Impact of genetic targets on primary brain tumor therapy: what's ready for prime time?

Primary brain tumors constitute a substantial public health problem with 66,290 cases diagnosed in the US in 2012, and 13,700 deaths recorded. With discovery of genetic factors associated with specific brain tumor subtypes, the goal of therapy is changing from treating a class of tumors to developing individualized therapies catering to the molecular composition of the actual tumor. For oligodendrogliomas, the loss of 1p/19q due to an unbalanced translocation improves both survival and the response to therapy, and is thus both a prognostic and a predictive marker. Several additional genetic alterations such as EGFR amplification, MGMT methylation, PDGFR activation, and 9p and 10q loss, have improved our understanding of the characteristics of these tumors and may help guide therapy in the future. For astrocytic tumors, MGMT is associated with a better prognosis and an improved response to temozolomide, and for all glial tumors, mutations in the IDH1 gene are possibly the most potent of good prognostic markers. Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance. Newer markers, such as CD 133, require additional investigation to determine their prognostic and predictive utility. In medulloblastomas, markers of WNT activation, MYCC/MCYN amplification, and TrkC expression levels are reliable prognostic indicators, but do not yet drive specific treatment selection. Many other proposed markers, such as 17q gain, TP53 mutations, and hMOF protein expression show promise, but are not yet ready for prime time. In this chapter, we focus on the markers that have shown convincing prognostic, predictive, and diagnostic value, and discuss potential markers that are being currently being intensively investigated. We also discuss serum profiling of tumors in an effort to discover additional potential markers.

Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999-2000).

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a global surveillance study established in 1999 to monitor antibacterial resistance of respiratory tract organisms. Thirteen centers from Argentina, Brazil and Mexico participated during 1999-2000; they collected 1806 isolates (Streptococcus pneumoniae 518, Haemophilus influenzae 520, Moraxella catarrhalis 140, Staphylococcus aureus 351, S. pyogenes 277). Overall, 218 (42.1%) of the S. pneumoniae isolates had reduced susceptibility to penicillin, 79 (15.3%) were penicillin-resistant and 79 (15.3%) were erythromycin-resistant. Mexico had the highest prevalence of penicillin (76.5%) and erythromycin (31.2%) resistance. Of 77 erythromycin-resistant S. pneumoniae tested for resistance genotype, 43 possessed mef(A), 33 possessed erm(B) and 1 possessed both erm(B) and mef(A) mechanism. All S. pneumoniae isolates were fully susceptible to telithromycin, linezolid, teicoplanin and vancomycin. Among H. influenzae isolates, 88 (16.9%) produced beta-lactamase, ranging from 11% (Brazil) to 24.5% (Mexico). Among M. catarrhalis isolates, 138 (98.6%) produced beta-lactamase. Twenty-four (8.7%) of the S. pyogenes isolates were erythromycin-resistant; resistance being attributable to mefA (n=18), ermTR (n=5) and ermB (n=1). All H. influenzae, M. catarrhalis and S. pyogenes were fully susceptible to telithromycin. Methicillin resistance was found in 26.5% of the S. aureus isolates (Argentina 15%; Mexico 20%; Brazil 31.3%). Telithromycin was effective against 97.7% of methicillin-susceptible isolates. PROTEKT confirms that antibacterial resistance is an emerging problem in Latin America. The previously reported high levels of pneumococcal resistance to the beta-lactam and macrolides were exceeded. New agents that do not induce resistance or that exert low selective pressure, e.g. telithromycin, are essential to safeguard future antibacterial efficacy.

Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999-2000)

PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a global surveillance study established in 1999 to monitor antibacterial resistance of respiratory tract organisms. Thirteen centers from Argentina, Brazil and Mexico participat ed during 1999-2000; they collected 1,806 isolates (Streptococcus pneumoniae 518, Haemophilus influenzae 520, Moraxella catarrhalis 140, Staphylococcus aureus 351, S. pyogenes 277). Overall, 218 (42.1 percent) of the S. pneumoniae isolates had reduced susceptibility to penicillin, 79 (15.3 percent) were penicillin-resistant and 79 (15.3 percent) were erythromycin-resistant. Mexico had the highest prevalence of penicillin (76.5 percent) and erythromycin (31.2 percent) resistance. Of 77 erythromycin-resistant S. pneumoniae tested for resistance genotype, 43 possessed mef(A), 33 possessed erm(B) and 1 possessed both erm(B) and mef(A) mechanism. All S. pneumoniae isolates were fully susceptible to telithromycin, linezolid, teicoplanin and vancomycin. Among H. influenzae isolates, 88 (16.9 percent) produced b-lactamase, ranging from 11 percent (Brazil) to 24.5 percent (Mexico). Among M. catarrhalis isolates, 138 (98.6 percent) produced b-lactamase. Twenty-four (8.7 percent) of the S. pyogenes isolates were erythromycin-resistant; resistance being attributable to mefA (n=18), ermTR (n=5) and ermB (n=1). All H. influenzae, M. catarrhalis and S. pyogenes were fully susceptible to telithromycin. Methicillin resistance was found in 26.5 percent of the S. aureus isolates (Argentina 15 percent; Mexico 20 percent; Brazil 31.3 percent). Telithromycin was effective against 97.7 percent of methicillin-susceptible isolates. PROTEKT confirms that antibacterial resistance is an emerging problem in Latin America. The previously reported high levels of pneumococcal resistance to the b-lactam and macrolides were exceeded. New agents that do not induce resistance or that exert low selective pressure, e.g. telithromycin, are essential to safeguard future antibacterial efficacy

Pathogen frequency and resistance patterns in Brazilian hospitals: summary of results from three years of the SENTRY Antimicrobial Surveillance Program.

BACKGROUND: Pathogen frequency and resistance patterns may vary significantly from country to country and also in different hospitals within a country. Thus, regional surveillance programs are essential to guide empirical therapy and infection control measures. METHODS: Rank order of occurrence and antimicrobial susceptibility of pathogenic species causing bloodstream infections (BSI), lower respiratory tract infections (LRTI), wound or skin and soft tissue infections (WSSTI), and urinary tract infections (UTI) in hospitalized patients were determined by collecting consecutive isolates over a specified period of time, as part of the SENTRY Antimicrobial Resistance Surveillance Program (SENTRY). All isolates were tested by reference broth microdilution. RESULTS AND CONCLUSIONS: A total of 3,728 bacterial strains were obtained from January, 1997, to December, 1999, from 12 Brazilian hospitals located in 4 states. The largest number of isolates were obtained from patients with BSI (2,008), followed by LRTI (822 cases), UTI (468 cases), and WSSTI (430 cases). Staphylococcus aureus was the most frequently isolated pathogen in general (22.8% - 852 isolates), followed by E. coli (13.8% - 516 cases) and Pseudomonas aeruginosa (13.3% - 496 cases). Staphylococcus aureus was also the most common species isolated from BSI (23.6%) and WSSTI (45.8%), and P. aeruginosa was the most frequent species isolated from patients with LRTI (29.4%). The main bacterial resistance problems found in this study were: imipenem resistance among P. aeruginosa (69.8% susceptibility) and Acinetobacter spp. (88.1% susceptibility); ESBL production among K. pneumoniae (48.4%) and E. coli (8.9%); resistance to third generation cephalosporins among Enterobacter spp. (68.1% susceptible to ceftazidime) and oxacillin resistance among S. aureus (34.0%) and coagulase negative staphylococci (80.1%). Only the carbapenems (88.1% to 89.3% susceptibility) showed reasonable activity against the Acinetobacter spp. isolates evaluated.

Evaluation of the in vitro activity of 9 antimicrobials against bacterial strains isolated from patients in intensive care units in brazil: MYSTIC Antimicrobial Surveillance Program.

