Clearance of Fungal Burden during Treatment of Disseminated Histoplasmosis with Liposomal Amphotericin B versus Itraconazole

Animal studies have shown that fungal burden correlates with survival during treatment with new antifungal therapies for histoplasmosis. The purpose of this report is to compare the clearance of fungal burden in patients with histoplasmosis treated with liposomal amphotericin B versus itraconazole. In two separate closed clinical trials that evaluated the efficacy of liposomal amphotericin B and itraconazole treatment of disseminated histoplasmosis in patients with AIDS, blood was cultured for fungus and blood and urine were tested for Histoplasma antigen. The clinical response rates were similar; 86% with liposomal amphotericin B (n = 51) versus 85% with itraconazole (n = 59). Of the patients with positive blood cultures at enrollment, after 2 weeks of therapy cultures were negative in over 85% of the liposomal amphotericin B group versus 53% of the itraconazole group (P = 0.0008). Furthermore, after 2 weeks, median antigen levels in serum fell by 1.6 U in the liposomal amphotericin B group versus 0.1 U in the itraconazole group (P = 0.02), and those in urine fell by 2.1 U in the liposomal amphotericin B group and 0.2 U in the itraconazole group (P = 0.0005). The more rapid clearance of fungemia supports the use of liposomal amphotericin B rather than itraconazole for initial treatment of moderately severe or severe histoplasmosis.     

Therapeutic effect of the triazole Bay R 3783 in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis.

A new triazole, Bay R 3783, was compared with ketoconazole, itraconazole, and fluconazole, which were given via the alimentary tract at three dosages, and amphotericin B, which was given at 1 mg/kg intraperitoneally, in murine models of the systemic mycoses coccidioidomycosis, histoplasmosis, and blastomycosis. In a pulmonary coccidioidomycosis model, Bay R 3783, fluconazole, and itraconazole were essentially equally efficacious and more active than ketoconazole in protecting mice against death; but they were inferior to amphotericin B. In a short-term organ load experiment, Bay R 3783 and amphotericin B were equally effective and were more effective than the other drugs in reducing the amount of Coccidioides immitis in the lungs. Against meningocerebral coccidioidomycosis, Bay R 3783, itraconazole, and fluconazole at 25 mg/kg and amphotericin B prevented death only during therapy, with mortalities ensuing shortly thereafter. In mice with systemic histoplasmosis, Bay R 3783 and itraconazole at 25 mg/kg and amphotericin B prevented death in all mice through a 44-day observation period. Clearance of Histoplasma capsulatum from organs was similar in mice treated with Bay R 3783 and itraconazole; this clearance was greater than that in mice treated with ketoconazole and fluconazole but less than that in mice treated with amphotericin B. In mice with systemic blastomycosis, Bay R 3783 at 25 mg/kg yielded 90% survivors at 60 days, which was greater than that achieved with amphotericin B (60%) or itraconazole (30%). Clearance of Blastomyces dermatitidis from the lungs was greatest with Bay R 3783, followed by that with amphotericin B, itraconazole, fluconazole, and ketoconazole, in that order. Therefore, Bay R 3783 showed effectiveness comparable to or exceeding those of itraconazole and fluconazole and exceeding that of ketoconazole against these systemic mycoses in mice.     

An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia

OBJECTIVES: This trial studied the efficacy and safety of itraconazole and fluconazole in the prevention of invasive fungal infections in neutropenic patients with haematological malignancies. PATIENTS AND METHODS: An 8 week, open-label, randomized, parallel-group, multicentre trial comparing itraconazole oral solution (2.5 mg/kg twice daily; N=248) with fluconazole oral solution or capsules (400 mg daily; N=246) in 494 patients with anticipated profound neutropenia (i.e. neutrophil count expected to be <500 cells/mm3 for at least 10 days) from tertiary care centres. RESULTS: Invasive fungal infections were reported for 4 out of 248 patients (1.6%) in the itraconazole group and 5 out of 246 patients (2.0%) in the fluconazole group. Invasive Aspergillus infections were proven for 2 out of 248 patients (0.8%) in the itraconazole group and 3 out of 246 patients (1.2%) in the fluconazole group. For both the ITT and profoundly neutropenic populations, no differences were detected between treatment groups in proven or suspected invasive fungal infections or other endpoints. The mortality rates owing to proven invasive fungal infections were 2 out of 248 patients (0.8%) for the itraconazole group and 3 out of 246 patients (1.2%) for the fluconazole group. There was also no difference between treatment groups in the number of patients who recovered from neutropenia or in the duration of neutropenia. More discontinuation of drug intake owing to nausea and more hypokalaemia occurred in the itraconazole group, other adverse events and the total number of adverse events were similar in both groups. CONCLUSIONS: In this study there were no differences in the efficacy and safety of itraconazole and fluconazole prophylaxis in neutropenic patients with haematological malignancies.     

