (BLPAR) (8.4%) and beta-lactamase negative ampicillin resistant H. influenzae (BLNAR) (18.3%). 4. Carbapenems and a fluoroquinolone had highly potent antimicrobial activity against BLPAR and BLNAR. However, there were clear differences among 4 carbapenems for the antimicrobial activity. Ceftriaxone (CTRX) was the most active among cepharosporins in this study. 5. The rate of P. aeruginosa isolates resistant to carbapenems, a fluoroquinolone and aminoglycosides were about 11 to approximately 16%, 15% and 0.6 to approximately 8%, respectively. None of the strains was resistant to all 3 antimicrobial classes, but 3 strains were resistant to combination of 2 classes. 6. The MIC50 and MIC90 values of various antibiotics against S. pneumoniae, H. influenzae and P. aeruginosa were different in all 4 regions. In conclusion, the antimicrobial surveillance programs are important for guiding empiric therapy and for focusing interventional control of antimicrobial resistance in regions and hospitals.     

Surveillance of susceptibility of clinical isolates to cefpodoxime between 2000 and 2003

For the post-marketing surveillance of cefpodoxime proxetil (CPDX-PR, Banan), MICs of oral cephem antibacterials including CPDX against clinical isolates from 15 medical institutions all over Japan are measured yearly and the incidence rates of resistance in various species are also evaluated. In the first surveillance from June 2000 to March 2001, 1,091 isolates of 22 species were tested, 993 isolates of the same 22 species were tested in the second surveillance from April 2001 to March 2002, and 1,115 isolates of the same 22 species were tested in the third surveillance from April 2002 to March 2003. No remarkable changes in the activity of CPDX were observed against most of the species in these surveillances spanning three years and in comparison with that in the studies conducted before Banan was launched. In the study, CPDX as well as other cephem antibacterials showed a gradual decrease in activity against all the strains of Streptococcus pneumoniae and Haemophilus influenzae in proportion to the increase in the incidence rates of penicillin-resistant S. pneumoniae (PRSP) and beta-lactamase-negative ampicillin-resistant H. influenzae (BLNAR). A small percentage of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, which are high-resistant strains, were isolated. The findings of this surveillance indicate that it is necessary to pay careful attention to the trends of resistant bacteria such as PRSP, BLNAR, and ESBL-producing strains.     

Antimicrobial susceptibility of Streptococcus pneumoniae and Haemophilus influenzae isolated in major hospitals in Nagano Prefecture

We determined the minimum inhibitory concentration (MIC) of various antimicrobial agents against 108 strains of Streptococcus pneumoniae and 144 strains of Haemophilus influenzae isolated from respiratory organs in the First Department of Internal Medicine, Shinshu University, and affiliated hospitals between January 2000 and February 2001. The following results were obtained. 1. Fifty-one (47.2%), 56 (51.9%), and 1 (0.9%) of 108 strains of S. pneumoniae were classified as penicillin-susceptible S. pneumoniae (PSSP), penicillin-intermediate S. pneumoniae (PISP), and penicillin-resistant S. pneumoniae (PRSP), respectively. 2. Three carbapenems had potent antimicrobial activity against PISP and PRSP. Furthermore, none of the strains were highly resistant (MIC > 2 micrograms/ml) to benzylpenicillin, ampicillin (ABPC), sulbactam/ampicillin (SBT/ABPC), cefotaxime (CTX), or cefepime (CFPM). 3. Eleven (7.6%) and 6 (4.2%) of 144 strains of H. influenzae were classified as beta-lactamase-producing ABPC-resistant strains and beta-lactamase negative ABPC-resistant H. influenzae (BLNAR), respectively. Levofloxacin, sulfamethoxazole/trimethoprim, and meropenem had potent antimicrobial activity against these resistant strains. 4. BLNAR strains were more highly resistant to CTX, CFPM, SBT/ABPC, and cefaclor than beta-lactamaseproducing strains. 5. In our surveillance study regarding clinical isolates of S. pneumoniae and H. influenzae from respiratory organs in Nagano prefecture, there were regional differences in the isolation rate and antimicrobial susceptibility. The isolation rates of resistant strains were lower than those reported in a nationwide survey.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2004

