A Descriptive Analysis of Urinary ESBL-Producing-Escherichia coli in Cerdanya Hospital.

Urinary tract infections caused by extended-spectrum ß-lactamase Escherichia coli (ESBL-EC) are increasing worldwide and are a current concern because treatment options are often limited. This study investigated antimicrobial susceptibility, antimicrobial resistance genes (ARGs), and the biological diversity of urinary ESBL-EC isolates at Cerdanya Hospital, a European cross-border hospital that combines French and Spanish healthcare models. Bacterial identification and susceptibility were determined using the Microscan WalkAway® system and ESBL production was examined by the double-disk synergy method. Isolates were sequenced using the Ion S5™ next-generation sequencing system, with the whole-genome sequences then assembled using SPADEs software and analyzed using PubMLST, ResFinder, FimTyper, PlasmidFinder, and VirulenceFinder. A phylogenetic analysis was performed by constructing an assembly-based core-SNV alignment, followed by a phylogenetic tree constructed using Parsnp from the Harvest suite. All isolates studied were multidrug-resistant and could be classified into 19 different sequence types characterized by a high genetic diversity. The most prevalent ESBL-enzymes were CTX-M-14 and CTX-M-15. High-risk international clones (ST131, ST10, and ST405) were also identified. The results demonstrated the absence of a single predominant clone of ESBL-MDR-EC at Cerdanya Hospital.

Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis.

OBJECTIVES: To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs). METHODS: Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions. RESULTS: Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid. CONCLUSIONS: There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.

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) microg/h/ml, respectively. C(max) values were 12.2 (10.7-14.5), 9.5 (6.8-13.9) and 10.0 (6.9-13.6) microg/ml, respectively. C(min) values were 9.1 (7.1-10.4), 5.6 (4.7-8.2) and 5.5 (4.2-7.5) microg/ml, respectively. No difference was observed for ATV AUC0-24 or C(max) between arms A and D. ATV C(min) 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.

[Tuberculous meningitis: a comparative study in relation to concurrent human immunodeficiency virus infection]. / Meningitis tuberculosa: estudio comparativo en relación con la coexistencia de infección por el virus de la inmunodeficiencia humana.

INTRODUCTION: This study assesses the epidemiological and clinical data, as well as therapy and evolution in a recent series of patients with tuberculous meningitis (MT). A comparative study was conducted between adult MT patients with and without concurrent human immunodeficiency virus (HIV) infection. METHODS: From 1987 to 2000, 75 episodes of MT were diagnosed, 39 of them (52%) in patients with prior HIV infection. A comparative study was performed of variables related to the presence or absence of HIV and MT coinfection. RESULTS: MT was more frequent in HIV patients (6.4% versus 1.2%, p < 0.01). CD41 lymphocyte value in HIV patients was 52 +/- 66 cells/mm3. There were no significant differences in clinical manifestations or cerebrospinal fluid biochemical alterations between the two groups. Extrameningeal TB was more frequent in patients with HIV coinfection than those without (61.5% vs. 36.1%, p = 0.03). Radiological alterations on cranial studies were more frequent in HIV-infected patients. Treatment with four antituberculosis drugs was also more frequent in HIV-infected patients (61.5% vs. 13.9%, p = 0.01). There were no differences in adverse effects between the groups. Overall mortality (20.5% vs. 22.51%) and neurological sequelae (7.7% vs. 5.6%) were also similar. CONCLUSIONS: Half of our MT patients were coinfected with HIV. Their clinical, microbiological and evolutionary characteristics were comparable to those of patients without HIV infection. These results indicate that the diagnostic and therapeutic strategies applied in MT patients with or without HIV coinfection can be similar.