Multi-resistant bacterial strains are increasingly prevalent in hospital environments. Bacterial resistance is an important problem, especially for practitioners in intensive care units (ICUs) because of the selective pressure on the prevalent bacteria in these environments. The MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) study has been monitoring the performance of carbapenems and other antibiotics in different hospitals for at least 3 years. The in vitro activities of meropenem, imipenem, ceftazidime, cefepime, cefotaxime, ciprofloxacin, piperacilin/tazobactam, gentamicin, and tobramycin were compared against 452 recent clinical aerobic isolates. The isolates consisted of 19 species of Gram-negative bacteria (n=290) including K. pneumoniae (n=49), E. coli (n=48), A. baumannii (n=47), Enterobacter spp. (n=41), and P. aeruginosa (n=33) and 9 species of Gram-positive bacteria (n=162) including Staphylococcus aureus (n=63), Enterococcus faecalis (n=22), Streptococcus pneumoniae (n=22) and coagulase negative Staphylococci (n=21). All isolates were collected from ICU patients. Minimal inhibitory concentrations (MICs) were determined by Etest methodology, using standardized and controlled procedures. Meropenem and imipenem showed the lowest MIC(90) for all species tested. Gram-negative isolates showed the following overall resistance percentages to the other 7 drugs: tobramycin (43.1%), cefotaxime (38.6%), gentamicin (34.1%), ceftazidime (31.7%), ciprofloxacin (25.5%), piperacillin/tazobactam (26.9%), and cefepime (18.6%). Carbapenems were the most active drugs overall and only P. aeruginosa presented some degree of resistance (18.2%). We also evaluated the production of extended spectrum beta-lactamase (ESBL) among all Enterobacteriaceae members (n=176) by Etest/ESBL strip. ESBL production was detected in 51 strains (29.0%). Among them, Klebsiella pneumoniae was the most prevalent at 59.2%, followed by Enterobacter spp. (19.5%) and E. coli (14.6%). The high level of resistance against several antimicrobials and the alarming rate of ESBL production may restrict therapeutic choice to the carbapenems in this selected group of patients.

Results of the 1997 SENTRY Antimicrobial Surveillance Program in Three Brazilian Medical Centers.

The SENTRY Antimicrobial Surveillance Program began in January, 1997, and is designed to monitor nosocomial and selected community acquired infections via a worldwide surveillance network of sentinel hospitals distributed equally by geographic location and size. Three sites in Brazil - Rio de Janeiro, Florianópolis, and São Paulo - participated in the SENTRY Antimicrobial Surveillance Program stet. Rank order of occurrence and antimicrobial susceptibility of pathogenic species causing bloodstream infections, pneumonia, wound or skin and soft tissue infections, and urinary tract infections (UTI) in hospitalized patients were determined by collecting consecutive isolates over a specified period of time. Antimicrobial susceptibilities of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis obtained from outpatients with respiratory tract infections were also evaluated. The isolates for the evaluated infections were: 1) bloodstream - 20 consecutive isolates in each calendar month during a 12-month period; 2) pneumonia - 100 consecutive isolates over a 6 month period; 3) wound or skin and soft tissue - 50 consecutive isolates over a 3 month period; and 4) UTI - 50 consecutive isolates over a 3 month period. Each hospital also contributed, over a 6 month period, consecutive clinically significant outpatient isolates (one isolate per patient) of S. pneumoniae, H. influenzae, and M. catarrhalis that were considered pathogens in respiratory tract infections. Data collected for each isolate included species identification, antimicrobial susceptibility profile, date of isolation, and specimen type. Molecular studies were performed on selected isolates. A total of 1,241 bacterial strains were obtained; the majority were cultured from hospitalized patients, while 139 were fastidious organisms from community acquired respiratory tract infections. Gram-negative bacilli and S. aureus were the predominant pathogens, and Enterobacter spp. was a significant pathogen. The predominance of P. aeruginosa and Acinetobacter spp. and the significant levels of resistance to most agents are of major concern, as is the epidemic rate of ESBL-producing strains of Klebsiella spp. and E. coli in Brazil, which is much higher than rates seen in other areas of the world. Resistance among P. aeruginosa and the Enterobacteriaceae to fluoroquinolones, oxacillin-resistant S. aureus, and penicillin- and trimethoprim-sulfamethoxazole-resistant pneumococci were other significant resistance issues identified in this surveillance study. Vancomycin resistance among the enterococci, S. aureus, and S. pneumoniae was not identified. This benchmark study will serve as comparison for future surveillance studies, including the ongoing SENTRY program, to monitor emerging resistance trends in Brazil. The high rates of resistance observed in this study underscore the need for global surveillance and local action.

Evaluation of the Antimicrobial Activity of Sparfloxacin, Relative to Other Oral Antibiotics Against 1,125 Bacterial Isolates from 10 Medical Centers in Brazil.

