Imma Ocaña

Effectiveness of Cloxacillin with and without Gentamicin in Short-Term Therapy for Right-Sided Staphylococcus aureus Endocarditis: A Randomized, Controlled Trial

Tricuspid valve endocarditis is a common infection in intravenous drug users and is caused by Staphylococcus aureus in more than 80% of cases [1-4]. Right-sided endocarditis is less aggressive than left-sided disease [5]. The prognosis for patients with isolated tricuspid valve endocarditis caused by S. aureus is generally favorable, and the condition promptly responds to medical therapy [6]. For this reason, and because of the difficulty of hospitalizing patients with right-sided endocarditis for 4 to 6 weeks [7], there has been considerable interest in short courses of intravenous treatment for managing this condition [8]. Several recent studies [9-11] have shown that a combination of a penicillinase-resistant penicillin and an aminoglycoside given for 2 weeks is useful in most patients with uncomplicated, right-sided S. aureus endocarditis. However, the efficacy of a penicillinase-resistant penicillin as single-agent therapy given for 2 weeks has not yet been evaluated. Thus, the benefit of adding an aminoglycoside to short-course regimens is only theoretical [8]. We did a randomized clinical trial to compare the efficacy of cloxacillin alone with that of cloxacillin plus gentamicin as short-course therapy for right-sided S. aureus endocarditis in intravenous drug users. Methods Patients All patients who were suspected of having right-sided staphylococcal endocarditis, who were hospitalized at our institution between March 1988 and February 1993, and who admitted that they used intravenous drugs were considered for inclusion in our study. Patients who presented with tricuspid endocarditis caused by S. aureus according to the criteria shown in Table 1 were eligible. The institutional review board of our hospital approved the study, and all patients gave informed consent. Table 1. Diagnostic Criteria for Tricuspid Valve Infective Endocarditis Patients were excluded if they had any of the following: allergy to study medications, infection with methicillin-resistant S. aureus, confirmed or suspected left-sided endocarditis shown by clinical examination (indicated by characteristic regurgitation murmur or systemic embolization) or echocardiography (indicated by vegetation or valvular insufficiency), vegetation on the pulmonic valves shown by echocardiography, systemic complications requiring prolonged therapy (osteomyelitis, abscesses that could not be drained surgically), or antibiotic therapy given for longer than 48 hours before hospitalization. Clinically significant hemodynamic compromise, extensive pulmonary embolism, and large tricuspid vegetations were not considered exclusion criteria. Study Design and Treatment Our study was an open, randomized trial. Consecutive patients were randomly assigned to receive cloxacillin, 2 g intravenously every 4 hours for 14 days, alone or combined with gentamicin, 1 mg/kg of body weight intravenously every 8 hours for the first 7 days. Randomization was done using a random-number table in sets of 10: In each consecutive set, 5 patients received cloxacillin alone and 5 received combination therapy. A sealed envelope labeled with the randomization number was opened at the start of treatment. The decision to start treatment was based on microbiological criteria (positive blood cultures) or clinical criteria (fever and evidence of pulmonary embolism or poor general condition attributable to the infection). Thus, some patients were randomly assigned to treatment before the results of some procedures (echocardiography and isolation of microorganism) that might have uncovered exclusion criteria were available. Follow-up Initial patient assessment included medical history, physical examination, chest radiography, radionuclide body scanning with technetium pyrophosphate, electrocardiography, and the following laboratory tests: complete blood count, standard blood chemistries, urinalysis, serologic testing for human immunodeficiency virus (HIV), and lymphocyte subpopulation counts (when the HIV test result was positive). Standard laboratory tests and chest radiography were done every week. Two-dimensional transthoracic echocardiography was done within 4 days of hospital admission and at the end of treatment. Blood cultures were done at the time of hospital admission, 3 days after the initiation of treatment, and 2 days after the end of treatment. Aerobic and anaerobic cultures were done by using the BACTEC NR 660 System (Becton Dickinson, Mountain View, California). Follow-up visits were scheduled at 2 weeks and at 1, 3, and 6 months after the end of therapy. At the 2-week visit, a physical examination, standard laboratory tests, chest radiography, and two blood cultures were done. Subsequent blood cultures were done only if evidence suggested infection. Nine patients did not attend a follow-up visit; outcome information for these patients was obtained by telephone. Evaluation Criteria In all