Daniel Curcio

Multidrug-Resistant Gram-Negative Bacterial Infections: Are you Ready for the Challenge?

Paralleling the developments in Gram-positive bacteria, infections caused by multidrug-resistant (MDR) Gramnegative bacilli have become a growing challenge. The most important resistance problems are encountered in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp., with increasing trends observed for all major anti- Gram-negative agents (beta-lactams, fluoroquinolones and aminoglycosides). A matter of major concern is the emergence of new beta-lactamases capable of degrading the expanded-spectrum cephalosporins and/or carbapenems, such as the extended-spectrum beta-lactamases (ESBLs) and the carbapenemases (ie. KPC, NDM and other metallo-β; -lactamases). This paper reviews the evidence in the published literature of the pharmacokinetic/pharmacodynamic profile, clinical efficacy of new antimicrobial agents, against MDR- Gram-negative pathogens, such us: i-new carbapenems (doripenem, biapenem, panipenem, tonopenem, FSI-1686); ii-new cephalosporins (ceftaroline, ceftobiprole); iii-tigecycline; and iv- β- lactamases inhibitors (BLI-489, Ro 48-1220, ME 1071, aviactam [NXL104]).

Uso inicial de tigeciclina en Argentina

Tigecycline is a new class of antibiotics active against emerging nosocomial pathogens as methicillin-resistant Staphylococcus aureus, extended spectrum (3-lactamases-producing enterobacteria and multidrug-resistant Acinetobacter sp. It was approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections, but its pharmacological and microbiological profile is attractive to physicians for using it in other pathologies caused by resistant pathogens. The aim of this study was to evaluate in which indications tigecycline was used in Argentinian usual clinical settings during the first months after its launch. We analyzed tigecycline prescriptions in 69 patients with severe infections in 15 institutions. Fifteen patients (21%) received tigecycline for approved indications, and 54 (79%) for off label indications (56%) with scientific support and 23%> with limited or without any scientific support). The most frequent off label use was ventilator associated pneumonia (VAP) (36 patients). The etiology of the infections was established in 61%> of the patients. In all cases the isolated bacteria were multi-drug resistant (MDR) Acinetobacter s/?.-carbapenems included. Our study shows that the off label use of tigecycline is frequent, specially in VAP. One of the reasons could be that for MDR-Acinetobacter sp. -VAP, there are few therapeutic options (for instance: colistin). Physicians must evaluate the benefits/risks to use this antibiotic for indications that lack rigorous scientific support.

Comment on: Efficacy and safety of tigecycline: a systematic review and meta-analysis

published a systematic review andmeta-analysis of 15 randomized clinical trials (RCTs) that com-pared tigecycline with other antibiotics for the treatment ofsevere infections. The overall 30 day mortality was estimatedto be higher with tigecycline compared with other regimens[relative risk (RR) 1.29, 95% confidence interval (CI) 1.02–1.64];therefore, the authors recommend that clinicians should avoidtigecycline monotherapy in the treatment of severe infectionsand reserve it as a last-resort drug.The authors performed a test of heterogeneity betweenstudies. Given that the test result was not significant at 5%, theydecided to pool all the RRs by using a fixed-effect meta-analysismodel.Unfortunately,thisisacommonpracticeinmeta-analysis,which usually leads to very misleading results. First of all, thepooled RR as well as its standard error are sensitive to theestimation of the between-studies standard deviation (SD).

