Characteristics of endemic human coronavirus infections during times of COVID-19 pandemic.

INTRODUCTION: After the implementation of mitigation strategies during the COVID-19 pandemic, the incidence of respiratory viruses, including human coronaviruses (HCoV), experienced a significant decrease. The aim of this study is to characterize the epidemiology and clinical aspects of HCoV infections in ambulatory adults during COVID-19 pandemic times. METHODS: descriptive, prospective, longitudinal study performed in a private hospital in La Plata, Buenos Aires, Argentina between November 2020 and October 2022; 458 outpatient adults with upper respiratory tract infections (URTI) were studied undergoing clinical and microbiological follow-up. RESULTS: 44 (9.6%) subjects were positive by multiplex PCR for HCoV. 14 of them for 229E (31.8%), 13 for OC43 (29.5%), 11 for HKU-1 (25.1%) and 6 for NL63 (13.6%). A repeated PCR was positive for the same HCoV in 19 (57%) of 33 patients on day 3-5. No hospitalizations or deaths were reported. DISCUSSION: Endemic HCoV caused a significant proportion of URTI among outpatient adults during COVID-19-related restrictions times. An alternating pattern of circulation between alfa-HCoV and beta-HCoV was observed.

Introducción: Tras la implementación de estrategias de mitigación durante la pandemia de COVID-19, la incidencia de virus respiratorios, incluyendo los coronavirus humanos (HCoV), disminuyó significativamente. El objetivo de este estudio es caracterizar la epidemiología y los aspectos clínicos de las infecciones por HCoV en adultos ambulatorios durante la pandemia de COVID-19. Métodos: estudio descriptivo, prospectivo, longitudinal, realizado en un hospital privado de La Plata, Buenos Aires, Argentina, entre noviembre de 2020 y octubre de 2022. Se estudiaron 458 pacientes adultos ambulatorios con infecciones del tracto respiratorio superior (ITRS) bajo seguimiento clínico y microbiológico. Resultados: 44 (9.6%) sujetos fueron positivos por PCR multiplex para HCoV. Se detectaron 14 229E (31.8%), 13 OC43 (29.5%), 11 HKU-1 (25.1%) y 6 NL63 (13.6%). Una segunda PCR fue positiva para el mismo HCoV en 19 (57 %) de 33 pacientes en los días 3-5. No se reportaron hospitalizaciones ni muertes. Discusión: los HCoV endémicos causaron una proporción significativa de ITRS entre pacientes adultos ambulatorios durante los tiempos de restricciones relacionados con COVID-19. Se observó un patrón alternante de circulación entre alfa-HCoV y beta-HCoV.

Characteristics of endemic human Coronavirus infections during times of COVID-19 pandemic / Características de las infecciones causadas por Corona virus humanos endémicos durante la pandemia COVID-19

Abstract Introduction : After the implementation of mitigation strategies during the COVID-19 pandemic, the incidence of respiratory viruses, including human coronaviruses (HCoV), experienced a significant decrease. The aim of this study is to characterize the epidemiology and clinical aspects of HCoV infections in ambulatory adults during COVID-19 pandemic times. Methods : descriptive, prospective, longitudinal study performed in a private hospital in La Plata, Buenos Aires, Argentina between November 2020 and October 2022; 458 outpatient adults with upper respiratory tract infections (URTI) were studied undergoing clinical and microbiological follow-up. Results : 44 (9.6%) subjects were positive by multiplex PCR for HCoV. 14 of them for 229E (31.8%), 13 for OC43 (29.5%), 11 for HKU-1 (25.1%) and 6 for NL63 (13.6%). A repeated PCR was positive for the same HCoV in 19 (57%) of 33 patients on day 3-5. No hospitalizations or deaths were reported. Discussion : Endemic HCoV caused a significant pro portion of URTI among outpatient adults during COVID- 19-related restrictions times. An alternating pattern of circulation between alfa-HCoV and beta-HCoV was observed.