patients who met the exclusion criteria after random assignment, treatment was modified accordingly. In the intention-to-treat analysis, these patients were considered to have had treatment failure. Three primary end points were considered to indicate treatment failure: 1) death during treatment, 2) continued clinical or microbiological evidence of active infection after 2 weeks of therapy, and 3) relapse of staphylococcal infection. Clinical recovery was defined as the disappearance of clinical evidence of infection and the absence of radiologic abnormalities (pleural effusion or active pulmonary abscesses) at 14 days of treatment. Bacteriologic recovery was defined as a negative blood culture obtained 48 hours after the end of treatment. Successful therapy was defined as clinical and microbiological recovery without subsequent relapse. Patients who showed signs of active infection after 14 days of treatment continued to receive cloxacillin for 2 more weeks. Relapses were treated with cloxacillin alone for 4 weeks. To differentiate between relapse and reinfection, we considered clinical criteria (resumption of drug use and duration of symptom-free interval after stopping treatment) and comparison of S. aureus isolates by phage-typing. Phage-typing was done at the National Reference Center of Microbiology, Virology and Immunology, Majadahonda, Madrid, by using the international set of phages applied sequentially at the standard test dilution and a 1:100 test dilution; typing was also done after heat treatment. Reverse phagotyping was done as described elsewhere [12]. The duration of fever and appearance of complications during treatment were also evaluated. In patients without previous renal dysfunction, acute renal insufficiency was defined as a serum creatinine level greater than 176.8 mol/L. In patients with previous renal dysfunction, renal insufficiency was defined as an increase in the serum creatinine level of more than 50%. Statistical Analysis We did two analyses. An intention-to-treat analysis was done for all randomly assigned patients, and an efficacy analysis was done after we excluded patients who were found, after treatment began, to have met an exclusion criterion. We used the Fisher exact test to compare categorical baseline characteristics and outcomes of the two groups, and we used the Student t-test or the Mann-Whitney U test to compare continuous characteristics and outcomes. In the primary efficacy analysis, we compared the rates of successful treatment. Because we assumed that treatment would be successful in 95% of patients who received combination therapy [9], we estimated that almost 38 evaluable patients had to receive each regimen in order for us to detect a difference in efficacy of 20% or more, with a power of 80% at a one-sided level of 0.05. Because we anticipated that 10% to 15% of patients might have to be excluded after random assignment, 45 patients were assigned to each group. Two-tailed P values were used for all calculations; thus, the power of the study to find no differences in the efficacy of the two regimens was 70%. Results Patients During the 5-year study period, 45 patients were randomly assigned to each treatment group. Of these 90 patients, 6 (13%) of those assigned to receive cloxacillin alone and 8 (18%) of those assigned to receive combination therapy were later excluded for the following reasons. Three patients (1 receiving cloxacillin alone and 2 receiving combination therapy) had endocarditis caused by Streptococcus viridans; 7 patients (3 receiving cloxacillin alone and 4 receiving combination therapy) had involvement of the mitral, aortic, or pulmonic valves; 3 patients (1 receiving cloxacillin alone and 2 receiving combination therapy) were allergic to penicillin or had methicillin-resistant S. aureus infection; and 1 patient receiving cloxacillin alone had osteomyelitis. Two patients (1 in each group) refused further in-hospital treatment 5 and 8 days after enrollment, respectively. Thus, 74 patients (38 receiving cloxacillin alone and 36 receiving combination therapy) remained available for the efficacy analysis. Clinical, radiologic, and echocardiographic findings and laboratory values were similar in the two groups. The exclusion of 16 patients from the efficacy analysis after randomization did not change these similarities (Table 2). Table 2. Selected Baseline Characteristics of 74 Patients Evaluable for the Efficacy Analysis* Efficacy of Therapy Table 3 shows the outcome of all patients randomly assigned to treatment, as determined by the intention-to-treat analysis. A successful overall outcome was seen in 34 of the 45 patients (76% [95% CI, 61% to 87%]) assigned to receive cloxacillin only and 31 of the 45 patients (69% [CI, 53% to 82%]) assigned to receive combination therapy (P > 0.2). Table 3. Outcome of All Randomly Assigned Patients according to Treatment Regimen (Intention-to-Treat Analysis) Table 4 shows the outcomes for the 74 patients that were available for the efficacy analysis. Treatment was successful in 34 of the

Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis

To determine whether rifampicin reduces serum concentrations of nevirapine and whether nevirapine modifies serum concentrations of rifampicin, levels of these agents were determined at steady state by high-performance liquid chromatography in 10 HIV-infected patients with tuberculosis. The median area under the curve (AUC) 0-12h of nevirapine before and after rifampicin was 56.2 and 32.8 microg/ml per hour, respectively ( p =.04). This represents a 31% reduction in serum nevirapine concentrations. The C(max) decreased from 5.6 to 4.5 microg/ml ( p =.04), which represented a 36% reduction. A 21% decrease in the C(min) was not statistically significant. Exposure to rifampicin did not significantly differ between those patients who were receiving and were not receiving nevirapine. However, our study shows that rifampicin reduces serum exposure to nevirapine. The clinical implications for this reduction remain to be established. Given that the lowest trough serum concentration of nevirapine exceeded by more than 40 times the protein binding adjusted median infective dose (IC(50)) of wild-type HIV in all patients, we suggest that there is no need to increase nevirapine dosage when it is given with rifampicin.

Prophylaxis of visceral leishmaniasis in human immunodeficiency virus-infected patients

OBJECTIVE To assess the effectiveness of two regimens with allopurinol or pentavalent antimony as secondary prophylaxis for visceral leishmaniasis (VL) in human immunodeficiency virus (HIV)-infected patients. DESIGN Retrospective, nonrandomized, open trial. SETTING A 1,000-bed academic tertiary institutional hospital in Barcelona. PATIENTS Forty-six individuals over 14 years old with HIV infection, who recovered from an episode of VL between January 1988 and February 1995. INTERVENTIONS Twenty patients did not receive any prophylaxis, nine received 300 mg/8 h of allopurinol, and 17 received 850 mg once-a-month of pentavalent antimony. Patients were followed-up every 3 months, and the endpoint of study was relapse of VL. RESULTS Twenty-one patients had recurrent VL: 13 of 20 in the control group (65%), 5 of 9 in the allopurinol group (56%), and 3 of 17 in the antimonial group (18%). Kaplan-Meier estimates of the probability of remaining relapse-free at 12 months were 9% without prophylaxis (95% CI, 0-22%), 21% with allopurinol (95% CI, 0-51%), and 93% with antimonials (95% CI, 82-100%) (P < 0.001). Multivariate analysis showed that the only significant variables related to relapsing course of VL were assignment to the antimonial group, and the fact that the patient had experienced a previous episode of VL. CONCLUSIONS Pentavalent antimony given once a month is effective in the prevention of VL relapses in HIV-infected individuals. It is a low-cost treatment that proved to be well tolerated. Therefore, pentavalent antimony should be considered a suitable agent for secondary prophylaxis against VL.

Improvements in subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine is switched to tenofovir (LIPOTEST study).

Abstract Background: Lipoatrophy is the most stigmatizing side effect of stavudine therapy. We assessed the long-term effects of replacing stavudine with tenofovir in HIV-infected patients with lipoatrophy. Method: Prospective switch study. Sixty-two clinically stable patients with antiretroviral therapy (ART) containing stavudine, HIV-1 RNA <50 copies/mL, and lipoatrophy at least in the face on physical examination were included. All patients switched from stavudine to tenofovir without changing any other drug. Objective (malar ultasonography, bioelectrical impedance analysis) and subjective measures of lipoatrophy were assessed. Results: Median age at baseline was 40 years, 44 patients (71%) were male, and median time on stavudine was 4.8 years. Median malar fat thickness increased 0.8 mm (25%) 24 months after switching. Total fat mass increased 3.9 kg (21%). Plasma lactate levels decreased significantly, mainly in patients with baseline hyperlactatemia (from 3.05 to 1.19 mmol/L). Significant improvement in total cholesterol (−12%), triglycerides (−31%), and total cholesterol/HDL cholesterol ratio (−11%) was observed at Month 24. Conclusions: In this study, switching from stavudine to tenofovir maintained durable virologic suppression when the HAART regimen included a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, led to a slow improvement of lipoatrophy, and improved the lipid profile and lactate levels with excellent tolerability. These results support the proactive change of stavudine to tenofovir.

Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

ABSTRACT Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC0-12), 85.1 μg/ml · h; maximum concentration of drug in serum (Cmax), 10.0 μg/ml; trough concentration of drug in serum (Ctrough), 7.3 μg/ml; and minimum concentration of drug in serum (Cmin), 5.5 μg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC0-12, 22.9 μg/ml · h; Cmax, 2.9 μg/ml; Ctrough, 1.6 μg/ml; and Cmin, 1.4 μg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.

Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen.

Objective:To assess the pharmacokinetics and tolerability of lopinavir (LPV), ritonavir (RTV) and atazanavir (ATV) as a double-boosted protease inhibitor regimen in HIV-infected adults. Methods:Sixteen patients who started LPV/RTV (400/100 mg b.i.d.) and ATV (300 mg q.d.) were enrolled in the study group (arm A). LPV pharmacokinetics were compared to those of two historical groups: arm B, 15 patients who received LPV/RTV (400/100 mg b.i.d.); and arm C, 25 patients who received LPV/RTV/saquinavir (SQV) (400/100/1000 mg b.i.d.). ATV pharmacokinetics were compared to those of 15 consecutive patients who received ATV and RTV (300/100 mg q.d.) (arm D). Drug concentrations were measured by HPLC. Results:LPV concentrations were significantly higher in arm A than in arms B and C. Median (interquartile range) LPV area under the curve (AUC)0–12 values were 115.7 (99.8–136.5), 85.2 (68.3–109.2) and 85.1 (60.6–110.1) μg/h/ml, respectively. Cmax values were 12.2 (10.7–14.5), 9.5 (6.8–13.9) and 10.0 (6.9–13.6) μg/ml, respectively. Cmin values were 9.1 (7.1–10.4), 5.6 (4.7–8.2) and 5.5 (4.2–7.5) μg/ml, respectively. No difference was observed for ATV AUC0–24 or Cmax between arms A and D. ATV Cmin values were 1.07 (0.61–1.79) in arm A and 0.58 (0.32–0.83) in arm D (P = 0.001). Treatment was not discontinued in any patient because of adverse effects. At 24 weeks, viral load was < 50 copies/ml in 13 of 16 patients. Conclusions:The combination of ATV and LPV/RTV provided high plasma concentrations of both PI, which seemed to be appropriate for patients with multiple prior therapeutic failures, yielding good tolerability and substantial antiviral efficacy.

Comparison of High and Low Doses of Trimethoprim-Sulfamethoxazole for Primary Prevention of Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

To evaluate the influence of the dose of co-trimoxazole prophylaxis on the risk of toxoplasmosis in human immunodeficiency virus (HIV)-infected patients, we performed a nested case-control study of 32 patients with toxoplasmosis (case patients) and 64 patients without toxoplasmosis (control patients) who were matched by CD4 cell count and Toxoplasma gondii serostatus; these patients were from a cohort of 521 HIV-infected patients who underwent a diagnostic neuroimaging study between March 1993 and January 1997. Twenty-seven (84.4%) of 32 case patients and 33 (51.6%) of 64 control patients received low doses of co-trimoxazole, a finding associated with an adjusted odds ratio (OR) of 9.36 (95% confidence interval [CI], 2.05-42.75) and indicating 89% protective efficacy for high doses. Fifteen (46.9%) of 32 case patients and 16 (25%) of 64 control patients were exposed to rifampin (adjusted OR, 3.38; 95% CI, 1.08-10.61). These results indicate that high doses of co-trimoxazole appear to be more effective than low doses for lowering the risk of toxoplasmosis in HIV-infected patients and that rifampin therapy may reduce the efficacy of co-trimoxazole.

Once-daily regimen of saquinavir, ritonavir, didanosine, and lamivudine in HIV-infected patients with standard tuberculosis therapy (TBQD Study).

