Role of oral extended-spectrum cephems in the treatment of acute exacerbation of chronic bronchitis.

Risk stratification is the recommended approach for treatment of acute exacerbation of chronic bronchitis (AECB) to optimize the chances of clinical success. The suggested oral therapy for "simple or uncomplicated" AECB, which is predominantly a result of infection due to Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae, includes advanced macrolides and 2nd- or 3rd-generation cephalosporins, in addition to the older 1st-line agents (aminopenicillins, doxycycline, trimethoprim/sulfamethoxazole, and erythromycin). In light of increasing resistance of H. influenzae and S. pneumoniae to the older agents, the specific directed structural modification of the cephalosporin nucleus resulted in the development of extended-spectrum 3rd-generation oral cephems with enhanced beta-lactamase stability and improved activity against Gram-positive pathogens (penicillin-susceptible S. pneumoniae and oxacillin-susceptible Staphylococcus aureus). Analysis of results of double-blind randomized clinical trials assessing efficacy of the extended-spectrum oral cephems published since 2000 demonstrates that both cefdinir and cefditoren have similar point estimates of success in comparison to their comparators (cefuroxime, cefprozil, or Locarbacef), when either the clinical cure or the bacteriologic response was analyzed. Thus, oral extended-spectrum 3rd-generation cephems, which retain antimicrobial efficacy against the traditional respiratory pathogens despite changing resistance patterns, offer excellent coverage against the key pathogens involved in simple or uncomplicated AECB.

Comparisons of parenteral broad-spectrum cephalosporins tested against bacterial isolates from pediatric patients: report from the SENTRY Antimicrobial Surveillance Program (1998-2004).

A contemporary collection of 12737 strains from pediatric patients (<18 years) isolated over a 7-year period (1998-2004) from 52 sentinel hospitals in North America was tested to determine the comparative antimicrobial potency of broad-spectrum parenteral cephalosporins and selected comparator agents. Most of the strains (84.1%) were isolated from blood stream or respiratory tract infections. The rank order of the top 10 pediatric pathogens analyzed was Streptococcus pneumoniae (15.5%) >Haemophilus influenzae (14.6%) >Staphylococcus aureus (13.8%) >Moraxella catarrhalis = coagulase-negative staphylococci (8.0%) >Escherichia coli (7.8%) >Pseudomonas aeruginosa (5.2%) >Klebsiella spp. (4.8%) >Enterococcus spp. (4.7%) > beta-hemolytic streptococci (4.4%). Both cefepime and ceftriaxone (MIC(90), 1 microg/mL; 93.9% and 93.7% susceptible, respectively) were highly active against S. pneumoniae. However, the S. pneumoniae strains showed reduced susceptibility to ceftazidime (56.6%), as well as penicillin (56.6%) < trimethoprim-sulfamethoxazole (57.1%) < erythromycin (66.2%) < tetracycline (71.4%). beta-Hemolytic streptococci showed 100.0% susceptibility to penicillin, cefepime, and ceftriaxone. Cefepime and ceftriaxone exhibited high activity against oxacillin (methicillin)-susceptible S. aureus, (MIC(90), 4 microg/mL; 100.0% and 99.8% susceptible, respectively), whereas ceftazidime (MIC(90), 16 microg/mL) was active against only 86.7% of strains. H. influenzae strains showed complete susceptibility to cefepime, ceftriaxone, and levofloxacin (MIC(90), < or =0.5 microg/mL; 100.0%), and 34.0% of H. influenzae and 99.2% of M. catarrhalis strains produced beta-lactamase. Although the 3 cephalosporins tested (cefepime, ceftriaxone, and ceftazidime) were very active (98.6-99.6% susceptible) against E. coli, cefepime (99.0% susceptible) was slightly more active than ceftriaxone and ceftazidime (96.4% and 95.1% susceptible, respectively) against Klebsiella spp. Cefepime was also the most active beta-lactam agent tested against Enterobacter spp. (MIC(90), 2 microg/mL; 99.3% susceptible), whereas the susceptibility rates of other broad-spectrum beta-lactams (ceftriaxone, ceftazidime and piperacillin-tazobactam) were significantly lower (78.4-81.5%). Against P. aeruginosa, imipenem and piperacillin-tazobactam showed the highest susceptibility rates (94.4% and 93.3%, respectively), whereas imipenem and cefepime showed the lowest resistance rates (1.4% and 2.3%, respectively). Our results indicate that cefepime was the most broad-spectrum cephalosporin analyzed and remains a very potent alternative for the treatment of contemporary pediatric infections in North America.

