José Hernández-Quero

Patients' characteristics and clinical implications of suboptimal CD4 T-cell gains after 1 year of successful antiretroviral therapy.

To describe characteristics and prognosis of patients with suboptimal immunological response to combined antiretroviral therapy (CART). Using data from a multicenter cohort study, we selected patients who initiated CART and showed suboptimal CD4-T cell response (defined as <50 cells/L increase) after 1 year of therapy, despite sustained virological suppression. Characteristics of those patients were compared with subjects who showed optimal immunological response. Of 650 patients with virological suppression, 108 (16.6%) showed suboptimal CD4-T cell response. Independent predictors of suboptimal response were previous injection drug use (OR, 1.85; 95% CI, 1.12-2.98) and age at CART initiation (OR, 1.04 per year increase; 95%CI, 1.01-1.06). Hepatitis C virus coinfection was not associated with impaired immunological response. As compared with patients with optimal immunological response, those with suboptimal response had a higher mortality rate (3.22 versus 0.71 per 100 person-years; p=.001), but a similar rate of new AIDS-defining events. In patients with sustained virological suppression with CART, previous injection drug use, but not hepatitis C virus coinfection, and older age at initiation of therapy were associated with suboptimal CD4 T-cell responses. Patients with suboptimal response had a higher mortality over time, mainly due to diseases other than AIDS-defining events.

Activity of linezolid and high-dose daptomycin, alone or in combination, in an in vitro model of Staphylococcus aureus biofilm

OBJECTIVES The aim of the study was to assess the in vitro activity of linezolid and daptomycin, alone and in combination, against three Staphylococcus aureus isolates using a pharmacokinetic/pharmacodynamic (PK/PD) model of biofilm for 3 days. METHODS One non-clinical methicillin-resistant S. aureus isolate (N315) and two clinical methicillin-resistant S. aureus isolates were evaluated. Simulated regimens included high-dose daptomycin (10 mg/kg once daily) and linezolid (600 mg twice daily), alone and in combination. RESULTS Against all three strains, neither linezolid nor daptomycin alone was bactericidal against biofilm-embedded bacteria (BB). Against planktonic bacteria (PB) only daptomycin was bactericidal. In contrast, the combination of linezolid and daptomycin demonstrated greater activity than either of the two agents alone, being bactericidal against both PB and BB, almost reaching the limit of detection at 72 h. CONCLUSIONS In this in vitro PK/PD model of mature biofilms, a combination of linezolid plus daptomycin was more effective than each agent alone, representing another potential option to treat S. aureus biofilm-associated infections.

Haemophilus influenzae Pneumonia in Human Immunodeficiency Virus-Infected Patients

Although Haemophilus influenzae is a common etiologic agent of pneumonia in patients infected with human immunodeficiency virus (HIV), the characteristics of this pneumonia have not been adequately assessed. We have prospectively studied features of H. influenzae pneumonia in 26 consecutive HIV-infected inpatients. Most of these patients were severely immunosuppressed; 73.1% had a CD4+ cell count <100/microL. A subacute clinical presentation was observed in 27% of the patients and was associated with a higher degree of immunosuppression (P=.04). Bilateral lung infiltrates were noted radiographically in 57.7% of the cases. The mortality attributable to H. influenzae pneumonia was 11.5%. Thus, pneumonia caused by H. influenzae affects mainly patients with advanced HIV disease, and since its clinical and radiological features may be diverse, this etiology should be considered when pneumonia occurs in patients with advanced HIV infection. The mortality rate associated with H. influenzae pneumonia is not higher than that occurring in the general population.

Usefulness of Sputum Culture for Diagnosis of Bacterial Pneumonia in HIV-Infected Patients

Abstract.The use of sputum culture in immunocompetent patients with community-acquired pneumonia is controversial. The usefulness of this technique in HIV-infected patients has not been evaluated. A prospective, observational, multicenter, hospital-based study of bacterial community-acquired pneumonia was carried out to analyze the value of sputum culture in HIV-infected patients. Only good-quality sputum samples were cultured. Altogether, 355 cases of bacterial community-acquired pneumonia were included. An etiological diagnosis was obtained in 190 (53.5%) cases. Sputum was cultured in 313 (88.1%) cases, being diagnostic in 108 (34.5%). The microorganism identified in sputum culture was the same as that identified in sterile samples in 26 of 27 (96.3%) cases in which both cultures were diagnostic. The microbiologic findings in sputum and bronchoscopic cultures were concordant in seven of eight (87.5%) cases in which both were positive. These results suggest that sputum culture is a useful technique, given its availability and ease of performance and its good correlation with culture of sterile samples.

