A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients.

BACKGROUND: Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients. METHODS: We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 µg or 200 µg IC43 with adjuvant, or 100 µg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days. RESULTS: Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 µg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1-10.6%) was observed in the IC43 groups. CONCLUSION: This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 µg IC43 without adjuvant compared with 200 µg IC43 with adjuvant, the 100 µg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

[Updated acute community-acquired pneumonia in adults: Guidelines for initial antimicrobial therapy based on local evidence from the South American Working Group (ConsenSur II)]. / Neumonía aguda adquirida en la comunidad en adultos: Actualización de los lineamientos para el tratamiento antimicrobiano inicial basado en la evidencia local del Grupo de Trabajo de Sudamérica (ConsenSur II).

Community-acquired pneumonia (CAP) in adults is probably one of the infections affecting ambulatory patients for which the highest diversity of guidelines has been written worldwide. Most of them agree in that antimicrobial therapy should be initially tailored according to either the severity of the infection or the presence of comorbidities and the etiologic pathogen. Nevertheless, a great variability may be noted among the different countries in the selection of the primary choice in the antimicrobial agents, even for the cases considered as at a low-risk class. This fact may be due to the many microbial causes of CAP and specialties involved, as well as the different health-care systems effecting on the availability or cost of antibiotics. However, many countries or regions adopt some of the guidelines or design their own recommendations regardless of the local data, probably because of the scarcity of such data. This is the reason why we have developed a guideline for the initial treatment of CAP by 2002 upon the basis of several local evidences in South América (ConsenSur I). However, several issues deserve to be currently rediscussed as follows: certain clinical scores other than the Physiological Severity índex (PSI) have become more popular in clinical practice (i.e. CURB-65, CRB-65); some pathogens have emerged in the región, such as community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) and Legionella spp; new evidences on the performance of the rapid test for the etiologic diagnosis in CAP have been reported (eg. urinary Legionella andpneumococcus antigens); new therapeutic considerations needs to be approached (i.e. dosage reformulation, duration of treatment, emergence of novel antibiotics and clinical impact of combined therapy). Like in the first versión of the ConsenSur (ConsenSur I), the various current guidelines have helped to organize and stratify the present proposal, ConsenSur II.

Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia.

Tigecycline (TGC), a glycylcycline, has expanded activity against Gram-positive and Gram-negative, anaerobic, and atypical bacteria. Two phase 3 studies were conducted. Hospitalized patients with community-acquired pneumonia (CAP) were randomized to intravenous (IV) TGC (100 mg followed by 50 mg bid) or IV levofloxacin (LEV) (500 mg bid). In 1 study, patients could be switched to oral LEV after at least 3 days intravenously. The coprimary efficacy end points were as follows: clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). The secondary end points were as follows: microbiologic efficacy and susceptibility to TGC for CAP bacteria. Safety evaluations were included. Eight hundred ninety-one were patients screened: 846 mITT (TGC 424, LEV 422), 574 CE (TGC 282, LEV 292). Most patients had Fine Pneumonia Severity Index II to IV (80.7% TGC, 74.4% LEV, mITT). At TOC (CE), TGC cured 253/282 patients (89.7%) and LEV cured 252/292 patients (86.3%); the absolute difference of TGC-LEV was 3.4% (95% confidence interval [CI], -2.2 to 9.1, noninferior [P < 0.001]). In c-mITT, TGC cured 319/394 patients (81.0%) and LEV cured 321/403 patients (79.7%); the absolute difference of TGC-LEV was 1.3% (95% CI -4.5 to 7.1, noninferior [P < 0.001]). The drug-related adverse events (AEs) of nausea (20.8% TGC versus 6.6% LEV) and vomiting (13.2% TGC versus 3.3% LEV) were significantly higher in TGC; elevated alanine aminotransferase (2.8% TGC versus 7.3% LEV) and aspartate aminotransferase (2.6% TGC versus 6.9% LEV) were significantly higher in LEV. Discontinuations for AEs were low (TGC, 26 patients [6.1%]; LEV, 34 patients [8.1%]). TGC appeared safe and achieved cure rates similar to LEV in hospitalized patients with CAP.

Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) require surgical intervention and empiric antibacterial therapy. Doripenem, a broad-spectrum carbapenem, provides coverage of key gram-negative and -positive aerobes and anaerobes encountered in cIAI. OBJECTIVE: This study was designed to compare the efficacy and safety profile of doripenem and meropenem in hospitalized adult patients with cIAI. METHODS: In this prospective, multicenter, doubleblind, noninferiority study, hospitalized adults with cIAI were randomly assigned to receive doripenem 500 mg IV q8h or meropenem 1 g IV q8h. After a minimum of 9 doses and adequate clinical improvement (relative to before the start of IV study drug, decreased body temperature and white blood cell count, improved or absent signs and symptoms of cIAI, and return of normal bowel function), patients could be switched to oral amoxicillin/clavulanate. Antibacterial therapy (IV plus subsequent oral) was given for a total of 5 to 14 days. The coprimary efficacy end points were the clinical cure rate (complete resolution or significant improvement of signs or symptoms of the index infection) in patients microbiologically evaluable (>or=1 baseline pathogen isolated from an intra-abdominal culture that was susceptible to both IV study drug therapies) at the test-of-cure (TOC) visit (21-60 days after the completion of study drug therapy) and the clinical cure rate in the microbiological modified intent-to-treat (mMITT) population (a bacterial pathogen identified at baseline, regardless of its susceptibility to the study drug). Noninferiority was concluded if the lower limit of the 2-sided 95% CI for the difference (doripenem minus meropenem) in the proportion of patients classified as clinical cures was >or=-15%. RESULTS: A total of 476 patients were enrolled. The microbiologically evaluable population (319 patients) was 62.7% male and 67.7% white, with a mean age and weight of 46.7 years and 77.2 kg, respectively. In this population, doripenem and meropenem were associated with clinical cure rates at the TOC visit of 85.9% and 85.3%, respectively. The corresponding treatment difference was 0.6% (95% CI, -7.7% to 9.0%); this difference was not statistically significant. Similarly, in the mMITT population (385 patients), the clinical cure rates were 77.9% and 78.9%, respectively, and the corresponding 1.0% treatment difference was not statistically significant (95% CI, -9.7% to 7.7%). Clinical cure rates were not significantly different between the 2 treatment arms in key subgroups (eg, age, sex, race, baseline Acute Physiology and Chronic Health Evaluation II score, primary infection site). Microbiological eradication rates for common pathogens isolated at study entry were not significantly different between the 2 treatment groups. Doripenem was well tolerated in the population studied. In the intent-to-treat population (471 patients), 83.0% and 78.0% of patients experienced >or=1 adverse event (AE) and 13.2% and 14.0% experienced >or=1 serious AE in the doripenem and meropenem treatment arms, respectively. In the doripenem and meropenem treatment arms, AEs resulted in study drug discontinuation in 5.1% and 2.1% of patients and death in 2.1% and 3.0% of patients, respectively. CONCLUSIONS: The present study found that doripenem (500 mg q8h) was effective in the treatment of cIAI, was therapeutically noninferior to meropenem (1 g q8h), with a safety profile not significantly different from that of meropenem in this selected population of patients with cIAI.

Safety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results from a double-blind randomized phase 3 comparison study with levofloxacin.

Tigecycline exhibits potent in vitro activity against many community-acquired pneumonia (CAP) pathogens, including antibiotic-resistant ones. Its spectrum of activity and ability to penetrate lung tissue suggest it may be effective for hospitalized CAP patients. Hospitalized CAP patients (n=418) were randomized to receive intravenous (i.v.) tigecycline or levofloxacin. Patients could be switched to oral levofloxacin after receiving 6 or more doses of i.v. study medication. Therapy duration was 7 to 14 days. Coprimary efficacy end points were clinical responses in the clinically evaluable (CE: tigecycline, n=138; levofloxacin, n=156) and clinical modified intent-to-treat (c-mITT: tigecycline, n=191; levofloxacin, n=203) populations at test-of-cure (TOC). Safety was assessed in the mITT population (tigecycline, n=208; levofloxacin, n=210). Cure rates in tigecycline and levofloxacin groups were comparable in CE (90.6% versus 87.2%, respectively) and c-mITT (78% versus 77.8%, respectively) populations at TOC. Nausea and vomiting occurred in significantly more tigecycline-treated patients; elevated alanine aminotransferase and aspartate aminotransferase levels were reported in significantly more levofloxacin-treated patients. There were no significant differences in hospital length of stay, median duration of i.v. or oral antibiotic treatments, hospital readmissions, or number of patients switched to oral levofloxacin. Tigecycline was safe, effective, and noninferior to levofloxacin in hospitalized patients with CAP.