Objectives:To assess the efficacy and safety of a once-daily regimen with didanosine, lamivudine, saquinavir, and low-dose ritonavir in antiretroviral (ARV)-naive patients with tuberculosis treated with rifampin and the influence of rifampin on plasma trough concentration (Ctrough) of saquinavir. Methods:Single-arm, prospective, multicenter, open-label pilot study, including 32 adult ARV-naive subjects with HIV infection and tuberculosis under standard treatment that included rifampin (600 mg q.d.) and isoniazid (300 mg q.d.). After 2 months of tuberculosis treatment, patients were started on once-daily ARV therapy, consisting of didanosine, lamivudine, ritonavir (200 mg), and saquinavir soft gel capsules (1600 mg). HIV RNA level, CD4 cell count, clinical and laboratory toxicity, and saquinavir Ctrough during and after antituberculosis therapy were analyzed. Results:After 48 weeks of follow-up, 20 of 32 patients (62.5%; 95% CI: 45.8% to 79.2%) in the intent-to-treat population and 20 of 28 (71.4%; 95% CI: 54.4% to 88.4%) in the on-treatment population had an HIV RNA level <50 copies/mL. Treatment tolerance was acceptable in all patients except for 2 with biologic hepatic toxicity leading to discontinuation. Seven patients had virologic failure. In 10 patients (36%), saquinavir Ctrough was <0.05 μg/mL during tuberculosis therapy and 5 of them had virologic failure. The median saquinavir Ctrough was 44% lower (interquartile range: 19% to 71%) with coadministration of rifampin than without. Conclusion:The combination of didanosine, lamivudine, saquinavir, and ritonavir may be a useful treatment regimen for patients with tuberculosis in whom a once-daily protease inhibitor-containing regimen is considered indicated. Nevertheless, on the basis of pharmacokinetic profile the dose of 1600/200 mg of saquinavir/ritonavir cannot be recommended. Further studies with higher doses of saquinavir (2000 mg) boosted with ritonavir are warranted.

Rifampin Reduces Concentrations of Trimethoprim and Sulfamethoxazole in Serum in Human Immunodeficiency Virus-Infected Patients

ABSTRACT To determine whether rifampin reduces concentrations of trimethoprim (TMP) and sulfamethoxazole (SMX) in serum of human immunodeficiency virus (HIV)-infected persons, levels of these agents were determined by high-performance liquid chromatography before and after more than 12 days of standard antituberculosis treatment for 10 patients who had been taking one double-strength tablet of co-trimoxazole once daily for more than 1 month. Statistically significant, 47 and 23% decreases in TMP and SMX mean areas under the concentration-time curve from 0 to 24 h (AUC0–24), respectively, were observed after administration of rifampin.N-Acetyl-SMX profiles without and with rifampin were similar. The steady-state AUC0–24 metabolite/parent drug ratio increased by 32% with rifampin administration. Our study shows that rifampin reduces profiles of TMP and SMX in serum of HIV-infected patients.

Impact of low-level viraemia on virological failure in HIV-1-infected patients with stable antiretroviral treatment.

BACKGROUND Low-level viraemia (LLV) occurs in 20-40% of patients achieving viral suppression with antiretroviral therapy (ART). The risk of virological failure (VF: confirmed HIV RNA >200 copies/ml) in these patients is still a matter of debate. METHODS This is a prospective cohort study in HIV-infected adults attending the HIV clinic of a tertiary care hospital in Spain. Patients with HIV RNA <25 copies/ml and stable ART for at least 6 months presenting LLV (defined as HIV RNA between 25-1,000 copies/ml) from January 2011 to January 2013 were included and followed until VF or end of follow-up in June 2014. RESULTS A total of 300 out of 1,733 (17.3%) patients with undetectable viraemia for 4.2 years showed LLV: 25-50 copies/ml in 167 (55.7%) patients, 51-200 copies/ml in 111 (37%) and 201-1,000 copies/ml in 22 (7.3%) cases. After a median follow-up of 2.6 years, 23 (7.7%) patients presented VF. No patient with a single or multiple unconfirmed LLV went on to develop VF. HIV RNA >200 copies/ml (HR 59.6; 95% CI 15.7, 227), ritonavir-boosted protease inhibtor (PI/r)-based dual therapy (HR 10.2; 95% CI 2.1, 49.8) and PI/r monotherapy (HR 7.9; 95% CI 1.4, 43.3) were associated with VF. Persistent LLV, defined as HIV RNA <200 copies/ml in at least three consecutive samples, for at least 12 weeks, was detected in 27 (1.6%) patients and 14 (51.9%) of those evolved to VF. CONCLUSIONS Nearly one-fifth of patients on suppressive ART showed LLV and 8% of them developed VF. HIV RNA >200 copies/ml was the strongest predictor of VF. Over half of patients with persistent viraemia <200 copies/ml showed VF.