Quinolone resistance is induced by mutations on target enzymes such as DNA gyrase (gyrase) and DNA topoisomerase IV (topo IV), and by mutations that prevent drug accumulation due to changes in outer membrane permeability and/or activation of the efflux pump. Mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene, which encodes A subunits of gyrase, and in the parC gene, which encodes A subunits of topo IV, usually cause resistance specifically to quinolones. In Escherichia coli, the hotspots most favored for causing high-level resistance to quinolones are at serine-83 and aspartic acid-87 of GyrA, and at serine-80 and glutamic acid-84 of ParC. Mutations in both gyrA and parC are common in clinical isolates highly resistant to quinolones. Mutations in the gyrB gene, which encodes B subunits of gyrase, and in the parE gene, which encodes B subunits of topo IV, are rare in clinical isolates but important to understanding the molecular mechanism of quinolone resistance. This mechanism in topo IV may be similar to that in gyrase; sites and amino acid changes in quinolone-resistant topo IV mutations are similar to those of quinilone-resistant gyrase mutations in most cases. Quinolones have 2 target enzymes, i. e., gyrase and topo IV, and the more sensitive enzyme determines the quinolone susceptibility of organisms. The primary target of most quinolones appears to be topo IV in gram-positive bacteria and has been described as a secondary target in gram-negative bacteria, but primarily in Streptococcus pneumoniae, sparfloxacin targets gyrase. Thus, whether topo IV or gyrase is the primary quinolone target depends on both the organisms and the compound tested. Another mechanism of resistance, the expression of efflux-pump systems, is attracting much attention in current antibiotic resistance research. Quinolone efflux of appears to be the major cause of decreased drug accumulation; for Staphylococcus aureus, the efflux pump involved in norfloxacin resistance is NorA, and for Streptococcus pneumoniae, PmrA. Pseudomonas aeruginosa possesses at least 4 different efflux pumps-MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM systems-whose activation produces an antibiotic multiresistant phenotype. The genetic landscape of quinolone resistance is more complicated than previously thought, but a new feature in this approach is the availability of the nearly complete genome sequences of major humam pathogens.

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Erythromycin has been reported to have a potent anti-inflammatory activity. We have reported that erythromycin increased the endogenous glucocorticoid levels in mice, and suggested that the agent has an anti-inflammatory activity. Since carbocisteine, an expectorant, was reported to protect against bleomycin-induced pneumonitis, we studied the effect of carbocisteine, as well as ambroxol, on erythromycin-induced gmcocorticomogenesis in mice. Intraperitoneal administration of erythromycin (100mg/kg) and carbocisteine (300mg/kg) increased serum glucocorticoid levels, whereas ambroxol (up to 10mg/kg) did not affect the levels. Concurrent administration of carbocisteine (50, 100 mg/kg) significantly enhanced the erytheomycin-induced increase in serum glucocorticoid levels. On the other hand, concurrent administrtration of ambroxol did not increase the erythromycin-induced glucocorticoidogenesis. These results suggest that concurrent administration of carbocisteine, not ambroxol, enhances the antiinflammatory activity of erythromycin through the increase of erythromycin-induced glucocorticoidogenesis.

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The risk factors for the development of intractable airway infections are said to be a patient age of over 65 years, an FEV 1.0% of less than 50%, a duration of illness of over 10 years, more than three relapses in one year, and a perennial production of sputum.Resistance to etiologic agents is expected to occur more frequently in patients who have any of these risk factors.The present study examined 144 specimens from which Haemophilus influenzae were isolated;the specimens were obtained from 125 patients with respiratory disorders between April and December 1998.20β-lactamase-positive (BLP) strains and 13β-lactamase-negative ampicillin (ABPC)-resistant (BLNAR) strains were used as, β-lactam-resistant microorganisms;the remaining 111 strains were used as sensitive organisms to study the relationship between patient background and pathologic state, as well as the development of resistance to β-lactam compounds.No relationship was observed between the development of resistance in these microorganisms and age, sex, history of smoking, type of infection, presence of any underlying diseases or complications, duration of illness, FEV 1.0%, PaO₂, or history of antibacterial medication.The proportions of H. influenzae that were resistant to β-lactam compounds in various patients groups were as follows: 64% in cases who had four or more relapses in one year, 20%(p=0.0008) in cases with fewer than four relapses, 36% in patients who produced purulent or mucopurulent sputum before the infection occured, 18%(p=0.023) in those producing no sputum or mucous sputum when uninfected, 42% in cases with simultaneous Pseudomonas aeruginosa infections, 29% in cases with recurrent H. influenzae infections, 19%(p=0.031) in cases in where bacteria were consistently not detected, 32% in cases treated continuously with macrolide preparations, and 18%(p=0.046) in cases without macrolide administration. Significant differences are indicated by the p values noted above.Thus, the risk factors for, β-lactam-resistant H. influenzae are as follows: 1) Four or more relapses within one year;2) the production of purulent or mucopurulent sputum prior to infection;3) colonization by P.aeruginosa or H. influenzae, and 4) dependence on continuous macrolide administration.

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We conducted combination therapy with cyclophosphamide, vincristine, and dacarbazine (CVD) for recurrent malignant pheochromocytoma. A 41-year-old woman with ectopic malignant pheochromocytoma had metastases to the liver and left cervical lymph node 7 months after removal of theprimary lesion. At the beginning of October 1999, she was treated with fhe CVD regimen. After 3 courses of chemotherapy, metastases disappeared and urinary catecholamine decreased to normal levels. Only serum noradrenalin was not normalized by the end of treatment. Nine months later, computed tomography (CT) scans of the cervix andabdomen showed recurrent tumors. The woman was treated with the CVD regimen again, but tumor size and biochemical tumor markers remained unchanged. The CVD regimen was thus effective as a primary treatment for malignant pheochiromocytoma with metastases.

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The 6-year cefdinir (CFDN) postmarketing surveillance program (1991-1997) was completed and an application was made for CFDN reapproval in 1997. CFDN safety and efficacy were reconfirmed by reexamination resulting in reapproval in 1999. The surveillance program included 11, 352 cases from 2, 448 institutions nationwide.Of these, 11, 082 were evaluated for safety and 9, 449 for efficacy.The summary is as follows:
1. The incidence of adverse reactions including abnormal laboratory findings was 1.12%(124/11, 082), lower than the incidence (8.74%, 230/2, 633) in premarketing studies.Frequently observed adverse reactions were liver and biliary system disorders (0.51%), e. g., increased AST (GOT) and ALT (GPT);gastrointestinal system disorders (0.39%), e. g., diarrhea;skin and appendages disorders (0.39%), e. g., exanthema;and metabolic and nutritional disorders (0.10%), e. g., increased Al-P.
2. Clinical efficacy by diagnosis in 9, 449 cases ranged from 82.5% to 100.0%, with a mean of 89.8%. Elimination of pathogenic microorganisms exceeded 90% for almost all bacteria.Both efficacy and elimination were approximately equivalent to those in premarketing studies.

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