Histoplasmosis: update 1998

Histoplasmosis is an important cause of morbidity and death in HIV-infected patients. Significant developments concerning the diagnosis, treatment, follow-up, and prophylaxis of histoplasmosis are discussed. Itraconazole is highly effective at both inducing and maintaining remission in mild to moderate cases of disseminated histoplasmosis. In cases of moderate to severe disease, amphotericin B remains the therapy of choice. A table presents comparative results of treating mild to moderate disseminated histoplasmosis with the drugs itraconazole versus fluconazole. Currently, no resistance of Histoplasmosis capsulatum to itraconazole has emerged from prolonged therapy. Maintenance therapy for life is recommended for patients with CD4 counts less than 100; however, feasibility studies are evaluating the possibility of its discontinuance. While no prophylaxis recommendations currently exist, patients with CD4 counts less than 100 who are exposed to histoplasmosis are recommended to begin oral itraconazole (200 mg daily).     

Hypothesis on the mechanism of resistance to fluconazole in Histoplasma capsulatum.

An AIDS patient with disseminated histoplasmosis who improved during treatment with fluconazole but remained fungemic and subsequently relapsed is described. Isolates obtained from blood during therapy showed a progressive increase in fluconazole MIC from 0.625 to 20 micrograms/ml. The pretreatment, or parent, isolate and the posttreatment, or relapse, isolate demonstrated identical genetic patterns by PCR fingerprinting with three different primers. Fluconazole was less potent inhibitor of the growth of the relapse isolate than of the pretreatment isolate (50% inhibitory concentration [IC50] = 11.7 microM), while itraconazole was more potent (relapse isolate IC50 = 0.0011 microM versus pretreatment isolate IC50 = 0.0064 microM). Neither the increased sensitivity to itraconazole nor the decreased activity of fluconazole on the growth of the relapse isolate results from changes in the intracellular content of these agents. To reach 50% inhibition of ergosterol synthesis in both the parent and relapse isolates, about 2 nM itraconazole was needed; with fluconazole, 50% inhibition was achieved at 20.9 microM and 55.5 microM, respectively. Resistance to fluconazole may develop during treatment and results from decreased sensitivity of ergosterol synthesis.     

Correlation of Histoplasma capsulatum polysaccharide antigen with the severity of infection in murine histoplasmosis

We sought to determine if Histoplasma capsulatum polysaccharide antigen (HPA) levels correlate with the extent of infection in murine of histoplasmosis. Separate groups of mice were inoculated intratracheally with varying numbers of H. capsulatum yeast cells. After 1 week, HPA levels and fungal burden (quantitative culture of lung and spleen and histopathologic stain of lung) were determined in lung and spleen, and HPA levels in serum. HPA levels, cultures and histopathological stain results of lung and spleen tissue showed a direct correlation with increasing inoculum size. HPA levels in serum also correlated with the size of inoculum. H. capsulatum antigen in lung correlated with silver stain scores of lung tissue, (R = 0.948, P less than 0.001) and with quantitative culture scores of lung, (R = 0.929, P less than 0.001). HPA levels in spleen tissue also correlated with spleen culture scores, (R = 0.724, P less than 0.001). These results indicate that determination of HPA level in serum and tissue may be a useful test in evaluating the severity of diseases as well as efficacy of antifungal therapy in histoplasmosis.     

A retrospective Evaluation of fluconazole for the treatment of Candida glabrata fungemia