Elution kinetics, antimicrobial activity, and mechanical properties of 11 different antibiotic loaded acrylic bone cement

Antibiotic-loaded acrylic bone cements (ALABC) spacers are routinely used in the treatment of prosthetic joint infections. The objectives of our study were to evaluate different ALABC for elution kinetics, thermal stability, and mechanical properties. A 10 or 20% mixture (w/w) beads of medium viscosity bone cement (DePuy, Inc) and vancomycin (VAN), gentamycin (GM), daptomycin (DAP), moxifloxacin (MOX), rifampicin (RIF), cefotaxime (CTX), cefepime (FEP), amoxicillin clavulanate (AmC), ampicillin (AMP), meropenem (MER), and ertapenem (ERT) were formed and placed into wells filled with phosphate-buffered saline. Antibiotic concentrations were determined using high-performance liquid chromatography. Antimicrobial activity was tested against Micrococcus luteus ATCC 9341 or Escherichia coli ATCC 25922. AmC, AMP, and FEP concentration rapidly decreased after day 2, being almost undetectable at day 4. Sustained and high elution rates were observed with VAN, GM, MOX, and RIF for the 30-day duration of the experiment. DAP, MER, ERT, and CTX elution rates constantly decreased from day 4. All antibiotics tested retained antimicrobial activity proving thermal stability. Mechanical properties of ALABC were maintained except when RIF was used.

Quantification of Viral Loads Lower than 50 Copies per Milliliter by Use of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, Version 2.0, Can Predict the Likelihood of Subsequent Virological Rebound to >50 Copies per Milliliter

ABSTRACT After 1 year of follow-up, patients on HAART with a baseline viral load (VL) of <20 copies/ml showed significantly lower odds of virological rebound to two consecutive VLs of >50 copies/ml than those with baseline VLs of 20 to 39 and 40 to 49 (P < 0.001). The time to virological rebound was also significantly shorter (P < 0.001) for the groups with baseline VLs of 20 to 39 and 40 to 49.

Pharmacokinetics of fosamprenavir plus ritonavir in human immunodeficiency virus type 1-infected adult subjects with hepatic impairment.

ABSTRACT The effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (Cmax), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC(0-τ)], similar values for the concentration at the end of the dosing interval (Cτ), and 114% higher unbound Cτ values. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavir Cmax values, 27% lower AUC(0-24) values, 57% lower Cτ values, and 21% higher unbound amprenavir Cτ values. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavir Cmax values, 23% lower AUC(0-24) values, 38% lower Cτ values, and similar unbound amprenavir Cτ values. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC(0-24) values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.

Eficacia y seguridad de daptomicina en dosis elevadas (≥ 8mg/kg/día)

INTRODUCTION There is a paucity of data regarding efficacy and safety of high dose (>8mg/kg/day) daptomycin. MATERIAL AND METHODS This ambispective study included all patients that received ≥8 mg/kg/day of daptomycin and had efficacy and safety data. RESULTS Sixty-nine patients were included. Fifty-nine patients (85.5%) were recorded as having been cured or improved. Six patients (8.6%) had a raised CPK during follow-up with no clinical signs of myopathy in any of them. CONCLUSIONS High dose daptomycin shows good efficacy without concerns about toxicity.

Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens.

Background and Objective Significant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens. Methods This retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure). Results A total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8−81.8) and 91.5% (CI95, 89.6–93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations. Conclusion Switching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug.

Recomendaciones españolas sobre el uso adecuado de enfuvirtida

Enfuvirtide is a high-cost, parenterally administered drug commonly used in late phases of HIV infection, when its efficacy may be compromised. To optimize enfuvirtide use, consensus recommendations for this purpose have been formulated by 247 physicians attending patients with HIV infection in Spain. A literature review was performed in which grades of evidence and recommendations were defined according to the origin of the data (randomized clinical trials, non-randomized studies, expert opinion). Twenty-eight local consensus meetings were held between May and September 2005 to discuss the most important aspects related to the use of enfuvirtide, following a pre-established system used in all the meetings. The main conclusions were as follows: a) enfuvirtide use is often excessively delayed and is given to patients with little chance of treatment success; b) enfuvirtide is indicated in patients who require antiretroviral treatment and for whom an optimum treatment with three other fully effective drugs cannot be designed; c) the most important prognostic factor is the availability of at least one other completely active drug; d) there is no infallible method to avoid the development of local reactions, but measures are available to decrease their incidence and severity; and e) patient counseling and training for correct administration of the drug are essential to improve adherence, the repercussions of local reactions and, of course, the efficacy of the treatment.