Pharmacokinetics and Pharmacodynamics of High-Dose Piperacillin-Tazobactam in Obese Patients.

BACKGROUND AND OBJECTIVE: Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients. METHODS: Those receiving standard-dose P-T with BMI ≥ 30 kg/m2 weighing 105-139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient's own pharmacokinetic values. RESULTS: Piperacillin and tazobactam half-lives ranged from 0.5-10.6 to 0.9-15.0 h, while volumes of distribution ranged from 13.6-54.8 to 11.5-60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T. CONCLUSION: Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. CLINICAL TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT01923363.

Pharmacokinetics of single-dose ceftaroline fosamil in children with cystic fibrosis.

BACKGROUND: Single-dose pharmacokinetics (PK) and safety of ceftaroline fosamil with population pharmacokinetic/pharmacodynamic (PK/PD) modeling for staphylococcal pneumonia was performed in children with CF. METHODS: Subjects between 6 and 18 years old were evaluated in this phase 1, open-label, single-dose, prospective study using 10 mg/kg (up to 600 mg). Non-compartmental analysis and population-based PK analyses with Monte Carlo simulation (for doses 8-20 mg/kg every 8 h, infused over 1-4 h) were conducted. RESULTS: A total of 20 subjects were enrolled. The median age and weight were 12 yr (range 6.3-17.4) and 38.7 kg (range 17.8-94.3), respectively. A 3-compartment linear model incorporating age and weight provided the best fit for the data. Comparing children 6 to <12 years to those 12 to <18 years, the mean posthoc Bayesian parameter estimates for total volume of distribution (VT ) were 0.32 ± 0.05 L/kg versus 0.32 ± 0.04 L/kg, P = 0.7; and total Clearance (CLT ), 0.50 ± 0.10 L/h/kg versus 0.30 ± 0.07 L/h/kg, P = 0.001. Using susceptibility data from pediatric MRSA lower respiratory tract isolates, 8 mg/kg (maximum of 1000 mg per dose) infused over 1 h every 8 h achieved free-drug plasma concentrations above the minimum inhibitory concentration for ≥60% of the dosing interval in at least 95% of virtual subjects. CONCLUSIONS: Since children with CF have increased ceftaroline CL compared with published data from non-CF children; greater dosages may be required in children with CF to achieve adequate exposure in the treatment of MRSA pneumonia. Pharmacodynamic-based dosing predicts that dosing should also be based on the patient's MRSA MIC.

Antimicrobial activity of ceftazidime-avibactam and comparator agents when tested against bacterial isolates causing infection in cancer patients (2013-2014).

We evaluated the antimicrobial susceptibility of 623 Gram-negative organisms causing infection in patients with cancer in 52 United States hospitals (2013-2014) as part of the International Network for Optimal Resistance Monitoring (INFORM) program. Isolates were tested for susceptibility by broth microdilution method. ß-lactamase encoding genes were evaluated for all Escherichia coli and Klebsiella spp. with an extended-spectrum ß-lactamase (ESBL) phenotype by microarray-based assay. ESBL-phenotype was observed among 17.3 and 9.9% of E. coli and Klebsiella pneumoniae, respectively; and 25.0% of Enterobacter cloacae were ceftazidime-non-susceptible. All Enterobacteriaceae (n=486) were susceptible to ceftazidime-avibactam (MIC50/90, 0.12/0.25µg/mL) with the highest MIC value at 1µg/mL. Meropenem was active against Enterobacteriaceae overall (MIC50/90, ≤0.06/≤0.06µg/mL; 99.6% susceptible); but showed more limited activity against Klebsiella spp. with an ESBL-phenotype (84.6% susceptible) and multidrug-resistant Enterobacteriaceae (93.3% susceptible). The most active agents tested against Pseudomonas aeruginosa were colistin (100.0% susceptible), amikacin (97.7% susceptible) and ceftazidime-avibactam (96.6% susceptible).

High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-ß-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center.

Resistance to the novel ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-ß-lactamase in diverse Enterobacteriaceae species.

Evolution of Ceftaroline-Resistant Mrsa in a Child with Cystic Fibrosis Following Repeated Antibiotic Exposure.