A multicenter study was carried out in order to compare the in vitro activity of sparfloxacin to ciprofloxacin, amoxicillin/clavulanic acid, cephalexin, cefuroxine and azithromycin, against 1,125 microorganisms recently isolated from clinical specimens, most of them representative of respiratory tract infections. Sparfloxacin demonstrated potent action and was more active than the beta-lactam agents and azithromycin against most of the bacterial strains tested. Sparfloxacin was more potent (96% and 95% sensitivity, with MIC(90) of 0.19µg/mL and 0.5µg/mL, respectively)than the other antimicrobial agents tested against the Enterobacteriaceae family (Escherichia coli and Elebsiella pneumoniae). It was found to be equivalent in activity to ciprofloxacin (96% and 91% sensitivity and MIC(90) of 0.25 and 0.75µg/mL, respectively). Sparfloxacin was also found to be very active against the most fastidious microorganisms commonly associated to respiratory tract infections such as the penicillin-susceptible and resistant Streptococcus pneumoniae (MIC(90) 0.5µg/mL and 0.38µg/mL, respectively), ampicillin-susceptible and -resistant Haemophilus influenzae (MIC(90) 0.016µg/mL and 0.38µg/mL, respectively), beta-lactamase producing Moraxella catarrhalis (MIC(90) 0.032µg/mL) and non beta-lactamase producing M.catarrhalis (MIC(90) 0.5µg/mL).

Evaluation of the in vitro activity of cefepime compared to other broad-spectrum cephalosporins against clinical isolates from eighteen Brazilian hospitals by using the Etest.

The in vitro activity of cefepime was compared to that of ceftazidime, ceftriaxone, and cefotaxime in a multicenter study involving 10 clinical microbiology laboratories and clinical isolates from 18 Brazilian hospitals from 7 cities (4 states). A total of 982 isolates consecutively collected between December 1995 and March 1996 were susceptibility tested by using Etest and following the NCCLS procedures for agar diffusion tests. The cefepime spectrum was broader than that of the other broad-spectrum cephalosporins against both Gram-negative rods and Gram-positive cocci. Cefepime was particularly more active against Enterobacter sp. (MIC90, 2 micrograms/ml), Serratia sp. (MIC90, 2 micrograms/ml) and oxacillin-susceptible Staphylococcus aureus (MIC90, 3 micrograms/ml). Against Pseudomonas aeruginosa, cefepime (MIC90, 16 micrograms/ml) was slightly more active than ceftazidime (MIC90, 32 micrograms/ml) and 8- to 16-fold more active than ceftriaxone of cefotaxime (MIC90, > 256 micrograms/ml). Our results show that nosocomial bacteria, especially Gram-negative rods, have a high rate of cephalosporin resistance in Brazil. However, part of these resistant bacteria remains susceptible to cefepime. The Etest was shown to be an excellent method for multicenter studies of the in vitro evaluation of new antimicrobial agents.

Comparative in vitro Activity of Meropenem Versus Other Extended-Spectrum Antimicrobial Agents Against 2,085 Clinical Isolates Tested in 13 Brazilian Centers.

Meropenem is a parenteral carbapenem antibacterial agent with a very broad spectrum of antibacterial activity. It is the second agent of its class to become available in Brazil. The in vitro antibacterial activity of meropenem was compared with imipenem and four other antimicrobial agents in a multicenter study. This study involved 13 clinical microbiology laboratories, 10 of which came from 8 Brazilian states. A total of 2,085 clinical isolates consecutively collected between December 1995 and March 1996 were susceptibility tested using the Etest and following the NCCLS procedures. Meropenem inhibited more than 90% of isolates of Enterobacteriaceae at 0.5 µg/mL, except for Citrobacter sp. (1 µg/ml). Generally, meropenem was slightly more active than imipenem against Gram-negative organisms and its spectrum of antimicrobial activity was broader than those of all other drugs tested. Against Pseudomonas aeruginosa, meropenem (MIC50, 0.38 µg/ml) was approximately 8-fold more active than imipenem (MIC 50,3 µg/mL). Imipenem was two-to eight-fold more active than meropenem against some Gram-positive specees oxacillin, including Enterococcus faecalis (MIC 50 of 0.75 µg/mL and 2 µg/mL respectively), oxacillin-susceptible Staphylococcus aureus (MIC 50 of 0.47 &mul;g/mL and 0.094 µg/mL), oxacillin-susceptible Staphylococcus epidermidis (MIC 50 of 0.064 µg/mL and 0.5mg/mL). Against Streptococcus sp. meropenem was slightly more active than imipenem (MIC 50, 0.016 µg/mL). The results of this study may be used to guide empiric therapy in Brazil and indicates that meropenem may have an important role in the treatment of infections caused by multiresistant strains of bacteria.