Resumen Introducción : Tras la implementación de estrate gias de mitigación durante la pandemia de COVID-19, la incidencia de virus respiratorios, incluyendo los coronavirus humanos (HCoV), disminuyó significati vamente. El objetivo de este estudio es caracterizar la epidemiología y los aspectos clínicos de las infecciones por HCoV en adultos ambulatorios durante la pandemia de COVID-19. Métodos : estudio descriptivo, prospectivo, longitudi nal, realizado en un hospital privado de La Plata, Buenos Aires, Argentina, entre noviembre de 2020 y octubre de 2022. Se estudiaron 458 pacientes adultos ambulatorios con infecciones del tracto respiratorio superior (ITRS) bajo seguimiento clínico y microbiológico. Resultados : 44 (9.6%) sujetos fueron positivos por PCR multiplex para HCoV. Se detectaron 14 229E (31.8%), 13 OC43 (29.5%), 11 HKU-1 (25.1%) y 6 NL63 (13.6%). Una segunda PCR fue positiva para el mismo HCoV en 19 (57 %) de 33 pacientes en los días 3-5. No se reportaron hospitalizaciones ni muertes. Discusión : los HCoV endémicos causaron una pro porción significativa de ITRS entre pacientes adultos ambulatorios durante los tiempos de restricciones rela cionados con COVID-19. Se observó un patrón alternante de circulación entre alfa-HCoV y beta-HCoV.

Impacto de la movilidad poblacional en el comportamiento de virus respiratorios durante la pandemia COVID-19 / Impact of population mobility on the behavior of respira tory viruses during the COVID-19 pandemic

Resumen Introducción : Durante la pandemia de SARS-CoV-2 en Argentina se implementaron intervenciones no farma cológicas que produjeron cambios en la movilidad de la población. El objetivo de este estudio fue relacionar los porcentajes de positividad y la diversidad viral con la movi lidad poblacional durante parte del período de restricciones. Métodos : Estudio retrospectivo analítico realizado en el Instituto Médico Platense durante los años 2020 a 2022 que incluyó 458 pacientes a los que se les tomó un hisopado nasofaríngeo para la búsqueda de patóge nos respiratorios por PCR multiplex. Se analizaron los cambios en la movilidad de la población utilizando los "Informes de Movilidad Local", herramienta desarrollada por Google, cuyos datos son de público acceso. Resultados : La movilidad poblacional se correlacionó significativamente con el porcentaje de positividad de las muestras (p = <0.01; R2 = 0.89) y la diversidad viral (p = 0.04; R2 = 0.78). Discusión : Las intervenciones no farmacológicas destinadas a limitar la propagación del SARS-CoV-2 tuvieron efecto en la circulación de otros virus respi ratorios, hallándose mayor porcentaje de positividad y diversidad a medida que las mismas disminuyeron su grado de restricción.

Abstract Introduction : During the SARS-CoV-2 pandemic, Ar gentina population suffered from significant changes in population mobility due to non-pharmaceutical interventions. The aim of this study was to describe the impact of the mobility restrictions to the rates of positivity and diversity among different respiratory viruses. Methods : Retrospective analytical study per formed at Instituto Médico Platense in La Plata that included 458 patients with nasopharyngeal swab to search for respiratory pathogens by multiplex PCR. Changes in mobility were studied using "Community Mobility Reports", data set developed by Google and publicly available. Results : Community mobility had significant cor relation with the percentages of viral test positiv ity (p = < 0.01; R2=0.89) and viral diversity (p = 0.04; R2 = 0.78). Discussion : Non-pharmaceutical interventions estab lished to contain SARS-CoV-2 spread had a significant impact in the circulation patterns of other respiratory viruses.

Factors associated with mortality among hospitalized patients with COVID-19 disease treated with convalescent plasma.

The use of convalescent plasma (CP) for hospitalized patients with SARS-CoV-2 infection might be a useful option in certain settings. Soon after the outbreak of COVID-19, the National Ministry of Health of Argentina recommended the use of CP transfusion for hospitalized patients with COVID-19 disease. Between 1 June and 3 October 2020, 480 patients, excluding those on invasive mechanical ventilation (IMV), received at least one CP infusion in the province of Santa Fe. We aimed to find factors associated with mortality among this cohort of patients. The median age was 60 years (interquartile range: 49-69 years) and 320 (66.7%) were males. Most of these patients (93.75%) received a single CP infusion, 82.1% and 95.6% before day 4 and day 7 of hospitalization, respectively. Anti-SARS-CoV-2 titers were determined in the CP units administered using Elecsys Anti-SARS-CoV-2 S assay. At 28 days of follow-up, 250 patients were discharged (52.1%), 131 (27.3%) remained hospitalized without and 16 (3.3%) with oxygen requirement, 27 (5.6%) were on IMV, and 56 (11.7%) had died. In the multivariate logistic regression analysis, the factors significantly associated with 28-day mortality were (i) requirement of IMV, (ii) the administration of CP after the third day of hospitalization, (iii) age, and (iv) number of comorbidities. The qualitative and quantitative analyses of antibodies against SARS-CoV-2 in the infused CP were not associated with mortality. Our findings may imply a seemingly favorable effect of CP administration among patients with severe COVID-19 disease when infused sooner after hospitalization.IMPORTANCEThe use of convalescent plasma (CP) could be an option for patients with severe COVID-19, especially in poor-resource countries where direct antiviral drugs are not commercially available. Currently, the U.S. Food and Drug Administration limits the CP administration for outpatients and inpatients with COVID-19 who are immunocompromised and only if high levels of anti-SARS-CoV-2 antibodies are confirmed in the CP unit. Although most of the randomized clinical trials failed to show a clear-cut benefit of CP in hospitalized patients with severe COVID-19, other studies have shown that if given early in the course of the disease, it might be a useful therapeutic option. In this retrospective study, we demonstrated that early treatment (within 3 days of hospitalization) was significantly associated with reduced 28-day mortality compared with those patients treated beyond day 3. The results from our study add up to the scientific evidence on the use of CP as a relatively safe, cheap, and possibly effective therapy in certain patients suffering from severe SARS-CoV-2 infection.