Meningitis tuberculosa: estudio comparativo en relación con la coexistencia de infección por el virus de la inmunodeficiencia humana / Tuberculous meningitis: a comparative study in relation to concurrent human immunodeficiency virus infection

Introducción. El objetivo de este estudio fue evaluar los datos epidemiológicos, clínicos, terapéuticos y evolutivos de una serie reciente de meningitis tuberculosa (MT) y efectuar un estudio comparativo entre los pacientes adultos con y sin infección por el virus de la inmunodeficiencia humana (VIH). Métodos. Desde 1987 a 2000 se diagnosticaron 75 episodios de MT, 39 de ellos (52%) en pacientes infectados por el VIH. Se realizó un estudio comparativo de las diferentes variables en relación a la coinfección. Resultados. La MT fue más frecuente en los pacientes infectados por el VIH (6,4% frente a 1,2%; p < 0,01). Los linfocitos CD41 en los pacientes infectados por el VIH fueron de 66 +/- 52 cél./ml. No se detectaron diferencias significativas en las manifestaciones clínicas y en las alteraciones bioquímicas del líquido cefalorraquídeo entre ambos grupos. La tuberculosis extrameníngea fue más frecuente en casos de coinfección por el VIH (61,5% frente a 36,1%; p = 0,03). Las alteraciones radiológicas fueron más frecuentes en los pacientes infectados por el VIH. La terapéutica con 4 fármacos antituberculosos fue más frecuente en los pacientes infectados por el VIH (61,5% frente a 13,9%; p = 0,01). Los efectos adversos no mostraron diferencias entre ambos grupos. La mortalidad global (20,5% frente a 22,51%) y las secuelas neurológicas (7,7% frente a 5,6%) fueron similares. Conclusiones. La mitad de los pacientes con MT están coinfectados por el VIH. Las características clínicas, microbiológicas y evolutivas son similares a la de los pacientes sin coinfección. La estrategia diagnóstica y terapéutica en la MT de los enfermos con o sin infección por el VIH pueden ser similares (AU)

Introduction. This study assesses the epidemiological and clinical data, as well as therapy and evolution in a recent series of patients with tuberculous meningitis (MT). A comparative study was conducted between adult MT patients with and without concurrent human immunodeficiency virus (HIV) infection. Methods. From 1987 to 2000, 75 episodes of MT were diagnosed, 39 of them (52%) in patients with prior HIV infection. A comparative study was performed of variables related to the presence or absence of HIV and MT coinfection. Results. MT was more frequent in HIV patients (6.4% versus 1.2%, p < 0.01). CD41 lymphocyte value in HIV patients was 52 +/- 66 cells/mm 3. There were no significant differences in clinical manifestations or cerebrospinal fluid biochemical alterations between the two groups. Extrameningeal TB was more frequent in patients with HIV coinfection than those without (61.5% vs. 36.1%, p = 0.03). Radiological alterations on cranial studies were more frequent in HIV-infected patients. Treatment with four antituberculosis drugs was also more frequent in HIV-infected patients (61.5% vs. 13.9%, p = 0.01). There were no differences in adverse effects between the groups. Overall mortality (20.5% vs. 22.51%) and neurological sequelae (7.7% vs. 5.6%) were also similar. Conclusions. Half of our MT patients were coinfected with HIV. Their clinical, microbiological and evolutionary characteristics were comparable to those of patients without HIV infection. These results indicate that the diagnostic and therapeutic strategies applied in MT patients with or without HIV coinfection can be similar (AU)

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 microg/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.

Steady-state pharmacokinetics of a double-boosting regimen of saquinavir soft gel plus lopinavir plus minidose ritonavir in human immunodeficiency virus-infected adults.

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 (AUC(0-12)), 85.1 microg/ml . h; maximum concentration of drug in serum (C(max)), 10.0 microg/ml; trough concentration of drug in serum (C(trough)), 7.3 microg/ml; and minimum concentration of drug in serum (C(min)), 5.5 microg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC(0-12), 22.9 microg/ml . h; C(max), 2.9 microg/ml; C(trough), 1.6 microg/ml; and C(min), 1.4 microg/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.