Bactericidal activity of cefepime and ceftriaxone tested against Streptococcus pneumoniae.

The bactericidal activities of cefepime and ceftriaxone were assessed by testing a contemporary collection of 50 Streptococcus pneumoniae strains. Minimum inhibitory and bactericidal concentrations (MIC and MBC, respectively) of cefepime and ceftriaxone were determined, and time-kill studies were performed on 14 selected strains (10 penicillin-resistant, 2-intermediate, and 2-susceptible). Cefepime and ceftriaxone showed essentially identical potency (MIC50, 1 microg/mL and MIC90, 2 microg/mL, for both compounds) and MBC values (MBC50, 1 microg/mL for both). MBC/MIC ratios were < or = 4 for cefepime and < or = 8 for ceftriaxone on 48 (96.0%) strains, and 2 strains (4.0%) displayed MBC/MIC ratios > or = 32 (tolerance) to the 2 cephalosporins. Time-kill curves corroborated the MBC/MIC studies. Cefepime and ceftriaxone bactericidal activity (> or = 3 log10 CFU/mL reduction in inoculum) was demonstrable after 24 h of exposure to 8x MIC for 13 (92.9%) of 14 strains, whereas 1 strain showed approximately 2 log10 CFU/mL reduction. In conclusion, our results indicate that cefepime and ceftriaxone exhibit comparable potency and bactericidal activities when tested against contemporary pneumococcal strains with varying penicillin susceptibility patterns. Both parenteral cephems offer alternative therapeutic choices for the treatment of invasive pneumococcal infections.

Activity of gemifloxacin tested against Neisseria gonorrhoeae isolates including antimicrobial-resistant phenotypes.

The antigonococcal potency of gemifloxacin and 5 reference comparator antimicrobials was determined for a selected collection of gonococcal isolates. The 250 Neisseria gonorrhoeae strains were inclusive of (1) 50 historic strains from Japan with elevated fluoroquinolone minimal inhibitory concentration values (QRNG) and (2) 200 contemporary strains from clinical specimens in 2004 (176 from 6 sentinel sites in the United States and 24 bacteremic isolates from the SENTRY Antimicrobial Surveillance Program). The rank order of potency of the tested antimicrobials for the entire collection was: ceftriaxone (MIC(90) = 0.06 microg/mL) > gemifloxacin (1 microg/mL) > tetracycline (2 microg/mL) > ciprofloxacin = levofloxacin = penicillin (4 microg/mL). The activity of gemifloxacin was not affected by penicillinase production; however, its activity was decreased for penicillin-resistant strains. Cross-resistance between gemifloxacin and the older fluoroquinolones was present, and the gemifloxacin MIC90 value was higher for the ciprofloxacin-resistant strains compared with the ciprofloxacin-susceptible strains (2 versus 0.016 mug/mL, respectively). More than 20.0% of the recent clinical strains were resistant to penicillin, tetracycline, and ciprofloxacin with >30.0% of gonococci resistant to ciprofloxacin in Washington State and Hawaii. The historic QRNG strains from the Far East were predominantly of intermediate susceptibility (88.0%) to ciprofloxacin, with a gemifloxacin MIC90 value of only 0.25 microg/mL. The bacteremic gonococcal strains were exquisitely susceptible to the 3 quinolones tested (ciprofloxacin, levofloxacin, and gemifloxacin, MIC90 at < or = 0.03 microg/mL) and ceftriaxone (MIC90 = 0.06 microg/mL). In summary, the potency of gemifloxacin was competitive and positioned between that of ceftriaxone and older quinolones or penicillin or tetracycline, irrespective of the gonococcal resistance phenotype. Gemifloxacin should be considered for further development as a therapeutic option to treat uncomplicated infections due to emerging strains resistant to penicillins, tetracycline, and some older fluoroquinolones.