Tigecycline for severe infections: the gap between the warning and the necessity

Sir, I have received the US FDA warning describing an increased mortality risk associated with the use of tigecycline when compared with other drugs in the treatment of avarietyof serious infections. The increased risk of mortality was determined using a pooled analysis of randomized clinical trials (RCTs) and was seen most clearly in patients treated for hospital-acquired pneumonia (HAP), especially ventilator-associated pneumonia (VAP), but was also seen in patients with complicated skin and skin structure infections (cSSSIs), complicated intra-abdominal infections (cIAIs), infections due to resistant pathogens and diabetic foot infections. 1 Although for each indication the mortality difference was not statistically significant, trends were present and, when pooled, a statistically significant difference was observed. Based on these data, the FDA recommends that alternatives to tigecycline should be considered in patients with severe infections. The FDA recommendation is thus based upon a combination of RCTs that were the scientific support for the FDA licensing approvals for tigecycline in cSSSI, 2 cIAI 3 and communityacquired bacterial pneumonia (CABP), 4 as well as other studies in which tigecycline did not achieve outcomes suitable for such approvals (e.g. VAP). 5 Clinicians are now faced with the conundrum that at present the FDA licensed approvals for tigecycline remain unaltered but an alert has been issued against severe sepsis, although tigecycline does not have an explicit licence for this indication. Understanding the context of both the alert and its relevance to the clinical circumstances facing doctors as they make decisions about severe sepsis management is therefore critical. The context of the FDA alert is that it is based on RCTs where only a small percentage of patients with severe infections were included. No severity score was used in the cSSSI RCT (only 25.8% of patients required surgery/drainage), 2 only 19.8% from the CABP RCT showed high pneumonia severity index (IV-V) values 4 and the mean APACHE II score in patients from the cIAI and HAP RCTs was ≤15 (6.2 and 12.3, respectively). 3,5 This lack of patients with severe sepsis in licensing studies is commonplace and not unique to tigecycline. For example the Infectious Diseases Society of America guidelines recommend doripenem for the treatment of high-risk community-acquired and healthcare-acquired IAI in adults, although appendicitis without peritonitis was the diagnosis in nearly 50% of patients included in the RCT and 87.7% of the patients had an APACHE II score ≤10. 6 Thus although RCTs are used extensively to characterize the efficacy and safety of new treatment options, the characteristics of the trial participants often do not reflect those of the wider patient population. Notwithstanding the FDA approved indications for the drug, we have published data indicating that tigecycline’s pharmacological and microbiological profiles encourage its use for off-label indications in severely ill patients in intensive care units [e.g. VAP due to multidrug-resistant (MDR) Acinetobacter spp.]. 7‐9 This practice is justified by the high regional resistance rates of MDR pathogens with limited therapeutic options [e.g. carbapenemresistant Acinetobacter spp. and Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae]. In addition, there is good evidence that early effective therapy for such infections in critically ill patients improves outcomes. 10,11

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)

Resumen La neumonia 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 mayoria de ellos concuerdan en que el tra-tamiento antimicrobiano debe ser ajustado inicialmente de acuerdo con la gravedad de la infeccion o con la presencia de co-morbilidades y el patogeno etiologico. Aun asi, se puede notar una gran variabilidad entre los diferentes paises en la seleccion de la eleccion primaria de los agentes antimicrobianos, incluso en los casos considerados como de bajo riesgo. Este hecho puede de-berse a las multiples causas microbianas de la NAC y las especialidades medicas involucradas, como asi tambien los diferentes sistemas de asistencia de salud que afectan la disponibilidad o el costo de los antimicrobianos. No obstante, muchos paises o regiones adoptan alguno de los lineamientos o disenan sus propias recomendaciones independientemente de los datos locales, probablemente debido a la escasez de dichos datos. Por esta razon desarrollamos lineamientos para el tratamiento inicial de la NAC hacia el ano 2002, sobre la base de varias evidencias locales en Sudamerica (ConsenSur I). Sin embargo, varios temas merecen discutirse nuevamente

Ventilator-Associated Pneumonia in Patients with 2009 Pandemic Influenza A (H1N1) Infection: An Observational Study