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 907 strains of Gram-positive bacteria, 1790 strains of Gram-negative bacteria, and 192 strains of anaerobic bacteria obtained from 30 medical institutions during 2004 was measured. The results were as follows; 1. MIC90 of MEPM for almost all of enterobacteriaceae and Haemophilus influenzae were 4-fold to 32-fold lower than those of other carbapenems. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and H. influenzae. MEPM were active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus. 2. As for Pseudomonas aeruginosa, imipenem (IPM) showed high cross-resistant rate againt meropenem-resistant P. aeruginosa (87.9%). MEPM showed low cross-resistant rate both againt IPM-resistant P. aeruginosa (49.2%) and ciprofloxacin-resistant P. aeruginosa (38.0%). 3. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli, 8.0% (2 strains) in Citrobacter koseri, 2.5% (3 strains) in Klebsiella pneumoniae, 2.5% (2 strains) in Enterobacter cloacae, 0.9% (1 strains) in Serratia marcescens, and 2.2% (2 strains) in Proteus mirabilis. The proportion of metallo-beta-lactamase strains was 1.6% (5 strains) in P. aeruginosa. 4. Of all species tested, Peptostreptococcus spp. was the only species, which MIC90 of MEPM was more than 4-fold higher than that in our previous study using clinical isolates during 2002 (0.25 microg/ml --> 1 microg/ml). Therefore, there is almost no siginificant decrease in susceptibility of clinical isolates to meropenem. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem at present, 9 years after available for commercial use.     

Comparative antibacterial activity of carbapenems against P. aeruginosa (1)

Comparative antibacterial activity of imipenem (IPM), panipenem (PAPM), meropenem (MEPM) and biapenem (BIPM) was determined against 288 clinical isolates of P. aeruginosa collected from various hospitals in 2000. The order of activity by comparison of MIC50/MIC80/MIC90 was: MEPM (1/4/8 micrograms/ml) > BIPM (1/4/16 micrograms/ml) > IPM (2/4/16 micrograms/ml) > PAPM (8/16/32 micrograms/ml). Moreover, the order of activity against 75 strains of P. aeruginosa (MIC of CAZ, AZT was > or = 16 micrograms/ml and MIC of IPM, MEPM was < or = 8 micrograms/ml) by comparison of MIC50/MIC80/MIC90 was: BIPM (1/2/8 micrograms/ml) > or = MEPM (1/4/8 micrograms/ml) > or = IPM (2/2/8 micrograms/ml) > PAPM (8/16/16 micrograms/ml). Judging from both correlation between the MICs of carbapenems and relationship between class C beta-lactamase activity and drug susceptibility of carbapenems, it becomes apparent that carbapenems, especially BIPM and MEPM will be useful for treatment of antipseudomonal cephem resistant pseudomonas infection.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2006

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 876 strains of Gram-positive bacteria, 1764 strains of Gram-negative bacteria, and 198 strains of anaerobic bacteria obtained from 30 medical institutions during 2006 was measured. The results were as follows; 1. MEPM was more active than the other carbapenem antibiotics tested against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MEPM was also active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus. 2. As for Pseudomonas aeruginosa, all of the MEPM-resistant strains were resistant to imipenem (IPM). MEPM showed low cross-resistant rate both againt IPM-resistant P. aeruginosa (41.8%) and ciprofloxacin-resistant P. aeruginosa (33.3%). 3. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 4.3% (6 strains) in Escherichia coli, 1.1% (1 strain) in Citrobacter freundii, 21.7% (5 strains) in Citrobacter koseri, 3.1% (4 strains) in Klebsiella pneumoniae, 3.3% (3 strains) in Enterobacter cloacae, 0.8% (1 strain) in Serratia marcescens, and 4.9% (2 strains) in Providencia spp. The proportion of metallo-beta-lactamase strains was 3.1% (10 strains) in P. aeruginosa. 4. Of all species tested, there were no species, which MIC90 of MEPM was more than 4-fold higher than those in our previous study. Therefore, there is almost no significant decrease in susceptibility of clinical isolates to meropenem. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem at present, 11 years after available for commercial use.     