Activity of faropenem tested against Neisseria gonorrhoeae isolates including fluoroquinolone-resistant strains.

We evaluated the anti-gonococcal potency of faropenem along with 7 comparator reference antimicrobials against a preselected collection of clinical isolates. The 265 isolates were inclusive of 2 subsets: 1) 76 well-characterized resistant phenotypes of gonococcal strains (53 quinolone-resistant strains--31 with documented quinolone resistance-determining region changes from Japan, 15 strains resistant to penicillin and tetracycline, and 8 strains with intermediate susceptibility to penicillin) and 2) 189 recent isolates from clinical specimens in 2004 from 6 states across the United States where quinolone resistance is prevalent. Activity of faropenem was adversely affected by l-cysteine hydrochloride in IsoVitaleX (4-fold increase in [minimal inhibitory concentration] MIC50; 0.06 versus 0.25 microg/mL). The rank order of potency of the antimicrobials for the entire collection was ceftriaxone (MIC90, 0.06 microg/mL) > faropenem (0.25 microg/mL) > azithromycin (0.5 microg/mL) > cefuroxime (1 microg/mL) > tetracycline (2 microg/mL) > penicillin = ciprofloxacin = levofloxacin (4 microg/mL). Using MIC90 for comparison, faropenem was 4-fold more potent than cefuroxime (0.25 versus 1 microg/mL), but was 4-fold less active than ceftriaxone (0.25 versus 0.06 microg/mL). Although the activity of faropenem was not affected by either penicillinase production (MIC90, 0.12 microg/mL, penicillinase-positive) or increasing ciprofloxacin MIC (0.25 microg/mL, ciprofloxacin-resistant), increasing penicillin MIC was associated with an increase in MIC90 values (0.016 microg/mL for penicillin-susceptible to 0.25 microg/mL for penicillin-resistant strains). Among the recent (2004) clinical gonococcal isolates tested, reduced susceptibility to penicillins, tetracycline, and fluoroquinolones was high (28.0-94.2%). Geographic distribution of the endemic resistance rates of gonococci varied considerably, with 16.7-66.7% of the gonococcal isolates being ciprofloxacin-resistant in Oregon, California, Washington, and Hawaii. Faropenem retained its potency against these recent clinical strains and also quinolone-resistant strains from Japan (MIC90, < or =0.25 microg/mL). In summary, the excellent activity of faropenem against the gonococcal strains analyzed irrespective of the resistance phenotype, along with its beta-lactamase stability, makes it an ideal contender for further development as an oral beta-lactam agent to treat uncomplicated gonococcal infections due to strains emerging with resistant to penicillins, tetracyclines, and fluoroquinolones.

Susceptibility patterns for amoxicillin/clavulanate tests mimicking the licensed formulations and pharmacokinetic relationships: do the MIC obtained with 2:1 ratio testing accurately reflect activity against beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis?

