Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogens, and Mycoplasma pneumoniae are causative pathogens widely detected in community-aquired respiratory tract infections (RTIs). In Japan, the rapidly increasing prevalence of isolates resistant to multiple antibiotics is becoming a serious clinical problem.Resistanceto β-lactam agents in S. pneumoniae and H. influenzae has occurred due to changes in penicillin-binding proteins (PBPs) encoded by pbp genes.Macrolide resistance in S. pneumoniae and S. pyogenes are mediated by 2 mechanisms-efflux pumping by the mefA gene and methylation of the ribosomal protein by ermB or ermA (ermTR) genes. Macrolide resistance in M. pneumoniae is also mediated by a mutation detected in domain V of the 23 S rRNA gene.
In Japan, although the frequency of S. pneumoniae resistant to new quinolones is 1-2%, we confirmed that the mechanism of resistance occurred due to mutations on the gyrA gene encoding DNA gyrase and those on the parC and parE genes encoding topoisomerase IV.
Resistance caused by qualitative changes in pathogen components is characterized as intermediate resistance not clearly distinguished by conventional susceptibility testing.The resistant level is also the approximate concentration aquired by oral antibiotics dosing of β-lactams, macrolides, and new quinolone agents.Microorganisms bearing mutations in genes encoding resistance-associated enzymes are easily selected by insufficient concentrations of oral antibioitics.
Several actions prevent such resistance from increasing: rapid identification of causative pathogens, vaccination against these pathogens, proper selection and use of antibiotics based on PK/PD, and the establishment of postmarketing surveillance of antibiotics.

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We investigated the combination effect of teicoplanin (TEIC) or vancomycin (VCM) and 6 β-lactams in vitro using 49 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated from neonates who were admitted to the newborn intensive care unit. We combined TEIC with imipenem (IPM), meropenem (MEPM), panipenem (PAPM), cefpirome (CPR), flomoxef (FMOX), or sulbactam (SBT)/ampicillin (ABPC). Synergistic effects were noted in 16 to 48 strains. In particular, the combinations of TEIC and IPM, MEPM, PAPM, or FMOX showed synergistic effects in many strains. Furthermore, 3 strains did not respond to the combination of TEIC and CPR; however, none of the strains exhibited antagonism. Combination with VCM and the above β-lactams produced synergistic effects in 1 to 32 strains. No changes were seen in 1 to 17 strains, and 2 to 6 strains exhibited antagonism. These results suggest that, when combined with the β-lactams tested, TEIC exhibits more potent synergistic effects than VCM.

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The number of methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates with reduced susceptibility to vancomycin (VCM) has been increasing, necessitating the development of measures against infections caused by such strains. We evaluated the antibacterial activity of a new agent, linezolid (LZD), in MRSA strains with varying VCM susceptibility. To do so, we used 3 methods-microbroth dilution to determine minimal growth inhibitory concentrations (MICs), chemiluminescence-based drug susceptibility testing, and the alamaBlue ^® reaction measuring bacterial metabolic activity. MICs of LZD ranged from 0.5μg/mL to 3μg/mL and did not correlate with those of VCM, which ranged from 0.5μg/mL to 8μg/mL. Chemiluminescence assay showed that LZD significantly reduced chemiluminescence intensity linked to bacterial metabolic activity. As the LZD concentration increased, intensity decreased steeply, indicating that LZD strongly suppress bacterial metabolism in short incubation. Although time-kill assays showed that LZD is bacteriostatic, alamaBlue ^® reactions reflecting bacterial metabolic activity showed that LZD had a suppression time curve similar to VCM. This data suggests that the initial time required for LZD to affect bacterial cells was nearly equal to that for VCM.Our data suggests that LZD has a strong antibacterial activity against MRSA strains, including VRSA, and that this drug is a promising new antibiotic for treating MRSA infections.

