Deep Dive Into Gaps and Barriers to Implementation of Antimicrobial Stewardship Programs in Hospitals in Latin America.

BACKGROUND: Antimicrobial resistance has worsened in Latin America. There is an urgent need to understand the development of antimicrobial stewardship programs (ASPs) and the barriers to implementing effective ASPs in light of limited national action plans or policies to promote ASPs in the region. METHODS: We performed a descriptive mixed-methods study of ASPs in 5 Latin American countries in March-July 2022. An electronic questionnaire with an associated scoring system (hospital ASP self-assessment) was used, and ASP development was classified based on the scores (inadequate, 0-25; basic, 26-50; intermediate, 51-75; or advanced, 76-100). Interviews among healthcare workers (HCWs) involved in antimicrobial stewardship (AS) inquired about behavioral and organizational factors that influence AS activities. Interview data were coded into themes. Results from the ASP self-assessment and interviews were integrated to create an explanatory framework. RESULTS: Twenty hospitals completed the self-assessment, and 46 AS stakeholders from these hospitals were interviewed. ASP development was inadequate/basic in 35% of hospitals, intermediate in 50%, and advanced in 15%. For-profit hospitals had higher scores than not-for-profit hospitals. Interview data validated the self-assessment findings and provided further insight into ASP implementation challenges, which included limited formal hospital leadership support, inadequate staffing and tools to perform AS work more efficiently, limited awareness of AS principles by HCWs, and limited training opportunities. CONCLUSIONS: We identified several barriers to ASP development in Latin America, suggesting the need to create accurate business cases for ASPs to obtain the necessary funding for their effective implementation and sustainability.

Effectiveness of vancomycin plus cloxacillin compared with vancomycin, cloxacillin and daptomycin single therapies in the treatment of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in a rabbit model of experimental endocarditis.

OBJECTIVES: To investigate if the addition of cloxacillin to vancomycin enhances the activity of both monotherapies for treating MSSA and MRSA experimental endocarditis (EE) in rabbits. METHODS: Vancomycin plus cloxacillin was compared with the respective monotherapies and daptomycin. In vitro time-kill studies were performed using standard (105 cfu) and high (108 cfu) inocula of five MRSA, one glycopeptide-intermediate (GISA) and five MSSA strains. One MSSA (MSSA-678) and one MRSA (MRSA-277) strain were selected to be used in the in vivo model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2 g/4 h IV and daptomycin 6 mg/kg/day IV were administered. To optimize vancomycin activity, dosage was adjusted to achieve an AUC/MIC ≥400. RESULTS: Daptomycin sterilized significantly more vegetations than cloxacillin (13/13, 100% versus 9/15, 60%; P = 0.02) and showed a trend of better activity than vancomycin (10/14, 71%; P = 0.09) and vancomycin plus cloxacillin (10/14, 71%; P = 0.09) against MSSA-678. Addition of cloxacillin to vancomycin (13/15, 87%) was significantly more effective than vancomycin (8/16, 50%; P = 0.05) and showed similar activity to daptomycin (13/18, 72%; P = 0.6) against MRSA-277. In all treatment arms, the bacterial isolates recovered from vegetations were re-tested and showed the same daptomycin susceptibility as the original strains. CONCLUSIONS: Vancomycin plus cloxacillin proved synergistic and bactericidal activity against MRSA. Daptomycin was the most efficacious option against MSSA and similar to vancomycin plus cloxacillin against MRSA. In settings with high MRSA prevalence, vancomycin plus cloxacillin might be a good alternative for empirical therapy of S. aureus IE.

Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis.

BACKGROUND: In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE). METHODS: Five MSSA strains were used in the in vitro time-kill studies at standard (105-106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h). RESULTS: At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC. CONCLUSIONS: The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.

AUC/MIC Pharmacodynamic Target Is Not a Good Predictor of Vancomycin Efficacy in Methicillin-Resistant Staphylococcus aureus Experimental Endocarditis.