Amoxicillin/clavulanate has recently undergone formulation changes (XR and ES-600) that represent 14:1 and 16:1 ratios of amoxicillin/clavulanate. These ratios greatly differ from the 2:1 ratio used in initial formulations and in vitro susceptibility testing. The objective of this study was to determine if the reference method using a 2:1 ratio accurately reflects the susceptibility to the various clinically used amoxicillin/clavulanate formulations and their respective serum concentration ratios. A collection of 330 Haemophilus influenzae strains (300 beta-lactamase-positive and 30 beta-lactamase-negative) and 40 Moraxella catarrhalis strains (30 beta-lactamase-positive and 10 beta-lactamase-negative) were tested by the broth microdilution method against eight amoxicillin/clavulanate combinations (4:1, 5:1, 7:1, 9:1, 14:1, and 16:1 ratios; 0.5 and 2 microg/mL fixed clavulanate concentrations) and the minimum inhibitory concentration (MIC) results were compared with those obtained with the reference 2:1 ratio testing. For the beta-lactamase-negative strains of both genera, there was no demonstrable change in the MIC values obtained for all ratios analyzed (2:1 to 16:1). For the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, at ratios >or=4:1 there was a shift in the central tendency of the MIC scatterplot compared with the results of testing 2:1 ratio. As a result, there was a 2-fold dilution increase in the MIC(50) and MIC(90) values, most evident for H. influenzae and BRO-1-producing M. catarrhalis strains. For beta-lactamase-positive strains of H. influenzae, the shift resulted in a change in the interpretive result for 3 isolates (1.0%) from susceptible using the reference method (2:1 ratio) to resistant (8/4 microg/mL; very major error) at the 16:1 ratio. In addition, the number of isolates with MIC values at or 1 dilution lower than the breakpoint (4/2 microg/mL) increased from 5% at 2:1 ratio to 32-33% for ratios 14:1 and 16:1. Our results indicate that, for the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, the results of the amoxicillin/clavulanate reference 2:1 ratio testing do not accurately represent all the currently licensed formulations. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment might be compromised when higher amoxicillin/clavulanate ratios are used clinically. With a better understanding of PK/PD parameters, reevaluation of the amoxicillin/clavulanate in vitro susceptibility testing should be considered by the standardizing authorities to reflect the licensed formulations and accurately predict clinical outcomes.

Reevaluation of Enterobacteriaceae MIC/disk diffusion zone diameter regression scattergrams for 9 beta-lactams: adjustments of breakpoints for strains producing extended spectrum beta-lactamases.

Validity of the current susceptibility breakpoint criteria for 9 beta-lactam antimicrobials and performance of proposed alternative breakpoints to improve prediction of clinical outcomes were analyzed by testing a contemporary collection of 350 Enterobacteriaceae, enriched for an overrepresentative collection of 70 (20.0%) strains producing extended-spectrum beta-lactamases (ESBLs). The majority of the strains were isolated from bloodstream infections (83.7% of the entire collection and 85.7% of the ESBL subset). The 9 beta-lactam antimicrobials analyzed were aztreonam, cefepime, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftriaxone, ceftizoxime, and cefuroxime. Reference broth microdilution MIC results were compared with those zone diameters obtained by the standardized disk diffusion test. The correlation coefficient (r) was acceptable for all antimicrobials, ranging from 0.87 (cefotetan) to 0.97 (aztreonam, cefotaxime, and ceftazidime). Using the current susceptible breakpoint criteria for Enterobacteriaceae, the intermethod categorical agreement ranged from 90.6% (cefotaxime) to 98.0% (ceftazidime). Very major (false-susceptible by disk test) and major errors (false-resistant) were nil (0.0%) for 6 of the 9 beta-lactams. Minor error rates ranged from only 0.9% (cefotetan) to 9.4% (cefotaxime). The proposed MIC breakpoint criteria (generally lower) adjusted to levels to accurately detect ESBL-producing strains and better predict clinical outcomes, also had acceptable intermethod concordance ranging from 90.6% (cefotetan) to 100.0% (ceftazidime). Remarkably, an improvement in the intermethod categorical agreement ranging from +1.7% to +8.3% was observed for 7 of the 9 antimicrobials, including the ESBL index or screening compounds (aztreonam, ceftazidime, cefotaxime, and ceftriaxone). No change in the breakpoint criteria, with removal of the intermediate category was tentatively proposed for cefoxitin and cefuroxime, resulting in an increase of the serious intermethod errors (very major and major), but the absolute intermethod agreement remained highly acceptable at 90.6% to 93.4%. Although the current breakpoint criteria remain acceptable in minimizing intermethod discords, the alternative susceptible breakpoint criteria proposed by combining pharmacokinetic/pharmacodynamic (PK/PD), microbiology MIC population analyses, and clinical success parameters possess improved intermethod agreement for the ESBL screening drugs and 5 other broad-spectrum beta-lactam compounds. The Clinical Laboratory Standards Institute (formerly, the National Committee for Clinical Laboratory Standards) should consider these changes to facilitate the detection of all Enterobacteriaceae with low PK/PD target attainment rates, therefore having the potential for suboptimal responses with usual therapeutic dosing.