Evaluation of antibiotics by the method of initial bactericidal activity

Minimum inhibitory concentration (MIC) has been generally used to evaluate the activity of antimicrobial agents. However, there is some discrepancy between clinical efficacy and the MIC value. We studied the relationship between initial bactericidal activity of imipenem (IPM), panipenem (PAPM), meropenem (MEPM), ceftazidime (CAZ) and amikacin (AMK) and the respective MIC values against Pseudomonas aeruginosa PAO1. Initial bactericidal activity was defined as percent reduction of initial bacterial cell concentration (10(6) cells/ml) after 1 hour incubation following addition of antibiotic. The concentration of antibiotic used in this experiment was the blood level of each antibiotic at 3 hours after administration by drip infusion of the usual dose (IPM, PAPM and CAZ were 1 g for 1 hour drip infusion, MEPM was 1 g for 0.5 hours drip infusion and AMK was 200 mg for 1 hour drip infusion, respectively). The antibiotic concentration of IPM, PAPM, MEPM, CAZ and AMK were 8.77 micrograms/ml, 6.37 micrograms/ml, 4.12 micrograms/ml, 12.0 micrograms/ml and 5.18 micrograms/ml, respectively. MICs of IPM, PAPM, MEPM, CAZ and AMK were 2 micrograms/ml, 64 micrograms/ml, 1 microgram/ml, 1 microgram/ml and 2 micrograms/ml, respectively. Initial bactericidal activity of IPM, PAPM, MEPM, and CAZ against P. aeruginosa PAO1 was 98.2%, 86.1%, 48.1%, and 43.4% reduction in bacterial concentration, respectively. AMK shows the strongest initial bactericidal activity with more than 99.9%. The killing speed of IPM was obviously the most rapid among the three carbapenems. The MIC of PAPM was significantly higher than the other antibiotics, and the initial bactericidal activity of PAPM was second to IPM. We can classify antibiotics into two groups based on initial bactericidal activity against P. aeruginosa; one class is antibiotics having rapid initial killing such as AMK, IPM and PAPM, the other is CAZ, MEPM showing slow initial killing.     

Antibacterial activity of biapenem against recent clinical isolates

Antibacterial activity of biapenem (BIPM) against clinical isolates of 8 species between 2000 and 2002 was compared with those of imipenem/cilastatin (IPM/CS), meropenem (MEPM), panipenem/betamipron (PAPM/BP) and ceftazidime (CAZ). The MICs of biapenem for Gram-positive bacteria were higher than those of IPM/CS and PAPM/BP, equal to those of MEPM and lower than those of CAZ. The MICs of BIPM for Gram-negative bacteria were higher than those of MEPM, equal to those of IPM/CS and PAPM/BP, and lower than those of CAZ. Antibacterial activity of BIPM against Pseudomonas aeruginosa was equal to those of IPM/CS and MEPM and superior to those of PAPM/BP and CAZ. In conclusion, BIPM showed broad antibacterial activity against both Gram-positive and Gram-negative clinical isolates. These results suggest that BIPM is useful for the treatment of various bacterial infections.     

Orally active carbapenem antibiotics I. Antibacterial and pharmacokinetic potential of 2-phenyl and 2-thienylcarbapenems

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.     