The aim of this in vivo study was to compare the efficacy of vancomycin at standard doses (VAN-SD) to that of VAN at adjusted doses (VAN-AD) in achieving a VAN area under the curve/MIC ratio (AUC/MIC) of ≥400 against three methicillin-resistant Staphylococcus aureus (MRSA) strains with different microdilution VAN MICs in an experimental endocarditis model. The valve vegetation bacterial counts after 48 h of VAN therapy were compared, and no differences were observed between the two treatment groups for any of the three strains tested. Overall, for VAN-SD and VAN-AD, the rates of sterile vegetations were 15/45 (33.3%) and 21/49 (42.8%) (P = 0.343), while the medians (interquartile ranges [IQRs]) for log10 CFU/g of vegetation were 2 (0 to 6.9) and 2 (0 to 4.5) (P = 0.384), respectively. In conclusion, this VAN AUC/MIC pharmacodynamic target was not a good predictor of vancomycin efficacy in MRSA experimental endocarditis.

Effect of vancomycin minimal inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus endocarditis.

BACKGROUND: Staphylococcus aureus endocarditis has a high mortality rate. Vancomycin minimum inhibitory concentration (MIC) has been shown to affect the outcome of methicillin-resistant S. aureus bacteremia, and recent data point to a similar effect on methicillin-susceptible S. aureus bacteremia. We aimed to evaluate the effect of vancomycin MIC on left-sided S. aureus infective endocarditis (IE) treated with cloxacillin. METHODS: We analyzed a prospectively collected cohort of patients with IE in a single tertiary-care hospital. Vancomycin, daptomycin, and cloxacillin MIC was determined by E-test. S. aureus strains were categorized as low vancomycin MIC (<1.5 µg/mL) and high vancomycin MIC (≥1.5 µg/mL). The primary endpoint was in-hospital mortality. RESULTS: We analyzed 93 patients with left-sided IE treated with cloxacillin, of whom 53 (57%) had a vancomycin MIC < 1.5 µg/mL and 40 (43%) a vancomycin MIC ≥ 1.5 µg/mL. In-hospital mortality was 30% (n = 16/53) in patients with a low vancomycin MIC and 53% (n = 21/40) in those with a high vancomycin MIC (P = .03). No correlation was found between oxacillin MIC and vancomycin or daptomycin MIC. Logistic regression analysis showed that higher vancomycin MIC increased in-hospital mortality 3-fold (odds ratio, 3.1; 95% confidence interval, 1.2-8.2) after adjustment for age, year of diagnosis, septic complications, and nonseptic complicated endocarditis. CONCLUSIONS: Our results indicate that vancomycin MIC could be used to identify a subgroup of patients with methicillin-susceptible S. aureus IE at risk of higher mortality. The worse outcome of staphylococcal infections with a higher vancomycin MIC cannot be explained solely by suboptimal pharmacokinetics of antibiotics.

Knowledge, attitudes and perceptions of Latin American healthcare workers relating to antibiotic stewardship and antibiotic use: a cross-sectional multi-country study.

BACKGROUND: The burden of antimicrobial resistance (AMR) in Latin America is high. Little is known about healthcare workers' (HCWs) knowledge, attitudes, and perceptions of antimicrobial stewardship (AS), AMR, and antibiotic use (AU) in the region. METHODS: HCWs from 42 hospitals from 5 Latin American countries were invited to take an electronic, voluntary, anonymous survey regarding knowledge, attitudes, and perceptions of AS, AMR, and AU between March-April 2023. FINDINGS: Overall, 996 HCWs completed the survey (52% physicians, 32% nurses, 11% pharmacists, 3% microbiologists, and 2% "other"). More than 90% of respondents indicated optimizing AU was a priority at their healthcare facility (HCF), 69% stated the importance of AS was communicated at their HCF, and 23% were unfamiliar with the term "antibiotic stewardship". Most (> 95%) respondents acknowledged that appropriate AU can reduce AMR; however, few thought AU (< 30%) or AMR (< 50%) were a problem in their HCF. Lack of access to antibiogram and to locally endorsed guidelines was reported by 51% and 34% of HCWs, respectively. Among prescribers, 53% did not consider non-physicians' opinions to make antibiotic-related decisions, 22% reported not receiving education on how to select antibiotics based on culture results and 60% stated patients and families influence their antibiotic decisions. CONCLUSIONS: Although HCWs perceived improving AU as a priority, they did not perceive AU or AMR as a problem in their HCF. AS opportunities include improved access to guidelines, access to AMR/AU data, teamwork, and education on AS for HCWs and patients and families.