Reevaluation of the cefepime minimal inhibitory concentrations and disk diffusion test zone diameter relationship for a worldwide collection of Enterobacteriaceae enriched for extended-spectrum beta-lactamase-producing organisms.

To reassess the validity of existing susceptibility breakpoint criteria and to propose alternative breakpoint criteria for disk diffusion testing at lower susceptible MIC breakpoints, we analyzed a contemporary global collection of Enterobacteriaceae isolates (350) strains enriched for extended-spectrum beta-lactamase (ESBL) producers (68 strains, 19.4%). The majority of the isolates (88.3% of the entire collection and 83.8% of the ESBL subset) were from bloodstream infections. Cefepime minimal inhibitory concentrations (MICs) were determined by broth microdilution methods and compared with the results obtained from disk diffusion testing for the entire collection of Enterobacteriaceae and for the ESBL subset alone. The regression coefficient was excellent for both scattergrams (r = 0.92-0.94). The intermethod categorical agreement remained excellent for the current breakpoints (susceptible at < or = 8 microg/mL or > or = 18 mm and resistant at > or = 32 microg/mL or < or = 14 mm) published by the National Committee for Clinical Laboratory Standards at 94.0%. The 2 alternative interpretive criteria considered at lower MIC breakpoints (i.e., susceptible as < or = 4 microg/mL and > or = 21 mm and susceptible as < or = 2 microg/mL and > or = 24 mm) did not compromise the intermethod test categorical accuracy, which remained excellent at 96.9% and 94.0%, respectively. Adopting the existing breakpoint criteria that remain accurate for ESBL-producing strains or any one of the above two alternative sets of breakpoint criteria analyzed would be acceptable, with excellent intermethod concordance between the MIC and disk diffusion results.

Bacteriological outcome after valve surgery for active infective endocarditis: implications for duration of treatment after surgery.

BACKGROUND: There has been no systematic evaluation of outcome after surgery for infective endocarditis with respect to duration of antibiotic treatment. METHODS: We performed a retrospective chart review of episodes of valve surgery for active infective endocarditis at Green Lane Hospital (Auckland, New Zealand) for 1963-1999. We recorded the duration of antibiotic treatment before and after valve surgery; the extent of infection at operation; Gram stain, culture, and histopathological testing results for valve samples; and the bacteriological outcome after surgery. The primary outcome measure was relapse, defined as endocarditis due to the same species within 1 year after surgery. RESULTS: For the 358 patients in our study, the median duration of follow-up was 4.8 years. Thirty-two patients (9%) had 36 subsequent episodes of endocarditis. Relapse occurred after 3 (0.8%) of the operations (95% CI, 0.2%-2.0%). Relapse of infection was unrelated to the duration of antibiotic treatment before or after surgery, positive valve culture results, positive Gram stain results, or perivalvular infection. Since 1994, we have reduced the duration of antibiotic treatment by approximately 7 days for those with positive valve culture results and by approximately 14 days for those with negative valve culture results, without any increase in the number of relapses. CONCLUSIONS: Relapse is an uncommon event following surgery for endocarditis. Commonly suggested indications for prolonging postoperative treatment are not associated with higher relapse rates, and their relevance is debatable. We conclude that it is unnecessary to continue treatment for patients with negative valve culture results for an arbitrary 4-6-week period after surgery. Two weeks of treatment appears to be sufficient, and, for those operated on near the end of the standard period of treatment, simply completing the planned course should suffice.

Susceptibility testing accuracy of a CTX-M-type extended-spectrum beta-lactamase organism-producing population of Enterobacteriaceae: intermethod analysis for 9 beta-lactams.

