Osteoarticular infections: insights on bacteremic clinical forms and antimicrobial alternatives against Pseudomonas aeruginosa from a translational perspective

Abstract

Osteoarticular infections are frequent in the clinical practice and have a high impact on patients and health systems. These infections may be associated with concomitant bacteremia and a characteristic feature is the presence of bacterial biofilm, which limits the efficacy of antimicrobial therapy. In recent years, the emergence of multidrug-resistant microorganisms has resulted in the need of new antimicrobial alternatives to improve patients’ outcomes. In this line, translational research plays a key role in providing therapeutic alternatives for the global management of osteoarticular infections. This thesis included clinical and experimental studies to deepen on the available knowledge of bacteremic osteoarticular infections (BOAs) and antimicrobial alternatives for these infections by Pseudomonas aeruginosa.

The first part of the thesis included four observational studies on bacteremic osteoarticular infections, performed at Hospital Universitari de Bellvitge (1985-2014). We observed that the incidence of BOAs increased during the study period, at the expense of nosocomial and healthcare-related infections, vertebral osteomyelitis (VO) and those affecting devices. Cases by methicillin-resistant Staphylococcus aureus (MRSA), Streptococci, Enterococci and Gram-negative bacilli (GNB) also increased. We then analyzed the association between BOAs and infective endocarditis (70 cases, 11.5% of endocarditis, 15% of OAs); there was an association between BOAs of the axial skeleton (arthritis or VO) and the presence of infective endocarditis. VO was mainly caused by low-virulent microorganisms (viridans and bovis Streptococci, Enterococci and coagulase-negative Staphylococci), whereas arthritis of the axial skeleton was mainly caused by S. aureus. The third study compared the characteristics of bacteremic septic arthritis according to the site acquisition. Nosocomial and healthcare-related cases affected more frequently older patients and with comorbidities and caused by MRSA and P. aeruginosa. Infections affecting the axial skeleton were more frequent in community-acquired and healthcare-related cases, whereas prosthetic joint infection was more common in nosocomial cases. Finally, 30-day mortality of BOAs was 12.2%, which was higher in peripheral septic arthritis and cases by MRSA. Mortality was lower in patients with peripheral septic arthritis managed with surgical debridement.

The second part of the thesis evaluated the role of therapeutic alternatives in OAs by P. aeruginosa. The first study was an observational study, which analysed the efficacy and therapeutic drug monitoring of continuous beta-lactam infusion in OAs by fluoroquinolone-resistant P. aeruginosa at Hospital Universitari de Bellvitge (2016-2018). 52 patients were included, 19 with fluoroquinolone-resistant strains (13; 68.4% MDR/XDR). Most patients had beta-lactam concentrations between 3-10xMIC and higher concentrations occurred in patients with renal impairment. There were no differences in failure rates between patients with fluoroquinolone-susceptible or resistant strains. The last two studies were experimental and used a dynamic in vitro biofilm model, the CDC Biofilm Reactor. The first evaluated the activity of ceftolozane-tazobactam, with/without colistin, against three MDR/XDR P. aeruginosa strains. Ceftolozane-tazobactam in monotherapy was ineffective and meropenem monotherapy was bactericidal against carbapenem-susceptible strains. Colistin was intitially effective, but regrowth occurred at the end of the experiments. Beta-lactam plus colistin combinations were more effective than monotherapies and prevented the emergence of colistin-resistant strains. Ceftolozane-tazobactam plus colistin was the most effective combination againts carbapenem-resistant strains, whereas meropenem plus colistin was for carbapenem-susceptible strains. The second study evaluated the pharmacokinetics/pharmacodynamics of continuous ceftazidime infusion, with/without colistin, against two susceptible strains (PAO1 and HUB8); growing clinically-achievable concentrations of ceftazidime (4-10-20-40 mg/L) were used. Higher ceftazidime concentrations (20-40) in monotherapy had higher anti-biofilm activity against PAO1, but not against HUB8. Ceftazidime resistance emerged with lower concentrations. Combinations of ceftazidime plus colistin increased the activity of monotherapies and prevented the emergence of colistin and ceftazidime resistance. With combinations against both strains, 40mg/L ceftazidime plus colistin had higher efficacy than 4mg/L ceftazidime plus colistin.

Los estudios clínicos y experimentales de esta tesis pretenden ampliar la información existente sobre las infecciones osteoarticulares bacteriémicas así como evaluar alternativas terapéuticas para estas infecciones por P. aeruginosa.

La primera parte de la tesis aborda la problemática de las infecciones osteoarticulares bacteriémicas e incluye 4 estudios realizados en el Hospital Universitari de Bellvitge (1985-2014). La incidencia de infecciones osteoarticulares aumentó a lo largo de los años, con incremento de las infecciones nosocomiales y asociadas al ámbito sanitario, además de las infecciones asociadas a material ortopédico y la osteomielitis vertebral. Los casos por S. aureus meticilin-resistente (SARM), estreptococos, enterococos y bacilos gram-negativos aumentaron. La infección osteoarticular bacteriémica con afectación del esqueleto axial (artritis o espondilitis) se asoció independientemente a la presencia de endocarditis infecciosa. Los casos nosocomiales y asociados al ámbito sanitario se presentaron más frecuentemente en individuos mayores y con más comorbilidades y fueron causados por SARM y P. aeruginosa. La mortalidad fue del 12.2%, mayor en la artritis séptica periférica y en infecciones por SARM. La mortalidad fue menor en los pacientes con artritis séptica periférica tratados con desbridamiento quirúrgico.

La segunda parte de la tesis pretende encontrar alternativas terapéuticas para la infección osteoarticular por P. aeruginosa. El primer estudio analiza infecciones osteoarticulares por P. aeruginosa tratados con beta-lactámicos en perfusión continua y monitorización plasmática de concentraciones. 52 pacientes incluidos, 19 con cepas resistentes a fluoroquinolonas (13;68.4% cepas MDR/XDR). La mayoría tenían concentraciones de 3-10xMIC, concentraciones superiores frecuntes en insuficiencia renal. No hubo diferencias en el fracaso entre aquellos con infecciones por cepas resistentes o sensible a fluoroquinolonas. Se realizaron dos estudios experimentales con un modelo in vitro dinámico de biofilm. El primero evalúa la actividad de ceftolozano-tazobactam, con/sin colistina, frente a P. aeruginosa multiresistente. Ceftolozano-tazobactam con colistina fue el tratamiento más eficaz ante la cepa resistente a meropenem, mientras que meropenem con colistina lo fue frente a cepas sensibles a carbapenems. El segundo analiza las características farmacocinéticas/farmacodinámicas de ceftazidima en infusión continua, con/sin colistina, frente P. aeruginosa sensible. Frente PAO1, se observó una actividad anti-biofilm ligeramente superior con concentraciones de ceftazidima de 20-40mg/L, además de mayor actividad anti-biofilm frente ambas cepas con combinaciones de colistina y ceftazidima a concentraciones de 40mg/L que con 4mg/L.