[Impact of population mobility on the behavior of respiratory viruses during the COVID-19 pandemic]. / Impacto de la movilidad poblacional en el comportamiento de virus respiratorios durante la pandemia COVID-19.

INTRODUCTION: During the SARS-CoV-2 pandemic, Argentina population suffered from significant changes in population mobility due to non-pharmaceutical interventions. The aim of this study was to describe the impact of the mobility restrictions to the rates of positivity and diversity among different respiratory viruses. METHODS: Retrospective analytical study performed at Instituto Médico Platense in La Plata that included 458 patients with nasopharyngeal swab to search for respiratory pathogens by multiplex PCR. Changes in mobility were studied using "Community Mobility Reports", data set developed by Google and publicly available. RESULTS: Community mobility had significant correlation with the percentages of viral test positivity (p = < 0.01; R2=0.89) and viral diversity (p = 0.04; R2 = 0.78). DISCUSSION: Non-pharmaceutical interventions established to contain SARS-CoV-2 spread had a significant impact in the circulation patterns of other respiratory viruses.

Introducción: Durante la pandemia de SARS-CoV-2 en Argentina se implementaron intervenciones no farmacológicas que produjeron cambios en la movilidad de la población. El objetivo de este estudio fue relacionar los porcentajes de positividad y la diversidad viral con la movilidad poblacional durante parte del período de restricciones. Métodos: Estudio retrospectivo analítico realizado en el Instituto Médico Platense durante los años 2020 a 2022 que incluyó 458 pacientes a los que se les tomó un hisopado nasofaríngeo para la búsqueda de patógenos respiratorios por PCR multiplex. Se analizaron los cambios en la movilidad de la población utilizando los "Informes de Movilidad Local", herramienta desarrollada por Google, cuyos datos son de público acceso. Resultados: La movilidad poblacional se correlacionó significativamente con el porcentaje de positividad de las muestras (p = <0.01; R2 = 0.89) y la diversidad viral (p = 0.04; R2 = 0.78). Discusión: Las intervenciones no farmacológicas destinadas a limitar la propagación del SARS-CoV-2 tuvieron efecto en la circulación de otros virus respiratorios, hallándose mayor porcentaje de positividad y diversidad a medida que las mismas disminuyeron su grado de restricción.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41- 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Ceftaroline as salvage therapy for methicillin susceptible Staphylococcus aureus complicated bacteremia.

Infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) are still associated with significant morbidity and mortality. Treatment failures of cefazolin (CFZ) have been reported and probably related to the inoculum effect. New treatments for severe MSSA infections are needed and ceftaroline fosamil (CPT) could be an option. Our aim was to describe the clinical characteristics of five patients with complicated MSSA bacteremia failing CFZ and successfully treated with CPT. We performed a retrospective chart review in a Hospital in Buenos Aires, Argentina; in a 12-month period, five patients (24%) of 21 with MSSA bacteremia experienced CFZ failure and were salvaged with CPT. The median time of CFZ therapy was 10 days before changing to CPT; four patients had evidence of metastatic spread and 2 had endocarditis. All patients experienced microbiological and clinical cure with CPT, which was used as monotherapy in 4 and in combination with daptomycin in another. One patient discontinued CPT due to neutropenia on day 23 of treatment. In patients with MSSA BSI failing current therapy, CPT could be a good therapeutic option.