To assess the wide geographical applicability of the current and proposed susceptibility breakpoint criteria for 9 beta-lactam antimicrobials, the performance characteristics of 2 standardized methods were analyzed by testing a contemporary collection of 354 isolates of Enterobacteriaceae, enriched (76; 21.5%) for extended-spectrum beta-lactamase (ESBL)-producing strains. Molecular characterization of 57 ESBL strains revealed that majority of the strains (94.7%) were CTX-M type, with a predominance (85.2%) of CTX-M-14 and -3 types, those types prevalent in China. Bloodstream isolates constituted 68.6% of the entire collection. The 9 beta-lactam antimicrobials analyzed were aztreonam, cefepime, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftriaxone, ceftizoxime, and cefuroxime. Reference broth microdilution minimal inhibitory concentration (MIC) results were compared to those zone diameters obtained by disk diffusion testing. The regression coefficient was acceptable for most antimicrobials, ranging from r = 0.84 (cefotetan) to r = 0.98 (cefotaxime, cefuroxime, and ceftriaxone). Using the current breakpoint criteria, the absolute intermethod categorical agreement was acceptable for 8 of the 9 antimicrobials (not cefoxitin, 85.1%) ranging from 92.6% (cefotaxime) to 97.8% (ceftazidime). Very major (false-susceptible) and major (false-resistant) errors were nil (0.0%) for 5 of the beta-lactams and minor errors ranged from 0.8% (cefotetan) to 14.1% (cefoxitin). The proposed (generally lower) MIC breakpoint criteria also had acceptable intermethod concordance ranging from 91.6% (cefoxitin) to 99.2% (cefotaxime and ceftriaxone). Furthermore, an improvement in the intermethod absolute categorical agreement ranging from +0.8% (ceftazidime) to +6.6% (cefotaxime) was observed for 7 of 9 antimicrobials tested, including the ESBL screening test compounds (aztreonam, ceftazidime, cefotaxime, and ceftriaxone). No modification of the susceptible breakpoint criteria, with removal of the intermediate category, was proposed for cefoxitin and cefuroxime, resulted in a shift of error type from minor to major or very major, but the categorical agreement improved (+ >or=1.2%) for both cephems. In conclusion, our results confirm that both the current and the proposed MIC breakpoint criteria with appropriately selected zone diameter correlates have acceptable intermethod error rates even when tested against an Enterobacteriaceae collection enriched with CTX-M-type ESBL-producing strains that are endemic in locations (China) outside the United States.

Susceptibility patterns of Streptococcus pneumoniae isolates in North America (2002-2003): contemporary in vitro activities of amoxicillin/clavulanate and 15 other antimicrobial agents.

A contemporary (2002-2003) national collection of 2100 strains of Streptococcus pneumoniae obtained from 30 sites in the nine United States (US) census regions were tested to determine the comparative antimicrobial properties of amoxicillin/clavulanate and 15 other antimicrobials. The rank order of antimicrobials with the lowest susceptibility rates was: penicillin (67.9%)or=41.1%), trimethoprim/sulphamethoxazole (38.9%), tetracyclines (22.2%) and clindamycin (10.0%). Geographical variation in the susceptibility patterns among US census zones was present with lowest penicillin and erythromycin susceptibility noted for West South Central and West North Central zones (or=+0.9%), sinus isolates (+2.7%), middle ear fluid isolates (+5.5%), penicillin-resistant strains (>or=+5.8%) and strains from patients <2 years of age (>or=+2.4%). Local and global surveillance studies of common respiratory pathogens such as S. pneumoniae remain instrumental to guide clinicians in appropriate empirical treatments and to emphasize the need for prudent antimicrobial use.

Comparative activity of oral and parenteral cephalosporins tested against multidrug-resistant Streptococcus pneumoniae: report from the SENTRY Antimicrobial Surveillance Program (1997-2003).