Ceftaroline is the first ß-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). We describe a ceftaroline-resistant MRSA strain, isolated from a girl with cystic fibrosis after 22 ceftaroline treatment courses. MRSA genome sequencing documented a Tyr446Asn alteration in penicillin binding protein 2 that appeared responsible for resistance. Noncompartmental ceftaroline pharmacokinetic evaluation in our patient documented increased clearance and volume of distribution compared with adults.

Performance of BD Max StaphSR for Screening of Methicillin-Resistant Staphylococcus aureus Isolates among a Contemporary and Diverse Collection from 146 Institutions Located in Nine U.S. Census Regions: Prevalence of mecA Dropout Mutants.

This study determined the performance of BD Max StaphSR and the rate of methicillin-resistant Staphylococcus aureus (MRSA) with an unrecognized staphylococcal cassette chromosome mec (SCCmec) right-extremity junction (MREJ) region among 907 methicillin-resistant S. aureus (MRSA) and 900 methicillin-susceptible S. aureus (MSSA) isolates. The rate of mecA/mecC dropout mutants was also evaluated. Only three MRSA isolates (99.7% sensitivity; 904/907) were classified as MSSA by the BD Max StaphSR assay, due to negative results for MREJ. Eight MSSA isolates (99.1% sensitivity; 892/900) were assigned as MRSA. However, six of these MSSA isolates had the mecA gene confirmed by PCR and sequencing (99.8% sensitivity; 898/900). Overall, 7.1% (64/900) of MSSA isolates showed results compatible with a mecA dropout genotype.

Linezolid update: stable in vitro activity following more than a decade of clinical use and summary of associated resistance mechanisms.

Linezolid, approved for clinical use since 2000, has become an important addition to the anti-Gram-positive infection armamentarium. This oxazolidinone drug has in vitro and in vivo activity against essentially all Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The in vitro activity of linezolid was well documented prior to its clinical application, and several ongoing surveillance studies demonstrated consistent and potent results during the subsequent years of clinical use. Emergence of resistance has been limited and associated with invasive procedures, deep organ involvement, presence of foreign material and mainly prolonged therapy. Non-susceptible organisms usually demonstrate alterations in the 23S rRNA target, which remain the main resistance mechanism observed in enterococci; although a few reports have described the detection of cfr-mediated resistance in Enterococcus faecalis. S. aureus isolates non-susceptible to linezolid remain rare in large surveillance studies. Most isolates harbour 23S rRNA mutations; however, cfr-carrying MRSA isolates have been observed in the United States and elsewhere. It is still uncertain whether the occurrences of such isolates are becoming more prevalent. Coagulase-negative isolates (CoNS) resistant to linezolid were uncommon following clinical approval. Surveillance data have indicated that CoNS isolates, mainly Staphylococcus epidermidis, currently account for the majority of Gram-positive organisms displaying elevated MIC results to linezolid. In addition, these isolates frequently demonstrate complex and numerous resistance mechanisms, such as alterations in the ribosomal proteins L3 and/or L4 and/or presence of cfr and/or modifications in 23S rRNA. The knowledge acquired during the past decades on this initially used oxazolidinone has been utilized for developing new candidate agents, such as tedizolid and radezolid, and as linezolid patents soon begin to expire, generic brands will certainly become available. These events will likely establish a new chapter for this successful class of antimicrobial agents.

Ceftaroline activity tested against contemporary Latin American bacterial pathogens (2011)