BACKGROUND: Candida glabrata accounts for 21% of Candida bloodstream isolates in the United States and ranges from susceptible-dose-dependent to resistant to fluconazole. A fluconazole dose of 800 mg/d ( approximately 12 mg/kg per day) is predicted to produce peak plasma concentrations that surpass the susceptible-dose-dependent MIC breakpoint of 16 to 32 mug/mL. Accordingly, the Infectious Diseases Society of America treatment guidelines for candidiasis recommend fluconazole 12 mg/kg per day as an alternative option for treatment of C glabrata fungemia. OBJECTIVE: The main objective of this study was to evaluate fluconazole retrospectively as a treatment for C glabrata fungemia. METHODS: Data were collected through a database that stores patient information electronically and can be accessed and queried, and chart review at Barnes-Jewish Hospital (St. Louis, Missouri) from January 1999 to August 2002. Eligible patients who had at least 1 positive blood culture for C glabrata and received at least 1 dose of fluconazole were identified through the electronic query. Chart reviews of these patients followed. The primary outcomes were fungemia eradication and in-hospital mortality. RESULTS: Of the total 124 cases of C glabrata fungemia identified, 54 patient charts were evaluable. Chart review revealed that 65% (17/26) of patients receiving fluconazole as the sole antifungal therapy had successful bloodstream eradication of C glabrata, whereas approximately 54% (15/28) of patients who were changed from fluconazole to an amphotericin B formulation had successful bloodstream eradication. Although no association was found between fluconazole dose and fungemia eradication in the entire study population, higher doses of fluconazole (> or =400 mg/d) were more likely to achieve fungemia eradication than lower doses (< or =400 mg/d) in the subset of patients who received only fluconazole (P = 0.042). Mortality rates were approximately 24% (4/17) and 40% (6/15) in patients having successful bloodstream eradication with fluconazole alone and with fluconazole followed by amphotericin B, respectively, compared with 38% (3/8) in patients with persistent fungemia who received fluconazole alone. CONCLUSIONS: Fluconazole was a viable therapy for C glabrata fungemia, with bloodstream eradication in 65% of patients and mortality rates of 24% to 40% in this retrospective chart review.     

Clearance of Histoplasma capsulatum variety capsulatum antigen is useful for monitoring treatment of experimental histoplasmosi

We sought to determine whether measurement of Histoplasma capsulatum var. capsulatum antigen concentration in tissues and blood provided a marker for antifungal effect of itraconazole in a nonlethal murine model of histoplasmosis. Treatment with itraconazole (Sporanox), in cyclodextrin, was evaluated in a pulmonary model of histoplasmosis. Mice infected with 4.0 × 10⁷ yeast-phase organisms by endotracheal inoculation were treated with itraconazole, 1.5 mg twice daily by gavage, for 10 consecutive days, beginning on day 4 of infection. All mice were sacrificed on day 15 of infection. Blood, spleen, and lung tissues were removed for culture and quantification of antigen. Numbers of organisms were significantly lower in spleens from the treated group: 20.8 ± 41.8 vs. 65.8 ± 39.1 in the control group, P = 0.017. Numbers of organisms in lung were 9.6 ± 27.3 colonyforming units in treated versus 24.2 ± 36.3 in control animals, P = 0.267. Antigen concentrations in spleen tissue and serum were lower in treated versus control mice: spleen, 1.8 ± .6 units in treated versus 11.0 ± 2.3 in controls, P < 0.001; serum, 0.8 ± 0.2 units in treated versus 2.2 ± 1.0 units in controls, P < 0.001. Lung antigen concentrations were similar in the two groups, 19.2 ± 1.4 units in treated compared to 17.9 ± 3.0 units in control mice, P = 0.142. The cyclodextrin formulation of itraconazole (Sporanox) demonstrated antifungal activity in experimental histoplasmosis. Antigen detection was a useful marker for antifungal effect. © 1994 Wiley-Liss, inc.     

Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection? The National Institute of Allergy and Infectious Diseases Mycoses study group

The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. Mucosal Candida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P = 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC(50)) for last-episode isolates from the itraconazole group was 0.125 microg/ml compared to 0.015 microg/ml for the placebo group subjects, P = 0.0001. The MIC(50) of fluconazole for the last isolates from the itraconazole group was 1.5 microg/ml compared to 0.5 microg/ml for the placebo subjects (P = 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P = 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) (P = 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively (P = 0.001); fluconazole susceptibility, 23 and 4%, respectively (P = 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole.     

COMPARISON OF CLOTRIMAZOLE,FLUCONAZOLE AND ITRACONAZOLE IN VAGINAL CANDIDIASIS

SUMMARY Women attending a genitourinary medicine clinic (n=229) with mycologically confirmed acute vulvovaginal candidiasis were randomised to receive either clotrimazole (500 mg pessary and 1% cream), fluconazole (150 mg single oral dose) or itraconazole (200 mg bd oral dose for 1 day). Mycological cure rates were 96% in the itraconazole group, 95% in the clotrimazole group, and 83% in the fluconazole group (P=0.008). The proportion of patients who were clinically cured showed a similar pattern (itraconazole 80%, clotrimazole 80%, fluconazole 62%). This suggests that itraconazole or clotrimazole are more effective than fluconazole in the treatment of acute vaginal candidiasis.     