Infecçöes relacionadas ao cateter venoso central em terapia intensiva / Central venous catheter-related infections in critically-ill-patients

OBJETIVO. Determinar a incidência, a etiologia e os fatores de risco das infecçoes relacionadas ao cateter venoso central em terapia intensiva. METODOLOGIA. Estudo observacional de coorte, prospectivo, em pacientes criticamente enfermos submetidos à cateterizaçao venosa profunda por punçao percutânea. Realizadas culturas quantitativa da pele, semiquantitativa da ponta e quantitativa do canhao do cateter, e hemocultura periférica. Os possíveis fatores de risco foram submetidos à análise univariada e multivariada. RESULTADOS. Foram estudados 57 períodos de cateterizaçao em 51 pacientes. A incidência de infecçao local foi de 21,1 por cento (33,8/1.000 dias-cateter), e de bacteremia, 8,7 por cento (l4,1/1.000 dias-cateter). A pele no local de inserçao estava colonizada em 32,7 por cento dos pacientes e o canhao, em 29,1 por cento. A origem dos microrganismos causadores de infecçao foi a pele em 41,2 por cento, o canhao em 29,4 por cento, infecçao a distância em 5,9 por cento, e nao ficou esclarecida em 23,5 por cento dos casos. Estafilococos coagulase-negativa foram os agentes etiológicos predominantes. Identificou-se, como variáveis independentemente associadas à infecçao local, a purulência no orifício de inserçao e a utilizaçao de outro dispositivo intravascular. As variáveis independentemente associadas à bacteremia foram a inserçao na veia jugular interna e a colonizaçao do canhao do cateter. CONCLUSOES. A bacteremia é uma complicaçao importante do cateterismo venoso central em terapia intensiva. Os estafilococos coagulase-negativa predominam nesta modalidade de infecçao hospitalar. A inserçao do cateter na veia jugular interna e a colonizaçao do canhao aumentam o risco de bacteremia relacionada à linha venosa central.

[Central venous catheter-related infections in critically ill patients]. / Infecções relacionadas ao cateter venoso central em terapia intensiva.

BACKGROUND: To determine incidence rate, etiology and risk factors for central venous catheter (CVC)-related infections in critically-ill patients, a prospective cohort study was conducted in the general Intensive Care Unit (ICU) of a 212 bed Hospital in Florianópolis, Brazil. MATERIAL AND METHOD: Patients admitted to ICU between May 1993 and February 1994, exposed to short-term CVC, were included in the study. Quantitative skin culture at CVC insertion site, semi-quantitative CVC tip culture, quantitative hub culture, and peripheral blood-culture were done. Results were submitted to univariate and multivariate analysis. RESULTS: Fifty-seven catheterization periods were analysed in 51 patients. The incidence rate was 21.1% (33.1 per 1,000 catheter-days) for local infection, and 8.7% (14.1 per 1,000 catheter-days) for catheter-associated bacteremia. The skin at the insertion site was colonized in 32.7% and the hub in 29.1% of the patients respectively. Potential sources of infection were the skin in 41.2% of the cases, the hub in 29.4%, remote site in 5.9% and unknown in 23.5%. The hub was implicated in 60% of the catheter-associated bacteremias. Coagulase-negative staphylococci were the main isolates. Another intravascular device and purulence at the insertion site were independently associated with local infection. Insertion at internal jugular site and hub colonization were independently associated with bacteremia. CONCLUSIONS: Catheter-associated bacteremia is a major complication of central venous catheterization in critically-ill patients. Internal jugular insertion and CVC hub colonization are important risk factors for significant catheter-related infections.