The 2009 pandemic influenza A (H1N1) virus has emerged to cause the first pandemic of the 21st century. As of mid-November, approximately 500,000 confirmed cases of 2009 pandemic influenza A (H1N1) infection had been reported to the World Health Organization (WHO). The true worldwide disease burden is yet unknown, but at least 100 times more people than those reported to the WHO have already been infected with this virus 1. Most clinical disease is relatively mild but complications leading to hospitalization, with the need for intensive care, can occur, especially in very young children, during pregnancy, in morbid obesity, and in those with underlying medical conditions such as chronic lung and cardiac diseases, diabetes, and immunosuppression. Pneumonia is the most common and serious complication of the 2009 influenza A (H1N1) and it has played a significant role in fatal cases 2. The clinical course of some cases was characterized by severe pneumonia, hypoxemia with multifocal infiltrates on chest x-ray, and rapid progression to acute respiratory distress syndrome and renal or multi-organ failure with requirement of advanced mechanical ventilation 3. The aim of this study was to describe the epidemiological characteristics, clinical features, antibiotic treatment and outcomes of patients with confirmed 2009 influenza A (H1N1) infection complicated by ventilator-associated pneumonia (VAP). The participating hospitals were from Argentina (n=2), Bolivia (n=1), Chile (n=2), Colombia (n=5), Ecuador (n=1), and Peru (n=2). The physicians used a standardized website form (http://www.clinicalrec.com.ar) that included demographic data, influenza-vaccination history for the previous year, risk factors for influenza disease, severity of illness at admission (measured by the APACHE II and SOFA scores), length of stay, microbiological documentation of VAP, antibiotic treatment and clinical outcomes. Established criteria were used to define VAP 4. Bacterial identification and susceptibility testing was performed according to the clinical microbiology procedures handbook 5. Outcomes were defined as clinical success (partial or complete improvement of signs/symptoms of infection), clinical failure (no improvement or deterioration of signs/symptoms of infection), or indeterminate. The study was based on a anonymous case registry methodology and did not require the prescription of specific drugs or other treatments, nor the performance of procedures or diagnostic tests other than the ones prescribed by the responsible physician; therefore inform consent was not required by the institutional review board from the participating institutions. Results are expressed as proportions. When applicable, two tailed hypothesis testing for difference in proportions was used (Proportion Test); a p value of 30m/kg), asthma, and diabetes mellitus, chronic obstructive were the risk factors more frequently observed (50% -20/40-, 42.5% -17/40and 25% -10/40respectively). No patient had received influenza-vaccination during the previous year, also, no patients had pathogens isolated in the respiratory samples taken at admission. The mean of days of mechanical ventilation (MV) and length of stay (LOS) was 10.9 days (range 1-72; SD ± 11.63) and 12.3 days (range 1-72; SD ± 12.5) respectively. Fifty-four percent of the patients (32/59) had VAP as nosocomial complication. The mean ICU stay before diagnosis of VAP was 9.5 days (range, 5-16). In 31/32 patients (97%) 41 microorganisms considered as the causative agent of the infection were isolated (monomicrobial 69% [22/32] and polymicrobial 31% [10/32]). Among these isolates, Acinetobacter spp. (72%, 23/32; in 37% of cases carbapenem-resistant), methicillin-resistant Staphylococus aureus (37.5%, 12/32), and extended-spectrum b-lactamase-producing Enterobacteriaceae (10%, 13/132) were the most common microorganisms, followed by Pseudomonas aeruginosa (6%, 2/32, in both cases carbapenem-susceptible) and Stenotrophomonas maltophilia (3%, 1/32). Seventeen patients (53%) had VAP with bacteremia; in all cases with positive blood cultures for Acinetobacter spp. Overall, attending physicians reported clinical success in 28 patients (47.5%). The clinical success rate showed no significant difference between patients with or without VAP (47% vs 48%, p= 0.6049; 95% CI= -0.27-0.24), as well as in patients with bacteriemic and non-bacteriemic VAP (35% vs 60%, p= 0.2971; 95% CI= -0.59-0.09) (Table 1). The global mortality was 49% (29/59 patients) without significant differences between patients with or without VAP (59% 1 Instituto Sacre Cour, Argentina; 2 Hospital Guillermo Grant Benavente, Chile; 3 Hospital Regional Rio Grande, Argentina; 4 Clinica Sagrado Corazon, Colombia; 5 Hospital Central de la Fuerza Aerea y Clinica San Gabriel, Peru; 6 Hospital Obrero No 1, Bolivia; 7 Hospital Eugenio Espejo, Ecuador; 8 Hospital San Pablo De Coquimbo, Chile; 9 Clinica Crecer, Colombia; 10 Clinica Universitaria del Norte de Santander, Colombia; 11 Clinica Universitaria Bolivariana, Colombia; 12 Clinica San Gabriel, Peru; 13 Fundacion Cardioinfantil, Colombia.