Comparison of itraconazole and fluconazole treatments in a murine model of coccidioidal meningitis

Coccidioidal meningitis (CM) is a devastating disease that requires long-term therapy and for which there is little hope of a cure. A model was used to compare the efficacies of itraconazole and fluconazole. CD-1 mice were infected intrathecally with 30 to 36 viable arthroconidia of Coccidioides. Oral therapy with cyclodextrin (control) or itraconazole or fluconazole at 10, 25, or 50 mg/kg of body weight twice daily (BID) was given for 12 days, from day 3 of infection. Treatment with both antifungals at all doses prolonged survival compared with that of the control treatment (P < 0.01 to 0.0001). At 50 mg/kg, itraconazole and fluconazole were equivalent, whereas itraconazole at 10 or 25 mg/kg prolonged survival compared to that achieved with fluconazole at these dosages (P < 0.05 and 0.01, respectively). Early histologic analysis (10 days of treatment) with 50 mg/kg BID itraconazole or fluconazole showed suppression of CM in all five animals per group; in quantitative cultures, three of three animals from each group had no detectable infection in the brain, spinal cord, or a site of secondary infection, the lungs. In contrast, four of seven controls showed mild to severe meningitis, with arteritis detected in three animals. In a short-term organ clearance study, 5 days of treatment with 10 or 50 mg/kg BID itraconazole or fluconazole reduced the tissue burdens in the brain and spinal cord compared to the tissue burdens in the controls (P < 0.02 to 0.0003). Fluconazole at 10 mg/kg did not reduce the fungal burden in secondary sites, the lungs and kidneys, whereas this itraconazole dose was more effective in clearing the fungi from both organs (P < 0.05 and P < 0.001, respectively). At 50 mg/kg, itraconazole and fluconazole were equivalent in clearing the fungi from the brain and kidney, but itraconazole was superior to fluconazole in clearing the fungi from the spinal cord and lungs (P < 0.05). Thus, both itraconazole and fluconazole were effective at controlling CM, but neither eliminated Coccidioides from tissues. Overall, itraconazole was more efficacious on an mg/kg basis; at high doses they were similarly effective.     

Serum itraconazole concentrations and clinical responses in Candida-associated denture stomatitis patients treated with itraconazole solution and itraconazole capsules

The aim of this study was to compare the concentrations of itraconazole in serum and saliva after treatment with itraconazole cyclodextrin solution or itraconazole capsules in Candida-associated denture stomatitis patients without evidence of immunodeficiency. Forty patients were randomly assigned to receive either itraconazole cyclodextrin solution or itraconazole capsules, both at a dosage of 100 mg bd for 15 days. On completion of treatment palatal erythema was assessed and an oral rinse and imprint cultures were collected. Serum and saliva samples were collected at the same time and itraconazole concentrations measured using reverse-phase high-performance liquid chromatography. Itraconazole susceptibilities of Candida albicans and Candida glabrata strains isolated at baseline were measured by a broth microdilution method. Serum itraconazole concentrations achieved did not differ significantly between the two preparations (P = 0.39) although a significantly higher number of patients in the itraconazole cyclodextrin group (P < 0.001) had detectable levels of itraconazole in their saliva compared with the capsule group. Mycologically cured patients had slightly, though not significantly (P = 0.28), higher serum itraconazole concentrations than those from whom yeasts were not eradicated. It was concluded that both formulations of itraconazole were equally effective in treatment of denture stomatitis. Among immunocompetent patients, the absorption of the liquid preparation is no greater than that of the capsules. Therapeutic success in this group was achieved with lower serum itraconazole concentrations than have been reported for immunocompromised groups.     