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The purpose of this study was to evaluate the number of treatment days in panipenem/betamipron (PAPM/BP) and cefozopran hydrochloride (CZOP) regimens, and the pharmacoeconomics of these drugs for the initial treatment of moderate or severe respiratory tract infections. On admission, patients with bacterial pneumoniae, community-acquired pneumonia, or acute secondary exacerbation of chronic pulmonary diseases were allocated randomly to a PAPM/BP or a CZOP therapy group. The number of days of parenteral antibacterial agent (including switched or concomitant ones) therapy and the number of days from admission until all body temperature, CRP and WBC results recovered to their standard values up to 29 days were evaluated. The total treatment cost during hospitalization and during parenteral antibacterial agent therapy were also estimated.
Ninety-two cases (PAPM/BP therapy group, 45 cases; CZOP therapy group, 47 cases) were examined for efficacy and included in the pharmacoeconomic analyses; nonbacterial infection cases were excluded from the 120 enrolled cases. The number of days of parenteral antibacterial agent therapy was 8.0 for the PAPM/BP group and 10.0 for the CZOP group (median, p=0.1480, Wilcoxon rank sum test). The number of days from admission until recovery of the three above-mentioned symptoms was 6.0 for the PAPM/BP group and 8.0 for the CZOP group (median, p=0.0268). Both time periods were shorter numbers for days for the PAPM/BP group than for the CZOP group.
The mean total treatment cost (including the costs of hospitalization, PAPM/BP or CZOP, switched and concomitant antibacterial agents, treatment for drug-related adverse events, and clinical tests) during hospitalization was ¥262, 862 for the PAPM/BP group and ¥276, 720 for the CZOP group (variance;¥-13, 858). The total treatment cost of parenteral antibacterial agent therapy was ¥218, 604 for the PAPM/BP group and ¥236, 421 for the CZOP group (variance;¥-17, 817). The cost was lower for the PAPM/BP group for both comparisons. Although the cost of PAPM/BP itself was higher than that of CZOP, in cost of other items was lower in PAPM/BP group.
The efficacy rates at the end of PAPM/BP or CZOP therapy were 97.8%(44/45) and 87.2%(41/47), respectively. The frequency of drug-related adverse events was 22.0%(13/59) and 32.2%(19/59), respectively. No severe drug-related adverse events occurred in either group, and all the events recovered or improved with the cessation or continuation of the drugs.
In conclusion, PAPM/BP therapy for the initial treatment of moderate or severe respiratory infectious diseases enable a shorter hospitalization and a lower treatment cost than CZOP therapy.

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We evaluated the efficacy and safety of Micafungin (MCFG) as an empiric therapy for febrile neutropenic patients refractory to antibacterial agents. MCFG was administered to patients with either adult hematopoietic disease or solid tumors refractory to anti-microbial agents which are known to be effective for Pseudomonas aeruginosa after performing appropriate laboratory tests and imaging studies. The MCFG dosages ranged from 50 mg to 150 mg once daily, including 300 mg once daily if judged to be necessary by the doctor. MCFG was administered for at least seven days unless any adverse events were observed. The clinical efficacy of MCFG was determined by the doctor based on the general status and from the results of imaging and laboratory tests for each patient. This study was carried out prospectively by the Kyushu Hematology Organization for Treatment (K-HOT) Study Group as a multicentric trial for two years from April 2003. Thirteen cases were analysed (4 males and 9 females) consisting of 12 cases with hematopoietic disease and one case with breast cancer. The patients were classified according to the number of neutrophils that they demonstrated, namely, 6 cases<100/μL, 4 cases 100/μL-500/μL and 3 cases>1, 000/μL, respectively. Efficacy was observed in 11 cases (85%) and the regimen was ineffective in 2 cases (15%). In one of the ineffective cases, MCFG was continued and judged to be effective on the fourteenth day. In the other ineffective case, however, MCFG was discontinued on the seventh day due to liver damage. No fatality occurred during the administration of MCFG, suggesting that MCFG is a safe and effective antifungal agent for patients with febrile neutropenia refractory to antibacterial agents.

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