A total of 2484 target bacterial pathogens were collected (one per patient episode) from patients in 16 Latin American medical centers located in seven nations during 2011. Isolate identity was confirmed at a coordinating laboratory and susceptibility testing was performed for ceftaroline and comparator agents according to reference broth microdilution methods. A total of 30.0% of isolates were from respiratory tract, 29.4% from skin and skin structure, 21.4% from blood stream, 7.9% from urinary tract and 11.3% from other sites. Ceftaroline was active againstStaphylococcus aureus (42.8% MRSA) with 83.6% of the isolates at <1mg/L and all isolates at <2mg/L (MIC5090, 0.25/2mg/L). National MRSA rates ranged from a low of 28.8% in Colombia to a high of 68.1% in Chile. All Streptococcus pyogenes and Streptococcus agalactiae were susceptible to ceftaroline (MIC50/90 values were at <0.015/<0.015mg/L for both). All Streptococcus pneumoniae were susceptible to ceftaroline, linezolid, tigecycline and vancomycin. Susceptibility to ceftriaxone was at 88.4% (CLSI non-meningitis interpretive criteria) and 73.9% (CLSI meningitis interpretive criteria) for all S. pneumoniae. Ceftriaxone susceptibility was only at 33.3% (CLSI non-meningitis interpretive criteria) and 0.0% (CLSI meningitis interpretive criteria) for penicillin-intermediate (penicillin MIC, 4mg/L) strains. AllHaemophilus influenzae (29.4% β-lactamase-positive) isolates were susceptible to ceftaroline, amoxicillin-clavulanate, ceftriaxone, and levofloxacin. For the Latin American region, the ESBL-phenotype rate was 37.6% for Escherichia coli and 53.3% for Klebsiella pneumoniae. Ceftaroline was not active against ESBL-phenotype strains but was active against >90.0% of the non-ESBL-phenotype. The spectrum of activity of ceftaroline against pathogens from Latin America indicates that it merits further study for its potential use in the Latin American region.

Susceptibility rates in Latin American nations: report from a regional resistance surveillance program (2011)

OBJECTIVE: To establish a resistance (R) surveillance program monitoring antimicrobial susceptibility patterns in Latin America (LATAM; Argentina [ARG], Brazil [BRA], Chile, Colombia [CBA], Costa Rica, Ecuador [ECU], Guatemala [GUA], Mexico [MEX], Panama [PAN], Peru, and Venezuela [VEN]). METHODS: In 2011, 4979 organisms were collected from 11 nations (20 laboratories) for susceptibility testing in a central laboratory design. Antimicrobials were tested by CLSI methods and results interpreted by CLSI and EUCAST breakpoints. Most common Gram-positive (Staphylococcus aureus [SA, 921], other staphylococci [CoNS; 299], enterococci [218], Streptococcus pneumoniae [SPN; 182], β-haemolytic streptococci [115]) and Gram-negative (E. coli [EC; 644], Klebsiella spp. [KSP; 517], Enterobacters [272], Pseudomonas aeruginosa [PSA; 586], Acinetobacters [ACB; 494]) pathogens were analyzed against linezolid (LZD), vancomycin (VAN), tigecycline (TIG), colistin (COL), cefoperazone/sulbactam (C/S), and amikacin (AMK). RESULTS: MRSA rates varied from 29% (CBA, BRA) to 79% (Peru); but LZD (MIC90, 2 mg/L), TIG (MIC90, 0.12mg/L) and VAN (MIC90, 1mg/L) covered all strains. Enterococci showed a 14% VRE rate, highest in BRA and MEX; all inhibited by TIG and daptomycin, but not LZD (three non-susceptible with G2576T mutations or cfr). Penicillin-R among SPN and viridans streptococci was 51.6 and 41.1%, respectively. LZD overall R against Gram-positives was 0.3%. High ESBL rates were observed in EC (54-71%) and KSP (>50%) from GUA, MEX and Peru, and six nations, respectively. Carbapenem-R in KSP was 9%, highest rates associated with KPC in BRA, CBA, ECU, PAN and VEN; also a NDM-1 in KSP from CBA. AMK, TIG, C/S and carbapenems were the broadest-spectrum agents tested against Enterobacteriaceae. Only COL inhibited >90% of PSA; COL and TIG (<2 mg/L) covered >85% of ACB. CONCLUSIONS: LATAM nations demonstrated variable levels of antimicrobial R especially among Enterobacteriaceae (β-lactamase-mediated), PSA and ACB. MRSA (48%), VRE (14%) and multidrug-R SPN were also regional therapeutic challenges.

Susceptibility rates in Latin American nations: report from a regional resistance surveillance program (2011).