Early in vitro and in vivo development of high-level daptomycin resistance is common in mitis group Streptococci after exposure to daptomycin.

The development of high-level daptomycin resistance (HLDR; MIC of ≥ 256 mg/liter) after exposure to daptomycin has recently been reported in viridans group streptococcus (VGS) isolates. Our study objectives were as follows: to know whether in vitro development of HLDR after exposure to daptomycin was common among clinical isolates of VGS and Streptococcus bovis; to determine whether HLDR also developed during the administration of daptomycin to treat experimental endocarditis caused by the daptomycin-susceptible, penicillin-resistant Streptococcus mitis strain S. mitis 351; and to establish whether combination with gentamicin prevented the development of HLDR in vitro and in vivo. In vitro studies were performed with 114 VGS strains (mitis group, 92; anginosus group, 10; mutans group, 8; and salivarius group, 4) and 54 Streptococcus bovis strains isolated from 168 consecutive patients with infective endocarditis diagnosed between 1995 and 2010. HLDR was only observed after 24 h of exposure to daptomycin in 27% of the mitis group, including 27% of S. mitis isolates, 47% of S. oralis isolates, and 13% of S. sanguis isolates. In our experimental model, HLDR was detected in 7/11 (63%) and 8/12 (67%) isolates recovered from vegetations after 48 h of daptomycin administered at 6 mg/kg of body weight/24 h and 10 mg/kg/24 h, respectively. In vitro, time-kill experiments showed that daptomycin plus gentamicin was bactericidal against S. mitis 351 at tested concentrations of 0.5 and 1 times the MIC and prevented the development of HLDR. In vivo, the addition of gentamicin at 1 mg/kg/8 h to both daptomycin arms prevented HLDR in 21 out of 23 (91%) rabbits. Daptomycin plus gentamicin was at least as effective as vancomycin plus gentamicin. In conclusion, HLDR develops rapidly and frequently in vitro and in vivo among mitis group streptococci. Combining daptomycin with gentamicin enhanced its activity and prevented the development of HLDR in most cases.

High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis.

We describe 3 patients with left-sided staphylococcal endocarditis (1 with methicillin-susceptible Staphylococcus aureus [MSSA] prosthetic aortic valve endocarditis and 2 with methicillin-resistant S. aureus [MRSA] native-valve endocarditis) who were successfully treated with high-dose intravenous daptomycin (10 mg/kg/day) plus fosfomycin (2 g every 6 h) for 6 weeks. This combination was tested in vitro against 7 MSSA, 5 MRSA, and 2 intermediately glycopeptide-resistant S. aureus isolates and proved to be synergistic against 11 (79%) strains and bactericidal against 8 (57%) strains. This combination deserves further clinical study.