Las infecciones causadas por Staphylococcus aureus sensible a la meticilina (SASM) todavía se asocian con una morbilidad y mortalidad significativas. Se han informado fallas en el tratamiento de cefazolina (CFZ) probablemente relacionadas con efecto inóculo. Nuevos tratamientos son necesarios para estas infecciones y ceftarolina fosamil (CPT) podría ser una opción. Nuestro objetivo fue describir las características clínicas de cinco pacientes con bacteriemia por SASM complicada con falla a CFZ y que fueron exitosamente tratados con CPT. Realizamos una revisión retrospectiva de historias clínicas en un hospital de Buenos Aires, Argentina; en un período de 12 meses, cinco pacientes (24%) de 21 con bacteriemia por SASM experimentaron falla a CFZ y fueron tratados con CPT. La mediana de tiempo de la terapia con CFZ fue de 10 días antes de cambiar a CPT; cuatro pacientes presentaban evidencia de diseminación metastásica y 2 tenían endocarditis. Todos los pacientes experimentaron curación microbiológica y clínica con CPT, que se utilizó como monoterapia en 4 y en combinación con daptomicina en otro. Un paciente interrumpió CPT debido a neutropenia el día 23 de tratamiento. En enfermos con infecciones graves por SASM que fallan en la terapia actual, CPT podría ser una buena opción terapéutica.

Ceftaroline as salvage therapy for methicillin susceptible staphylococcus aureus complicated bacteremia / Ceftarolina como tratamiento de rescate para la bacteriemia complicada por Staphylococcus aureus sensible a la meticilina

Abstract Infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) are still associated with significant morbidity and mortality. Treatment failures of cefazolin (CFZ) have been reported and probably related to the inoculum effect. New treatments for severe MSSA infections are needed and ceftaroline fosamil (CPT) could be an option. Our aim was to describe the clinical characteristics of five patients with com plicated MSSA bacteremia failing CFZ and successfully treated with CPT. We performed a retrospective chart review in a Hospital in Buenos Aires, Argentina; in a 12-month period, five patients (24%) of 21 with MSSA bacteremia experienced CFZ failure and were salvaged with CPT. The median time of CFZ therapy was 10 days before changing to CPT; four patients had evidence of metastatic spread and 2 had endocarditis. All patients experienced microbiological and clinical cure with CPT, which was used as monotherapy in 4 and in combination with daptomycin in another. One patient discontinued CPT due to neutropenia on day 23 of treatment. In patients with MSSA BSI failing current therapy, CPT could be a good therapeutic option.

Resumen Las infecciones causadas por Staphylococcus aureus sensible a la meticilina (SASM) todavía se asocian con una morbilidad y mortalidad significativas. Se han informado fallas en el tratamiento de cefazolina (CFZ) probablemente relacionadas con efecto inóculo. Nuevos tratamientos son necesarios para estas infecciones y ceftarolina fosamil (CPT) podría ser una opción. Nuestro objetivo fue describir las características clínicas de cinco pacientes con bacteriemia por SASM complicada con falla a CFZ y que fueron exitosamente tratados con CPT. Realizamos una revisión retrospectiva de historias clínicas en un hospital de Buenos Aires, Argentina; en un período de 12 meses, cinco pacientes (24%) de 21 con bacteriemia por SASM experimentaron falla a CFZ y fueron tratados con CPT. La mediana de tiempo de la terapia con CFZ fue de 10 días antes de cambiar a CPT; cuatro pacientes presentaban evidencia de diseminación metastásica y 2 tenían endocarditis. Todos los pacientes experimen taron curación microbiológica y clínica con CPT, que se utilizó como monoterapia en 4 y en combinación con daptomicina en otro. Un paciente interrumpió CPT debido a neutropenia el día 23 de tratamiento. En enfermos con infecciones graves por SASM que fallan en la terapia actual, CPT podría ser una buena opción terapéutica.

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.

BACKGROUND: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. METHODS: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).

Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis.

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A ß-lactamase (ßla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its ßla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 µg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the ßla-cured derivative, TX0117c, compared to time zero (t0) (P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Abstract Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200 mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600 mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N = 182) vs linezolid (N = 171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48–72 h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p = 0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200 mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections.

Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48-72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Polyclonal outbreak of bacteremia caused by Burkholderia cepacia complex and the presumptive role of ultrasound gel.