In vitro combined effect of meropenem and various antimicrobial agents against beta-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae and penicillin-resistant Streptococcus pneumoniae

As a basic study of combination therapy for bacterial meningitis, in vitro combined effect of meropenem (MEPM) and various antimicrobial agents against beta-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR) and penicillin-resistant Streptococcus pneumoniae (PRSP) was investigated. The following findings were obtained. 1. In the checker board assay using 23 clinical isolates of BLNAR, MEPM+cefotaxime (CTX), MEPM+ampicillin (ABPC), and MEPM+rifampicin (RFP) showed synergistic effect (21 strains, 6 strains, 4 strains, respectively) or additive effect (2 strains, 17 strains, 19 strains, respectively). 2. In the checker board assay using 19 clinical isolates of PRSP, MEPM+CTX, MEPM+teicoplanin (TEIC), and MEPM+RFP showed synergistic effect (5 strains, 8 strains, 1 strain, respectively), additive effect (14 strains, 11 strains, 17 strains, respectively) or indifference (0 strain, 0 strain, 1 strain, respectively). 3. The time-kill assay with BLNAR demonstrated synergistic bactericidal effect of MEPM+CTX and MEPM+RFP, but not MEPM+ABPC. 4. The time-kill assay with PRSP demonstrated synergistic or additive bactericidal effect of MEPM+CTX, MEPM+TEIC, and MEPM+RFP. 5. There were no antagonistic effect in any combination tested in this study. These findings suggest that combination therapy with MEPM and various antimicrobial agents tested in this study are useful in treating bacterial meningitis caused by BLNAR and PRSP.     

Antibacterial activities of piperacillin for several resistant strains from respiratory infections--in reference to MRSA, PRSP, BLNAR and P. aeruginosa

We investigated antibacterial activities of piperacillin (PIPC) for several resistant strains of bacteria isolated from patients with respiratory infections from 1998 to 1999 in comparison with reference drugs and obtained the following results: 1. The majority of methicillin resistant strains of Staphylococcus aureus (MRSA) showed high resistance to beta-lactam antibiotics including PIPC. 2. MIC90 of PIPC was 1 and 4 micrograms/ml for penicillin intermediate and penicillin resistant strains of Streptococcus pneumoniae (PISP/PRSP), respectively. 3. MIC90 of PIPC was 0.25 microgram/ml for beta-lactamase negative ampicillin resistant strains of Haemophilus influenzae (BLNAR), showing higher antibacterial activity than the reference drugs. 4. PIPC exhibited the MICs of 8 micrograms/ml or less in 19 out of 40 IPM resistant (MIC > or = 16 micrograms/ml) strains of Pseudomonas aeruginosa. From these results, PIPC is proved to possess extremely favorable antibacterial activities for BLNAR, and it was suggested that PIPC might be a drug of choice even for PISP/PRSP and IPM resistant strains of P. aeruginosa.     

Study on antibiotics susceptibility and mechanism of carbapenem-resistance in clinical isolates of Pseudomonas aeruginosa]

The susceptibility of 260 strains of Pseudomonas aeruginosa to several antibiotics and the mechanism of resistance to carbapenems were investigated. The number of strains of P. aeruginosa moderately resistant or resistant to ofloxacin, ceftazidime and imipenem (IPM) were 76 (29.2%), 31 (11.9%) and 30 (11.5%), respectively. There was no clear relationship between the drug resistance of P. aeruginosa and serum type. Fourteen strains (46.6%) out of 30 IPM-resistant strains were susceptible to meropenem (MEPM). Twenty seven (90.0%) IPM-resistant strains showed cross resistant to panipenem (PAPM), and 12 strains (44.4%) out of the 27 strains showed high susceptibility to MEPM. P. aeruginosa becomes resistant to IPM and PAPM only by the decrease in the outer membrane permeability of these carbapenems. In contrast, P. aeruginosa becomes equally resistant to MEPM by concurrent occurrence of the increase in the efflux of the antibiotics and the decrease in the outer membrane permeability of the antibiotics. The possibility that both mechanisms are taken place concurrently in P. aeruginosa is considered to be low, and it was also supported by the results of the present study.