血清HBeAg定量检测对慢性乙型肝炎患者核苷(酸)类似物治疗后e抗原血清转换的预测作用

目的 观察HBeAg阳性慢性乙型肝炎(CHB)患者核苷(酸)类似物抗病毒治疗后不同时期外周血HBeAg滴度的变化,并探讨其与HBeAg血清转换之间的关系.方法 对22例核苷(酸)类似物抗病毒治疗的HBeAg阳性CHB患者随访2年,分别于抗病毒治疗的基线、12周、24周、48周和96周收集患者的血清,化学发光法定量检测HBsAg、HBeAg水平;实时荧光定量聚合酶链反应(PCR)检测血清HBV DNA载量;同时全自动生化分析仪检测血清ALT水平.结果 抗病毒治疗2年后,7例患者发生HBeAg血清转换,15例患者HBeAg仍为阳性.两组在基线状态下HBV DNA、HBsAg和HBeAg定量无统计学差异(P>0.05).在治疗过程中,发生HBeAg血清转换的患者12周HBV DNA和12周、24周、48周HBeAg滴度的下降率均高于未转换的患者(P<0.05).12周达到HBV-DNA阴转的患者在后期仍有36.4%的概率不发生HBeAg的血清学转换.12周、24周和48周HBeAg水平小于0.976、1.059和0.369(log10 S/CO)以及12周HBeAg较基线下降大于45.3%、48周较基线下降大于82.1%,均可预测2年后e抗原的血清转换,ROC曲线下面积分别是0.833,0.859,0.962,0.872和0.910(P<0.05),敏感性均为83.3%,特异性分别为92.3%,92.3%,100%,92.3%和100%.结论 HBeAg阳性CHB患者核苷(酸)类似物抗病毒治疗后,血清HBeAg定量的快速下降,可作为预测后期HBeAg血清转换的良好指标.     

Efficacy of ravuconazole in treatment of systemic murine histoplasmosis

Ravuconazole (RCZ) was evaluated for efficacy in comparison to fluconazole (FCZ) and itraconazole (ITZ) in murine models of disseminated histoplasmosis. All regimens tested prolonged survival (P < 0.05 to 0.0001). At equivalent doses of 50 mg/kg of body weight, RCZ and ITZ were equally effective and RCZ was more effective than FCZ (P = 0.02). Clearance of fungal burden from the livers and spleens of mice showed RCZ and ITZ at doses of 50 mg/kg to be efficacious but not curative. These data indicate that RCZ should be studied further.     

真菌血症31例临床分析

目的对真菌血症的临床及微生物学特征进行分析,为临床诊治提供参考。方法收集2004年8月—2005年12月期间我院31例真菌血症患者的临床资料进行回顾分析。结果超过80%的真菌血症患者患有2种或以上的基础疾病。半数以上患者均有导管留置,而且83．9%患者在血培养采样前1周内均不同程度使用抗菌药物。31例真菌血症中,24例(77．4%)与念珠菌有关,但仅3例由白念珠菌引起,念珠菌血症患者的病死率为45．8%。不同念珠菌对抗真菌药物存在不同程度的耐药率。结论真菌血症多发生于基础疾病严重者,由非白念珠菌导致的败血症在真菌血症中占很大比例;部分真菌对氟康唑、伊曲康唑耐药。     

In Vitro Susceptibilities of Candida and Cryptococcus neoformans Isolates from Blood Cultures of Neutropenic Patients

Fluconazole-resistant Candida albicans and intrinsically fluconazole-resistant Candida species have been reported as bloodstream isolates. However, an association between the isolation of fluconazole-resistant Candida from the bloodstream and patient risk factors for fungemia has not been established. The purpose of this study was to determine the prevalence of fluconazole resistance in bloodstream isolates of Candida species and Cryptococcus neoformans collected from patients with neutropenia, one of the most important risk factors for fungemia. MICs of voriconazole, fluconazole, itraconazole, ketoconazole, amphotericin B, and flucytosine were determined by the National Committee for Clinical Laboratory Standards M27-A method (1997). Voriconazole, on a per-weight basis, was the most active azole tested. Fluconazole resistance (MIC >/= 64 microg/ml) was not identified in any of the C. albicans (n = 513), Candida parapsilosis (n = 78), Candida tropicalis (n = 62), or C. neoformans (n = 38) isolates tested.     