A nosocomial polyclonal outbreak associated to bacteremia caused by different Burkholderia cepacia complex (BCC) species and clones is reported. Molecular characterization identified Burkholderia stabilis, Burkholderia contaminans, and Burkholderia ambifaria among BCC isolates obtained from patients in neonatal and adult intensive care units. BCC was also isolated from an intrinsically contaminated ultrasound gel, which constituted the presumptive BCC source. Prior BCC outbreak related to contaminated ultrasound gels have been described in the setting of transrectal prostate biopsy. Outbreak caused strains and/or clones of BCC have been reported, probably because BCC are commonly found in the natural environment; most BCC species are biofilm producers, and different species may contaminate an environmental source. The finding of multiple species or clones during the analysis of nosocomial BCC cases might not be enough to reject an outbreak from a common source.

Cefazolin high-inoculum effect in methicillin-susceptible Staphylococcus aureus from South American hospitals.

OBJECTIVES: Clinical failures with cefazolin have been described in high-inoculum infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) producing type A ß-lactamase. We investigated the prevalence of the cefazolin inoculum effect (InE) in MSSA from South American hospitals, since cefazolin is used routinely against MSSA due to concerns about the in vivo efficacy of isoxazolyl penicillins. METHODS: MSSA isolates were recovered from bloodstream (n = 296) and osteomyelitis (n = 68) infections in two different multicentre surveillance studies performed in 2001-02 and 2006-08 in South American hospitals. We determined standard-inoculum (10(5)cfu/mL) and high-inoculum (10(7) cfu/mL) cefazolin MICs. PFGE was performed on all isolates that exhibited a cefazolin InE. Multilocus sequence typing (MLST) and sequencing of part of blaZ were performed on representative isolates. RESULTS: The overall prevalence of the cefazolin InE was 36% (131 isolates). A high proportion (50%) of MSSA isolates recovered from osteomyelitis infections exhibited the InE, whereas it was observed in 33% of MSSA recovered from bloodstream infections. Interestingly, Ecuador had the highest prevalence of the InE (45%). Strikingly, 63% of MSSA isolates recovered from osteomyelitis infections in Colombia exhibited the InE. MLST revealed that MSSA isolates exhibiting the InE belonged to diverse genetic backgrounds, including ST5, ST8, ST30 and ST45, which correlated with the prevalent methicillin-resistant S. aureus clones circulating in South America. Types A (66%) and C (31%) were the most prevalent ß-lactamases. CONCLUSIONS: Our results show a high prevalence of the cefazolin InE associated with type A ß-lactamase in MSSA isolates from Colombia and Ecuador, suggesting that treatment of deep-seated infections with cefazolin in those countries may be compromised.

In Vivo Effects of Cefazolin, Daptomycin, and Nafcillin in Experimental Endocarditis with a Methicillin-Susceptible Staphylococcus aureus Strain Showing an Inoculum Effect against Cefazolin.

Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P = 0.005; daptomycin versus nafcillin, P = 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log10 reduction of 1.4 versus 5.5, respectively; P = 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity.

Telavancin for the treatment of hospital-acquired pneumonia: findings from the ATTAIN studies.

Treatment options for hospital-acquired pneumonia caused by Gram-positive organisms are far from ideal. The increase in vancomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates, and the slow bactericidal action and poor lung penetration of vancomycin have driven the search for an alternative agent. Telavancin, a once-daily lipoglycopeptide, displays strong bactericidal activity against S. aureus. Two large Phase III randomized trials have recently compared intravenous telavancin (10 mg/kg every 24 h) with vancomycin (1 g intravenously every 12 h) for 7-21 days for the treatment of hospital-acquired pneumonia caused by Gram positives. No significant differences were observed in the cure rates in the all-treated (n = 1503), the clinically evaluable (n = 654) and the microbiologically evaluable (n =480) populations. Telavancin performed better than vancomycin in patients with monomicrobial S. aureus pneumonia (84.2 vs 74.3%; 95% CI: 0.7-19.1), with MRSA (81.8 vs 74.1%; 95% CI: -3.5 to 19.3), and with strains having vancomycin MICs ≥1 µg/ml (87.1 vs 74.3; 95% CI: 0.5-23). The rate of adverse events, including serious adverse events, was similar in both groups, with a slightly higher rate of serum creatinine increase in the telavancin-treated group. Based on these results, telavancin (already approved for this indication by the EMA) could certainly be added to the current treatment options, particularly in patients with MRSA pneumonia.

Telavancin versus vancomycin for hospital-acquired pneumonia due to gram-positive pathogens.

BACKGROUND: Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens. METHODS: Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit. RESULTS: A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%). CONCLUSIONS: The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.