A large international collection of Streptococcus pneumoniae (21605 strains) was analyzed to determine the comparative activity of selected oral (cefuroxime and cefpodoxime) and parenteral (ceftriaxone and cefepime) cephalosporins when tested against different antimicrobial resistance phenotypes including penicillin-resistant strains and strains displaying additional resistances to other agents (erythromycin, clindamycin, tetracycline, and trimethoprim/sulfamethoxazole). The multidrug-resistant (MDR) rate ranged from 17.6% (penicillin- and erythromycin-resistant only) to 5.7% (resistance to all 5 drugs). The parenteral cephalosporins retained wider activity for all MDR phenotypes studied with the resistance rates (minimum inhibitory concentration > or = 4 mug/mL) being lower for cefepime (1.3-1.9%) when compared with ceftriaxone (3.0-4.4%) or the orally administered cephalosporins, cefpodoxime (64.4-74.1%), and cefuroxime (69.3-79.1%). Our findings confirm that the parenteral cephalosporins, cefepime, and ceftriaxone possess significant activity against those MDR pneumococci responsible for an increasing number of serious respiratory tract infections.

Evaluation of alternative disk diffusion methods for detecting mecA-mediated oxacillin resistance in an international collection of staphylococci: validation report from the SENTRY Antimicrobial Surveillance Program.

To validate the current National Committee for Clinical Laboratory Standards recommendations of the cefoxitin disk as a preferred surrogate marker to detect oxacillin resistance in staphylococcal isolates, 304 staphylococcal isolates originating from 49 sites in 16 countries in the SENTRY Antimicrobial Surveillance Program (2003) were tested. Two hundred three Staphylococcus aureus and 101 coagulase-negative staphylococci (CoNS), of which >95% were bloodstream isolates, were evaluated by comparing the results of the National Committee for Clinical Laboratory Standards broth microdilution method for oxacillin with those of the disk diffusion test using oxacillin, cefoxitin and ceftizoxime disks. Discrepancies were resolved using the PBP2a latex agglutination test. For S. aureus, the cefoxitin disk performed without interpretive error followed by the ceftizoxime disk (1% major and 0.5% minor errors; > or =20 mm = susceptible); use of the oxacillin disk test had the highest error rates with 4.4% major and 1.5% minor errors, whereas the oxacillin minimal inhibitory concentration (MIC) test was 99.0% accurate. For CoNS, the oxacillin disk test had the highest error rate with 4.0% major errors, followed by the cefoxitin (3.0% major error rate) and the ceftizoxime (1% very major and 1% minor error: > or =20 mm = susceptible) disk tests. The oxacillin MIC test was also 99.0% accurate for CoNS testing. Modification of the ceftizoxime disk diffusion breakpoints for CoNS resulted in complete intermethod categorical agreement. The overall accuracy of the four tests was as follows: modified ceftizoxime disk (99.3%) > oxacillin MIC = cefoxitin disk (99.0%) > current ceftizoxime disk (98.4%) > oxacillin disk (94.7%). In conclusion, these results confirm the superior performance characteristics of cefoxitin and ceftizoxime disk tests as surrogate markers to detect oxacillin resistance; by using an international collection of clinically significant staphylococcal isolates, we also demonstrate its wide global application.

Culture results of heart valves resected because of streptococcal endocarditis: insights into duration of treatment to achieve valve sterilization.

OBJECTIVES: To analyse the culture results of heart valves removed following streptococcal endocarditis in order to gain insight into the duration of treatment required for valve sterilization. PATIENTS AND METHODS: Retrospective review of 131 episodes of streptococcal endocarditis: 94 due to alpha-haemolytic streptococci; 15 due to beta-haemolytic streptococci; 10 due to nutritionally deficient streptococci; eight due to the Streptococcus anginosus group and four due to Streptococcus pneumoniae. Patients had their valves removed during antimicrobial treatment. Culture results were analysed with respect to duration of treatment before surgery. RESULTS: For alpha-haemolytic streptococci, 17 (18%) valves were culture-positive and 77 (82%) culture-negative after a median (range) of 4 (1-20) and 16 (4-58) days of treatment, respectively, P < 0.001. For beta-haemolytic streptococci, two valves (13%) were culture-positive; both patients had received < or = 4 days of treatment. Four patients (40%) with nutritionally deficient streptococci were culture-positive, and had received < or = 8 days of treatment. For the S. anginosus group, two valves (25%) were culture-positive; both patients had received < or = 4 days of treatment before operation. Overall, only one of 131 (0.8%) valves was culture-positive after 14 days of treatment. All valves infected with beta-haemolytic streptococci, nutritionally deficient streptococci and the S. anginosus group, who were treated for more than 8 days before surgery, were culture-negative. CONCLUSIONS: Our findings support current treatment guidelines for endocarditis caused by alpha-haemolytic streptococci. We suggest that the recommended duration of treatment for endocarditis resulting from other streptococci may be excessive and treatment trials evaluating 2 and 4 week regimens are justified.