Localización intraoperatoria de las recurrencias en cáncer de tiroides mediante la inyección de azul de metileno guiada por ecografía / Intraoperative localization of recurrences in thyroid cancer by ultrasound-guided injection of methylene blue

Introducción. La cirugía para extirpación de metástasis en un cuello previamente intervenido afronta un reto para lograr una resección exitosa. El presente estudio pretende demostrar la utilidad de la técnica de inyección de azul de metileno, guiada por ecografía, para la localización intraoperatoria de lesiones recurrentes en cáncer de tiroides, para facilitar su resección. Métodos. Se realizó un estudio observacional, descriptivo y retrospectivo, en pacientes reintervenidos por recurrencia de carcinoma diferenciado de tiroides, durante un periodo de dos años y medio. Se utilizó la inyección intratumoral de azul de metileno guiada por ecografía para su identificación intraoperatoria de recurrencia. Se hizo análisis de variables demográficas y clínicas. Resultados. Este estudio incluyó 10 procedimientos en 9 pacientes, 77,8 % mujeres, con una media de edad de 54 años. Todos tenían un nivel de tiroglobulina detectable y elevado antes de la intervención; posteriormente, el 89 %presentó un descenso y el 33 % una adecuada respuesta bioquímica. La técnica agregó 10 minutos al tiempo quirúrgico. En el 100 % se identificaron de manera intraoperatoria los ganglios marcados; el promedio de ganglios resecados fue de 12, de los cuales, 6 fueron positivos, todos con carcinoma papilar de tiroides. Esta técnica se consideró de gran utilidad y de bajo costo en todos los casos. Discusión. Esta técnica se muestra como una estrategia efectiva para la identificación intraoperatoria de las recurrencias corregionales en carcinoma de tiroides, permitiendo una disección ganglionar exitosa, disminuyendo complicaciones, tiempo quirúrgico y, especialmente, costos frente a otras intervenciones

Introduction. The approach of a previously operated neck for metastasis resection faces a challenge to achieve a successful resection. The present study aims to demonstrate the usefulness of the ultrasound-guided injection of methylene blue technique for the intraoperative localization of recurrent lesions in thyroid cancer to facilitate their resection. Methods. An observational, descriptive and retrospective study was conducted in patients reoperated for recurrences of differentiated thyroid carcinoma over a period of two and a half years, using ultrasound-guided intratumoral injection of methylene blue for its intraoperative identification. An analysis of demographic and clinical variables was carried out and its advantages over other methods were identified. Results. This study included 10 procedures in nine patients, 77.8% women and 22.2% men, with a mean age of 54 years. All had a detectable and elevated thyroglobulin level before the intervention, 89% had a decrease in its level and 33% had an adequate biochemical response. The technique added 10 minutes to the surgical time. All marked lymph nodes were identified intraoperatively. The average number of lymph nodes resected was 12, of which six were positive, all with papillary thyroid carcinoma. It was considered of great utility and low cost in all cases. Discussion. This technique shows to be an effective strategy for the intraoperative identification of locoregional recurrences in thyroid carcinoma, allowing a successful lymph node dissection, reducing complications, surgical time and especially costs compared to other interventions

Epidemiology and prognosis of coagulase-negative staphylococcal endocarditis: impact of vancomycin minimum inhibitory concentration.

This study describes coagulase-negative staphylococcal (CoNS) infective endocarditis (IE) epidemiology at our institution, the antibiotic susceptibility profile, and the influence of vancomycin minimum inhibitory concentration (MIC) on patient outcomes. One hundred and three adults with definite IE admitted to an 850-bed tertiary care hospital in Barcelona from 1995-2008 were prospectively included in the cohort. We observed that CoNS IE was an important cause of community-acquired and healthcare-associated IE; one-third of patients involved native valves. Staphylococcus epidermidis was the most frequent species, methicillin-resistant in 52% of patients. CoNS frozen isolates were available in 88 patients. Vancomycin MICs of 2.0 µg/mL were common; almost all cases were found among S. epidermidis isolates and did not increase over time. Eighty-five patients were treated either with cloxacillin or vancomycin: 38 patients (Group 1) were treated with cloxacillin, and 47 received vancomycin; of these 47, 27 had CoNS isolates with a vancomycin MIC <2.0 µg/mL (Group 2), 20 had isolates with a vancomycin MIC ≥ 2.0 µg/mL (Group 3). One-year mortality was 21%, 48%, and 65% in Groups 1, 2, and 3, respectively (P = 0.003). After adjusting for confounders and taking Group 2 as a reference, methicillin-susceptibility was associated with lower 1-year mortality (OR 0.12, 95% CI 0.02-0.55), and vancomycin MIC ≥ 2.0 µg/mL showed a trend to higher 1-year mortality (OR 3.7, 95% CI 0.9-15.2; P=0.069). Other independent variables associated with 1-year mortality were heart failure (OR 6.2, 95% CI 1.5-25.2) and pacemaker lead IE (OR 0.1, 95%CI 0.02-0.51). In conclusion, methicillin-resistant S.epidermidis was the leading cause of CoNS IE, and patients receiving vancomycin had higher mortality rates than those receiving cloxacillin; mortality was higher among patients having isolates with vancomycin MICs ≥ 2.0 µg/mL.