OBJECTIVE: To establish a resistance (R) surveillance program monitoring antimicrobial susceptibility patterns in Latin America (LATAM; Argentina [ARG], Brazil [BRA], Chile, Colombia [CBA], Costa Rica, Ecuador [ECU], Guatemala [GUA], Mexico [MEX], Panama [PAN], Peru, and Venezuela [VEN]). METHODS: In 2011, 4979 organisms were collected from 11 nations (20 laboratories) for susceptibility testing in a central laboratory design. Antimicrobials were tested by CLSI methods and results interpreted by CLSI and EUCAST breakpoints. Most common Gram-positive (Staphylococcus aureus [SA, 921], other staphylococci [CoNS; 299], enterococci [218], Streptococcus pneumoniae [SPN; 182], ß-haemolytic streptococci [115]) and Gram-negative (E. coli [EC; 644], Klebsiella spp. [KSP; 517], Enterobacters [272], Pseudomonas aeruginosa [PSA; 586], Acinetobacters [ACB; 494]) pathogens were analyzed against linezolid (LZD), vancomycin (VAN), tigecycline (TIG), colistin (COL), cefoperazone/sulbactam (C/S), and amikacin (AMK). RESULTS: MRSA rates varied from 29% (CBA, BRA) to 79% (Peru); but LZD (MIC90, 2mg/L), TIG (MIC90, 0.12mg/L) and VAN (MIC90, 1mg/L) covered all strains. Enterococci showed a 14% VRE rate, highest in BRA and MEX; all inhibited by TIG and daptomycin, but not LZD (three non-susceptible with G2576T mutations or cfr). Penicillin-R among SPN and viridans streptococci was 51.6 and 41.1%, respectively. LZD overall R against Gram-positives was 0.3%. High ESBL rates were observed in EC (54-71%) and KSP (≥50%) from GUA, MEX and Peru, and six nations, respectively. Carbapenem-R in KSP was 9%, highest rates associated with KPC in BRA, CBA, ECU, PAN and VEN; also a NDM-1 in KSP from CBA. AMK, TIG, C/S and carbapenems were the broadest-spectrum agents tested against Enterobacteriaceae. Only COL inhibited >90% of PSA; COL and TIG (≤2mg/L) covered ≥85% of ACB. CONCLUSIONS: LATAM nations demonstrated variable levels of antimicrobial R especially among Enterobacteriaceae (ß-lactamase-mediated), PSA and ACB. MRSA (48%), VRE (14%) and multidrug-R SPN were also regional therapeutic challenges.

Spectrum and potency of ceftaroline against leading pathogens causing community-acquired respiratory tract and skin and soft tissue infections in Latin America, 2010

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in vitro bactericidal activity against Gram-positive organisms, including methicillinsusceptible and -resistant Staphylococcus aureus, β-haemolytic and viridans group streptococci, and Streptococcus pneumoniae, as well as common Gram-negative organisms. In this study a total of 986 isolates collected in 2010 from patients in 15 medical centers in five Latin American countries from the Assessing Worldwide Antimicrobial Resistance Evaluation Program were identified as community-acquired respiratory tract or skin and soft tissue infection pathogens. Ceftaroline was the most potent agent tested against S. pneumoniae with a MIC90 value (0.12 µg/mL) that was eight-fold lower than ceftriaxone, levofloxacin, and linezolid. Its spectrum of coverage (100.0% susceptible) was similar to tigecycline, linezolid, levofloxacin and vancomycin. Against Haemophilus influenzae and Moraxella catarrhalis, ceftaroline was the most active agent tested. The activity of ceftaroline against S. aureus (including MRSA) was similar to that of vancomycin and tetracycline (MIC90,1 µg/mL) and linezolid (MIC90,2 Jg/mL). The 1-haemolytic streptococci exhibited 100.0% susceptibility to ceftaroline. Ceftaroline activity against Escherichia coli, Klebsiella spp., and Enterobacter spp. was similar to that of ceftriaxone and ceftazidime. These parenteral cephalosporin agents have potent activity against non-extended-spectrum These parenteral cephalosporin agents have potent activity against non-extended-spectrum-lactamase-phenotype strains, but are not active against extended-spectrum β-lactamase-phenotype strains. These results confirm the in vitro activity of ceftaroline against pathogens common in communityacquired respiratory tract and skin and soft tissue infection in Latin America, and suggest that ceftaroline fosamil could be an important therapeutic option for these infections.

Update of contemporary antimicrobial resistance rates across China: reference testing results for 12 medical centers (2011).