Infección por el virus de inmunodeficiencia humana: identificación in situ de las células inflamatorias de la mucosa rectal por técnicas inmunocitoquímicas / Infections by human inmunodeficiency: identification in situ of the cells inflammatory of the rectal mucosa for immunochemistry techniques

Actualmente existen pocos estudios inmunofenotípicos que caracterizan los leucocitos en la mucosa rectal de pacientes infectados con el virus de inmunodeficiencia humana (VIH). Treinta y tres biopsias rectales provenientes de pacientes VIH positivo y 7 biopsias controles de pacientes VIH negativo, fueron analizadas utilizando la técnica de avidinainmunoperoxidasa y los siguientes anticuerpos monoclonales: S-100, ki-1 (CD30), LCA, p21, p53, PCNA, CD4 y HLADR. Los resultados mostraron una diferencia significativa (p<-0,05) en el número de células de la mucosa rectal de los pacientes VIH positivo y controles que expresan las siguientes moléculas: S-100, Ki-1 (CD30), LCA, p21, p53, PCNA, y CD4. Numerosos leucocitos de la mucosa rectal de los pacientes VIH positivo estaban activados y expresaban moléculas HLA-DW mientras que ningún leucocito de las biopsias controles mostró alguna expresión. Además, observamos una diferencia significativa (p<-0,05) en la expresión de las siguientes moléculas: LCA, PCNA, S-100 y CD4 al comparar las biopsias rectales de pacientes VIH positivo con y sin folículos linfoides. Nuestro estudio muestra la primera evidencia de un incremento de las células dendríticas S-100 + en la mucosa rectal de pacientes VIH positivo. Los marcadores de activación y proliferación también se presentaron elevados. Los resultados obtenidos sugieren la posibilidad del desarrollo de una proliferación monoclonal en la mucosa rectal de pacientes VIH positivo

Efficacy of ceftriaxone and gentamicin given once a day by using human-like pharmacokinetics in treatment of experimental staphylococcal endocarditis.

We compared the efficacy of ceftriaxone combined with gentamicin, both given once a day, with that of cloxacillin given every 4 h plus gentamicin given once a day or in three daily doses (t.i.d.) for the treatment of experimental methicillin-susceptible staphylococcal endocarditis. The antibiotics were administered by using human-like (H-L) pharmacokinetics that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10(5) CFU of Staphylococcus aureus S5 (MICs and minimal bactericidal concentrations of cloxacillin, ceftriaxone, and gentamicin, 0.5 and 2 microg/ml, 4 and 8 microg/ml, and 0.5 and 1 microg/ml, respectively). The animals were then treated for 24 h with cloxacillin at a dose of 2 g that simulated H-L pharmacokinetics (H-L 2 g) every 4 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg of body weight every 8 h or H-L 4.5 mg/kg every 24 h) or with ceftriaxone at H-L 2 g every 24 h alone or combined with gentamicin (administered at doses of H-L 1 mg/kg every 8 h or H-L 4.5 mg/kg every 24 h). The results of therapy for experimental endocarditis due to the S5 strain showed that (i) cloxacillin alone is more effective than ceftriaxone alone in reducing the bacterial load (P < 0.01), (ii) the combination of cloxacillin or ceftriaxone with gentamicin is more effective than each of these drugs alone (P < 0.01), and (iii) Ceftriaxone H-L plus gentamicin H-L 4.5 mg/kg, both administered every 24 h, showed efficacy similar to that of the "gold standard," cloxacillin H-L plus gentamicin H-L 1 mg/kg t.i.d. (P > 0.05). An increase in the interval of administration of gentamicin to once daily resulted in a reduction in the numbers of bacteria in the vegetations equivalent to that achieved with the recommended regimen of cloxacillin plus gentamicin t.i.d. in the treatment of experimental endocarditis due to methicillin-susceptible S. aureus. Ceftriaxone plus gentamicin, both administered once a day, may be useful for home-based therapy for selected cases of staphylococcal endocarditis.