Risk factors for pericardial effusion in native valve infective endocarditis and its influence on outcome.

Data on the incidence, associated factors, and prognosis of pericardial effusion (PE) in patients with infective endocarditis (IE) are scarce. Patients with native valve IE were prospectively followed in our center from 1990 to 2007. A logistic regression analysis was performed to identify independent variables associated with PE and mortality. We included 479 episodes of IE from 459 patients (70% men, mean age 51 years). Small-to-moderate PE was observed in 109 episodes (23%) and large-to-very large PE was observed in 9 episodes (2%). Patients with small-to-moderate PE had a greater prevalence of intravenous drug use (38% vs 23%) and more frequent right-sided IE than patients without PE (33% vs 17%). Patients with large-to-very large PE had a higher rate of systemic emboli (22% vs 18%) and periannular abscess (22% vs 6%) than patients without PE. Renal failure was associated with a higher risk of PE (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.3 to 3.3); age was associated with a lower risk of PE (OR 0.98, 95% CI 0.97 to 0.99). One-year mortality of patients with IE with large-to-very large PE was higher than that of patients with small-to-moderate and absence of PE (56%, 18%, and 24%, respectively, p = 0.033). Large-to-very large PE increases the 1-year mortality of IE (OR 3.0, 95% CI 1.2 to 7.9). In conclusion, renal failure and younger age are associated with a higher risk of PE. Large-to-very large PE was associated with an increase in 1-year mortality.

Clinical utility of daptomycin in infective endocarditis caused by Gram-positive cocci.

Gram-positive bacteria account for >80% of all cases of endocarditis. Currently, staphylococci are the leading cause of endocarditis worldwide. Daptomycin is the drug of choice for empirical antibiotic therapy of staphylococcal endocarditis due to its optimal activity both against meticillin-susceptible Staphylococcus aureus and meticillin-resistant S. aureus (MRSA) strains. Daptomycin has not been proven to be superior to vancomycin in the treatment of MRSA endocarditis. However, daptomycin should be considered the drug of choice for the treatment of MRSA endocarditis caused by strains with a vancomycin minimum inhibitory concentration (MIC) of 2µg/mL, for heterogeneous vancomycin-intermediate S. aureus (hVISA) phenotypes and for glycopeptide-intermediate S. aureus (GISA) strains. Daptomycin is the drug of choice for rescue therapy in cases of MRSA endocarditis in which vancomycin has failed. The appropriate dose of daptomycin has not yet been established; however, for treatment of left-sided endocarditis the dose of daptomycin should be higher than the recommended dose of 6mg/kg/day. Combination antibiotic therapy with daptomycin (e.g. combined with fosfomycin) is a promising treatment for MRSA endocarditis and warrants further investigation. In vivo studies show that daptomycin is superior to vancomycin in the treatment of meticillin-resistant coagulase-negative staphylococci experimental endocarditis, although clinical data are required. Daptomycin could represent an efficacious treatment for vancomycin-resistant Enterococcus faecium endocarditis. Finally, the pharmacokinetic profile of daptomycin makes it an excellent drug for outpatient parenteral antimicrobial therapy.