Antimicrobial resistance (R) surveillance across Asia and especially in China has documented unique patterns and mechanisms. This 2011 study reports results for 2278 isolates from 12 hospitals in China (94-216 strains/site); most from bacteremia (20.4%), pneumonias (29.1%), or skin and skin structure infections (20.9%). Samples were tested by reference broth microdilution methods, interpreted by published susceptibility (S) breakpoints. The most common species were Staphylococcus aureus (343, 45.8% MRSA), Escherichia coli (EC; 288), Pseudomonas aeruginosa (PSA; 221), Klebsiella spp. (KSP; 208), acinetobacters (ACB; 178), enterobacters (155), Streptococcus pneumoniae (SPN; 154, 46.8% penicillin-S), and enterococci (ENT; 137). Among 849 Gram-positive (GP) cocci, linezolid, tigecycline (TIG), daptomycin, and vancomycin provided best antimicrobial coverage (≥99.7% S). Resistance patterns of concern were 0.3% VISA, 15.4% teicoplanin non-S coagulase-negative staphylococci, 1.5% vancomycin-R ENT (all Enterococcus faecium), 1.9% levofloxacin-R ß-haemolytic streptococci, and 35.1 and 12.7% ceftriaxone-non-S rates for SPN and viridans group streptococci, respectively. For Gram-negative bacilli, R among Enterobacteriaceae was highest against ß-lactams (extended spectrum ß-lactamase-phenotype strains at 73.6 and 42.8% in EC and KSP, respectively; carbapenem-R was only 2.1-4.3% with KPC and IMP type enzymes detected in KSP). The widest spectrum agents were cefoperazone/sulbactam (79.5-86.1%), piperacillin/tazobactam (88.9-92.0%), TIG (98.6-100%), amikacin (AMK; 91.8-93.7%), and meropenem (95.7-97.1% S). PSA was most inhibited by AMK (90.5% S) and colistin (COL; 99.5%), with cefepime (67.9%) best among the tested ß-lactams. Only COL (100% S) and TIG (MIC90, 2 µg/mL) showed significant potencies against ACB. In conclusion, R among pathogens from 12 Chinese hospitals illustrates several agents active against GP pathogens, but more serious R problems were noted among Enterobacteriaceae, PSA, and ACB. Combination treatment for the latter multidrug-R strains appears necessary, guided by local antibiograms and national surveillance results applying reference methods.

Trends in Klebsiella pneumoniae carbapenemase-positive K. pneumoniae in US hospitals: report from the 2007-2009 SENTRY Antimicrobial Surveillance Program.

We report the prevalence of carbapenemase-positive Klebsiella pneumoniae among clinical isolates collected from US medical centers (n = 42) from 2007-2009 through the SENTRY Antimicrobial Surveillance Program. Isolates with imipenem or meropenem MIC ≥ 2 µg/mL were screened by PCR for various carbapenemase genes. Of 2049 K. pneumoniae isolates, 126 (6.1%) were non-susceptible to imipenem or meropenem. blaKPC was identified in 113 isolates (5.5%). No other carbapenemase genes were identified. For US regions combined, prevalence of K. pneumoniae carbapenemase (KPC)-positive isolates were 5.9% in 2007, 4.9% in 2008, and 5.7% in 2009. Rates were highest in the Mid-Atlantic region (28.6% overall), with fluctuation over time (29%, 23%, and 33% from 2007-2009), followed by the East North Central region (2.4% overall), with a slightly increasing trend (nil, 3.1%, 3.8% from 2007-2009). All KPC-positive organisms were carbapenem non-susceptible according to updated CLSI breakpoints, although all but one was similarly classified according to previous breakpoints.

Escherichia coli resistance to quinolones at a comprehensive cancer center.

As part of Meropenem Yearly Susceptibility Test Information Collection/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and aminoglycosides was noted over the 10-year span (P < 0.0001), which was significantly reduced compared with the average susceptibility of all sites. Introduction of quinolone prophylaxis has led to a significant decline in susceptibility of E. coli to all quinolones. The organisms remain susceptible to carbapenems, cefepime, and piperacillin/tazobactam. Periodic surveillance allows for detection of resistance patterns and adjustment of empiric antibiotic choice in patients at high risk for infection.

Occurrence of vancomycin-tolerant and heterogeneous vancomycin-intermediate strains (hVISA) among Staphylococcus aureus causing bloodstream infections in nine USA hospitals.