Neumonía aguda adquirida en la comunidad en adultos: actualización de los lineamientos para el tratamiento antimicrobiano inicial basado en la evidencia local del Grupo de Trabajo de Sudamérica (ConsenSur II) / Updated acute community-acquired pneumonia in adults: guidelines for initial antimicrobial therapy based on local evidence from the South American Working Group (ConsenSur II)

Community-acquired pneumonia (CAP) in adults is probably one of the infections affecting ambulatory patients for which the highest diversity of guidelines has been written worldwide. Most of them agree in that antimicrobial therapy should be initially tailored according to either the severity of the infection or the presence of comorbidities and the etiologic pathogen. Nevertheless, a great variability may be noted among the different countries in the selection of the primary choice in the antimicrobial agents, even for the cases considered as at a low-risk class. This fact may be due to the many microbial causes of CAP and specialties involved, as well as the different health-care systems effecting on the availability or cost of antibiotics. However, many countries or regions adopt some of the guidelines or design their own recommendations regardless of the local data, probably because of the scarcity of such data. This is the reason why we have developed a guideline for the initial treatment of CAP by 2002 upon the basis of several local evidences in South América (ConsenSur I). However, several issues deserve to be currently rediscussed as follows: certain clinical scores other than the Physiological Severity índex (PSI) have become more popular in clinical practice (i.e. CURB-65, CRB-65); some pathogens have emerged in the región, such as community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) and Legionella spp; new evidences on the performance of the rapid test for the etiologic diagnosis in CAP have been reported (eg. urinary Legionella andpneumococcus antigens); new therapeutic considerations needs to be approached (i.e. dosage reformulation, duration of treatment, emergence of novel antibiotics and clinical impact of combined therapy). Like in the first versión of the ConsenSur (ConsenSur I), the various current guidelines have helped to organize and stratify the present proposal, ConsenSur II.

La neumonía adquirida por adultos en la comunidad (NAC) es, probablemente, una de las infecciones que afecta a los pacientes ambulatorios para la cual se ha escrito la mayor diversidad de lineamientos en todo el mundo. La mayoría de ellos concuerdan en que el tratamiento antimicrobiano debe ser ajustado inicialmente de acuerdo con la gravedad de la infección o con la presencia de co-morbilidades y el patógeno etiológico. Aun así, se puede notar una gran variabilidad entre los diferentes países en la selección de la elección primaria de los agentes antimicrobianos, incluso en los casos considerados como de bajo riesgo. Este hecho puede deberse a las múltiples causas microbianas de la NAC y las especialidades médicas involucradas, como así también los diferentes sistemas de asistencia de salud que afectan la disponibilidad o el costo de los antimicrobianos. No obstante, muchos países o regiones adoptan alguno de los lineamientos o diseñan sus propias recomendaciones independientemente de los datos locales, probablemente debido a la escasez de dichos datos. Por esta razón desarrollamos lineamientos para el tratamiento inicial de la NAC hacia el año 2002, sobre la base de varias evidencias locales en Sudamérica (ConsenSur I). Sin embargo, varios temas merecen discutirse nuevamente como sigue: ciertos puntajes clínicos además del índice Fisiológico de Severidad (IFS) se hicieron más populares en la práctica clínica (por ej. CURB-65, CRB-65); emergieron algunos patógenos en la región, tal como Staphylococcus aureus resistente adquirido en la comunidad (SAMR-AC) y Legionella spp; se reportaron nuevas evidencias sobre el desempeño de la prueba rápida para el diagnóstico etiológico de NAC (por ejemplo, Legionella urinaria y antígenos de Streptococcus pneumoniae); deben abordarse nuevas consideraciones terapéuticas (por ej.: reformulación de la dosis, duración del tratamiento, emergencia de antimicrobianos nuevos e impacto clínico del tratamiento...

A prospective, multicenter, randomized, double-blind study comparing ertapenem and ceftriaxone followed by appropriate oral therapy for complicated urinary tract infections in adults.