The effect of clarithromycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283)

BACKGROUND: Dapsone hydroxylamine formation is thought to be the cause of the high rates of adverse reactions to dapsone in human immunodeficiency virus (HIV)-infected individuals. Therefore we studied the effect of the commonly coadministered drugs fluconazole, clarithromycin, and rifabutin on hydroxylamine formation in individuals with HIV infection. METHODS: HIV-infected subjects (CD4 + > or =200 cells/mm 3 ) were enrolled in a 2-part (A or B) open-label drug interaction study. In part A, subjects (n = 12) received dapsone (100-mg tablet once daily) alone for 2 weeks and then, in a randomly assigned order, received dapsone and either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 11) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. On the last study day of each 2-week period, plasma and urine were collected over ascorbic acid for 24 hours. RESULTS: In part A, fluconazole decreased the area under the plasma concentration-time curve, percent of dose excreted in 24-hour urine, and formation clearance of the hydroxylamine by 49%, 53%, and 55% (n = 12, P < .05), respectively. This inhibition of in vivo hydroxylamine formation was quantitatively consistent with that predicted from human liver microsomal experiments. Rifabutin had no effect on hydroxylamine area under the plasma concentration-time curve or percent excreted in 24-hour urine but increased formation clearance of the hydroxylamine by 92% (n = 12, P < .05). Dapsone clearance was increased by rifabutin or rifabutin plus fluconazole (67% and 38%, respectively) (n = 12, P < .05) but was unaffected by fluconazole or clarithromycin. In part B, hydroxylamine production was unaffected by clarithromycin but was affected by fluconazole in a manner identical to that in part A. CONCLUSIONS: On the basis of these data and with the assumption that the exposure to the hydroxylamine is a determinant of dapsone toxicity, we predict that coadministration of fluconazole should decrease the rate of adverse reactions to dapsone in persons with HIV infection but that rifabutin and clarithromycin will have no effect. When dapsone is given in combination with rifabutin, dapsone dosage adjustment may be necessary in light of the increase in dapsone clearance.     

Ciprofloxacin pharmacokinetics in patients with normal and impaired renal function.

The pharmacokinetics of ciprofloxacin following single oral doses of 500 and 750 mg in 32 patients with various degrees of renal function impairment were investigated in an open, randomized crossover fashion. Ciprofloxacin was administered after overnight fasting; the washout time between the two doses was 1 week. Serum and urine samples were collected serially between 0 and 24 h and subjected to bioassay and high-performance liquid chromatography. Pharmacokinetic parameters were analyzed, assuming an open two-compartment model with first-order input and elimination. A distinct difference was observed in pharmacokinetic parameters between patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) and those with normal renal function (creatinine clearance, greater than or equal to 50 ml/min per 1.73 m2). For the former group, the area under the curve of serum concentration versus time was doubled, the renal clearance of ciprofloxacin was cut to one-fourth, the total and nonrenal ciprofloxacin clearance was reduced by 50%, and the elimination half-life was prolonged by a factor of approximately 1.7. The correlation between renal drug clearance and creatinine clearance was highly significant (r = 0.890; P less than 0.001). On the basis of these findings, it appears that a 50% dose reduction of ciprofloxacin in patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) may be indicated to achieve concentrations in serum similar to those observed in normal individuals. As the concentration of ciprofloxacin in urine after 24 h remained above the MIC for most urinary pathogens, this drug appears to be of potential benefit for the treatment of urinary tract infections in patients with impaired renal function.     

结肠透析配合尿毒清颗粒保留灌肠治疗慢性肾功能衰竭的疗效

目的:观察结肠透析配合尿毒清颗粒保留灌肠治疗慢性肾功能衰竭(CRF)的临床疗效.方法:将80例CRF患者随机分为观察组与对照组各40例.两组常规治疗相同,对照组采用尿毒清颗粒直接保留灌肠;观察组先行结肠透析,之后以尿毒清颗粒保留灌肠.观察两组治疗前后临床症状和血肌酐(Scr)、血尿素氮(BUN)及血清β2-微球蛋白(β2-MG)指标的变化.结果:两组治疗后临床症状体征、Scr、BUN、β2-MG较治疗前均有不同程度的改善(P＜ 0.01或P＜0.05),观察组改善优于对照组(P＜0.01),两组总有效率比较差异有显著性(P＜0.01).结论:尿毒清灌肠治疗CRF有一定疗效,而结肠透析配合尿毒清颗粒保留灌肠治疗CRF疗效更为显著.     

Randomized trial of entecavir plus adefovir in patients with lamivudine-resistant chronic hepatitis B who show suboptimal response to lamivudine plus adefovir

A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudine-resistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV+ADV, n = 45) or continuation of lamivudine plus adefovir (LAM+ADV, n = 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log(10) IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV+ADV group than in the LAM+ADV group (n = 13, 29%, versus n = 2, 4%, respectively; P = 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV+ADV group than in the LAM+ADV group (-2.2 log(10) IU/ml versus -0.6 log(10) IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV+ADV group but in 15% of patients in the LAM+ADV group (P = 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.