BACKGROUND: The bactericidal activities of vancomycin and daptomycin were evaluated in a large collection of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia strains from nine major USA medical centres. OBJECTIVES: To evaluate the occurrence of heterogeneous vancomycin-intermediate S. aureus (hVISA) among MRSA strains tolerant to vancomycin and/or with increased vancomycin or daptomycin MIC values. The accuracy of the macro Etest method (MET) compared with population analysis profiling (PAP) for the detection of hVISA was also assessed. METHODS: A total of 1800 MRSA strains were collected from bloodstream infections at the nine sites (40 strains per year, per medical centre during the 2002-06 study period). Vancomycin and daptomycin MIC testing was performed by reference broth microdilution (all strains) and MBC tests on 50% of strains (randomly selected). A subset of isolates (n = 268) having an increased vancomycin MBC (> or =16 mg/L), an increased vancomycin MIC (> or =1 mg/L) and/or an increased daptomycin MIC (>0.5 mg/L) were tested for susceptibility to vancomycin and teicoplanin by MET. RESULTS: Overall, 181 of 900 (20.1%) MRSA tested exhibited vancomycin tolerance, varying from 10% to 43% among the medical centres evaluated, and from 11.7% in 2004 to 27.8% in 2005. No resistance trend was observed in any medical centre or in the overall study data. Daptomycin showed bactericidal activity against all strains tested. The accuracy of MET for identifying hVISA strains varied significantly with the criteria applied for positivity. CONCLUSIONS: The most frequently used criteria to define hVISA, i.e. MET reading values > or =8 mg/L for both vancomycin and teicoplanin or > or =12 mg/L for teicoplanin only, detected 20 of 36 PAP-positive strains (55.6% sensitivity), indicating that the prevalence of hVISA could be higher than currently appreciated. Daptomycin was bactericidal against hVISA strains.

Tigecycline (GAR-936) activity against Streptococcus gallolyticus (bovis) and viridans group streptococci.

Viridans group streptococci including Streptococcus gallolyticus (formerly S. bovis) represent serious invasive pathogens often associated with endocarditis or sepsis among immunocompromised or cancer patients. Tigecycline (GAR-936), the first clinically studied glycylcycline, has a potent gram-positive activity with a potential treatment option for these streptococcal infections. The studied collection (848 strains) included 100 isolates each of Streptococcus anginosus, Streptococcus constellatus, Streptococcus intermedius, Streptococcus mitis, Streptococcus oralis, Streptococcus salivarius, Streptococcus sanguis, and fewer strains of S. gallolyticus (98 strains) and Streptococcus mutans (50 strains). These strains were isolated from patients on 3 continents in the SENTRY Antimicrobial Surveillance Program and tested for susceptibility and interpreted by Clinical and Laboratory Standards Institute broth microdilution methods and criteria (< or = 0.25 microg/mL for tigecycline per US Food and Drug Administration). Penicillin susceptibility rates for the entire collection varied from 61% (S. sanguis) to 98% (S. constellatus), and macrolide susceptibility was also compromised (49-88%; average, 69%). Tigecycline was active against all isolates tested, in contrast to tetracycline resistance rates of 8-66%, and highest for S. gallolyticus. In conclusion tigecycline was quite active against bacteremic isolates of viridans group streptococci species and S. gallolyticus with an overall MIC90 at < or = 0.06 microg/mL; the highest MIC was only 0.25 microg/mL.

Increased resistance to first-line agents among bacterial pathogens isolated from urinary tract infections in Latin America: time for local guidelines?