OBJECTIVES: To compare the efficacy and safety of ertapenem, a new once-daily parenteral beta-lactam, with that of ceftriaxone for the initial empiric treatment of adults with complicated urinary tract infections (cUTIs). METHODS: In a multicenter, prospective, double-blind study, patients with cUTIs were stratified as to whether they had acute pyelonephritis or other cUTIs (without pyelonephritis) and randomized to receive ertapenem, 1 g once a day, or ceftriaxone, 1 g once a day. After 3 days, patients with a satisfactory clinical response could be switched to an oral antimicrobial agent. RESULTS: Of 258 randomized patients, 97 (55.4%) in the ertapenem group and 53 (63.9%) in the ceftriaxone group were evaluated microbiologically. Almost all patients in each treatment group were switched to oral therapy. The mean duration of therapy was similar in both treatment groups: parenteral, approximately 4 days; total, approximately 13 days. The most common pathogen was Escherichia coli. At the primary efficacy endpoint, 5 to 9 days after treatment, 85.6% of patients who received ertapenem and 84.9% who received ceftriaxone had a favorable microbiologic response, indicating that the two treatment groups were equivalent. The frequency and severity of drug-related adverse events were generally similar in both treatment groups. CONCLUSIONS: In this study, ertapenem was as effective as ceftriaxone for the initial treatment of cUTI in adults, was generally well tolerated, and had a similar safety profile.

Tigeciclina versus vancomycin más aztreonam en el tratamiento de infecciones complicadas de piel y tejidos blandos: Experiencia en Latinoamérica / Tigecycline as effective as vancomycin plus aztreonam in the treatment of complicated skin and skin structure infections: Experience in Latin America

BACKGROUND: Treating complicated skin and skin structure infections (cSSSIs) can be challenging. Tigecycline was compared to vancomycin/aztreonam in patients with cSSSIs in a multinational trial; this article reports on the Latin American (LA) population. METHODS: Patients were randomly assigned to receive tigecycline or vancomycin/ aztreonam. Primary endpoint was clinical cure rate at test-of-cure (TOC). Several secondary endpoints and safety were also assessed. RESULTS: A subtotal of 167 LA patients from the multinational trial (N = 573) received ≥ 1 dose of study drug. At TOC, cure rates were similar between tigecycline and vancomycin/aztreonam in the clinically evaluable population.) Noninferiority of tigecycline could not be demonstrated (insufficient sample sizes). Tigecycline-treated patients had higher incidences of nausea, vomiting, anorexia; vancomycin/aztreonam-treated patients had higher incidences of pruritus and rash. CONCLUSIONS: Efficacy results in the LA population were consistent with the multinational study suggesting that tigecycline is noninferior to vancomycin/aztreonam in treating patients with cSSSI.

INTRODUCCIÓN: El tratamiento de infecciones complicadas de piel y tejidos blandos (ICPTB) puede representar un desafío. Se comparó la eficacia de tigeciclina versus vancomicina/aztreonam en pacientes con ICPTB en un estudio multicéntrico; este artículo se refiere a la experiencia en Latinoamérica (LA). MÉTODO: Se asignaron, en forma randomizada, los pacientes a dos grupos de tratamiento: tigeciclina o vancomicina/aztreonam. La meta a evaluar (outcome) primaria fue la curación clínica, denominada test de curación (TC). Se establecieron, además, metas secundarias y la evaluación de seguridad del fármaco. RESULTADOS: Un subtotal de 167 pacientes procedentes de LA, de un estudio multinacional que incluyó 573 pacientes, recibieron ≥ 1 dosis del fármaco en estudio. Al TC, los porcentajes de curación fueron similares entre tigeciclina y vanco-micina/aztreonam en los pacientes clínicamente evaluables). La no inferioridad de tigeciclina no pudo ser demostrada (tamaño de muestra insuficiente). Los pacientes tratados con tigeciclina tuvieron mayor incidencia de náuseas, vómitos y anorexia; los pacientes que recibieron vancomicina/aztreonam tuvieron mayor incidencia de prurito y rash. CONCLUSIONES: Los resultados de eficacia en LA fueron consistentes con el estudio multinacional sugiriendo que tigeciclina no es inferior a vancomicina/aztreonam en el tratamiento de pacientes con ICPTB.