Emerging resistance phenotypes and antimicrobial resistance rates among pathogens recovered from community-acquired urinary tract infections (CA-UTI) is an increasing problem in specific regions, limiting therapeutic options. As part of the SENTRY Antimicrobial Surveillance Program, a total of 611 isolates were collected in 2003 from patients with CA-UTI presenting at Latin American medical centers. Each strain was tested in a central laboratory using Clinical Laboratory Standard Institute (CLSI) broth microdilution methods with appropriate controls. Escherichia coli was the leading pathogen (66 percent), followed by Klebsiella spp. (7 percent), Proteus mirabilis (6.4 percent), Enterococcus spp. (5.6 percent), and Pseudomonas aeruginosa (4.6 percent). Surprisingly high resistance rates were recorded for E. coli against first-line orally administered agents for CA-UTI, such as ampicillin (53.6 percent), TMP/SMX (40.4 percent), ciprofloxacin (21.6 percent), and gatifloxacin (17.1 percent). Decreased susceptibility rates to TMP/SMX and ciprofloxacin were also documented for Klebsiella spp. (79.1 and 81.4 percent, respectively), and P. mirabilis (71.8 and 84.6 percent, respectively). For Enterococcus spp., susceptibility rates to ampicillin, chloramphenicol, ciprofloxacin, and vancomycin were 88.2, 85.3, 55.9, and 97.1 percent, respectively. High-level resistance to gentamicin was detected in 24 percent of Enterococcus spp. Bacteria isolated from patients with CA-UTI in Latin America showed limited susceptibility to orally administered antimicrobials, especially for TMP/SMX and fluoroquinolones. Our results highlight the need for developing specific CA-UTI guidelines in geographic regions where elevated resistance to new and old compounds may influence prescribing decisions.

Survey of bloodstream infection isolates: SENTRY Antimicrobial Surveillance Program in Buenos Aires, Argentina (1997-2002)

Regional antimicrobial surveillance programs might help to guide empiric antimicrobial therapy. This study reports the antimicrobial susceptibility patterns of 2198 isolates from bloodstream infections in a period of 1997 to 2002. Susceptibility testing was performed by broth microdilution methods. The most frequent organism was Staphylococcus aureus (23.4%) with an oxacillin-resistance rate of 41.8%. Extended Spectrum Beta Lactamases phenotype was presented in 10.0% of Escherichia coli and 49.4% in Klebsiella pneumoniae isolates. Imipenem and meropenem were active against 74.3% and 84.0% of Acinetobacter spp. and Pseudomonas aeruginosa, respectively. Bacterial resistance continues to be a great problem in Argentinean medical centers.

Influence of patient age on the frequency of occurrence and antimicrobial resistance patterns of isolates from hematology/oncology patients: report from the Chemotherapy Alliance for Neutropenics and the Control of Emerging Resistance Program (North America).

The Chemotherapy Alliance for Neutropenics and the Control of Emerging Resistance Program (CANCER) monitored the susceptibility of pathogens recovered in hematology/oncology centers from 2000 to 2002. A total of 3970 isolates from 32 hospitals (26 United States, 6 Canada) were analyzed at a central location (JMI Laboratories, North Liberty, IA) for trends in pathogen occurrence and reference antimicrobial susceptibility profiles. The top 5 ranking pathogens were Staphylococcus aureus (19.3%), coagulase-negative staphylococci (CoNS) (14.1%), Escherichia coli (13.4%), Enterococcus spp. (10.2%), and Klebsiella spp. (9.5%). A total of 35.5% of S. aureus and 78.8% of CoNS were resistant to oxacillin, whereas 22.0% of Enterococcus spp. were resistant to vancomycin. E. coli and Klebsiella spp. were highly susceptible (>90%) to piperacillin/tazobactam, 3rd-generation cephalosporins, and ciprofloxacin, but 3.9% and 2.4% of these species, respectively, met screening criteria for extended spectrum beta-lactamase production. Enterobacter spp. were less susceptible to piperacillin/tazobactam, ceftazidime, and ceftriaxone (83.7-88.2%) because of Amp C production and were most inhibited by cefepime and imipenem. Amikacin and polymyxin B were very active against Pseudomonas aeruginosa (97.4-97.7% susceptible). Prevalence of S. aureus, E. coli, Enterobacter spp., and Klebsiella spp. increased significantly (+48% to 98%) with age, whereas CoNS and viridans group streptococci decreased markedly (-62% to 69%) with advancing age. The isolation of Gram-positive pathogens declined (55% to 47%) with age (< or =14 to > or =65 years). Fluoroquinolones generally exhibited decreased susceptibility with increased age against nearly all listed pathogens. Oxacillin resistance rates for S. aureus increased with age (6-46%) as did vancomycin resistance rates for enterococci (nil in < or =14 years group to 18-24% in adults). Pathogens infecting neutropenic patients did not reflect greater resistance than those found in the general hospitalized patients. Gram-positive organisms were only slightly more predominant (53.4%), and cited age-related variations in pathogen occurrence and/or susceptibility patterns by species must be considered for empiric regimes for hematology and oncology patients.