Clinical isolates of Staphylococcus intermedius masquerading as methicillin-resistant Staphylococcus aureus.

Staphylococcus intermedius is a zoonotic organism that can be associated with human disease. We report two separate cases of S. intermedius infection in which a false-positive rapid penicillin binding protein 2a latex test in conjunction with the phenotypic properties of beta-hemolysis and coagulase positivity allowed the clinical isolates to masquerade as methicillin-resistant Staphylococcus aureus. 16S rRNA gene sequencing and the absence of mecA revealed the strains to be methicillin-susceptible S. intermedius.

Bacteriological outcome of combination versus single-agent treatment for staphylococcal endocarditis.

OBJECTIVE: To analyse the bacteriological outcome of combination versus single-agent antimicrobial treatment in staphylococcal endocarditis. PATIENTS AND METHODS: Retrospective review of 152 episodes: 91 cases of native valve endocarditis (NVE), 74 due to Staphylococcus aureus and 17 due to coagulase-negative staphylococci (CoNS); and 61 cases of prosthetic valve endocarditis (PVE), 29 due to S. aureus and 32 due to CoNS. RESULTS: Valves from patients with S. aureus NVE treated with any kind of combination antibiotic treatment were no more likely to be culture-negative than those treated with a single agent [19 (45%) of 42 versus 13 (41%) of 32; P = 0.69]. This finding remained unchanged when cases of CoNS NVE were added to the S. aureus group. In PVE, after adjusting for duration of treatment, valves from patients receiving any kind of combination treatment were 5.9 times (95% confidence interval 1.3-27.5) more likely to be culture-negative than those receiving monotherapy (P = 0.024). Patients treated for >14 days were more likely to be culture-negative than those treated for

NmcA carbapenem-hydrolyzing enzyme in Enterobacter cloacae in North America.

An imipenem-resistant Enterobacter cloacae isolate was recovered from the blood of a patient with a hematologic malignancy. Analytical isoelectric focusing, inhibitor studies, hydrolysis, induction assays, and molecular sequencing methods confirmed the presence of a NmcA carbapenem-hydrolyzing enzyme. This first report of NmcA detected in North America warrants further investigation into its distribution and clinical impact.

Nocardia veterana, a new emerging pathogen.

Nocardia veterana is a newly described species named after the veteran's hospital where it was first isolated. This initial type strain was not thought to be clinically significant. We describe three cases of pulmonary disease attributable to N. veterana: two cases in patients presenting with multiple pulmonary nodules in a setting of immunocompromise and one case of exacerbation of chronic pulmonary disease. The isolates were susceptible to ampicillin, imipenem, gentamicin, amikacin, and trimethoprim-sulfamethoxazole and had reduced susceptibilities to ceftriaxone, cefotaxime, minocycline, and ciprofloxacin. The MICs of amoxicillin-clavulanate were higher than that of ampicillin alone, and the bacteria produced a beta-lactamase detectable only after induction with clavulanic acid. Phenotypically, the isolates could not be characterized beyond the Nocardia genus level. All three isolates were definitively identified as N. veterana by PCR and sequencing of the 16S rRNA gene. On the basis of their susceptibility and restriction enzyme analysis profiles, our findings indicate that they could potentially be misidentified as N. nova. These cases illustrate the pathogenic potential of this newly described species and emphasize the importance of accurate identification of Nocardia isolates to the species level by integrated use of phenotypic and genotypic methods.

Gram stain, culture, and histopathological examination findings for heart valves removed because of infective endocarditis.

Retrospective chart review was undertaken for 480 patients who underwent a total of 506 valve replacements or repair procedures for infective endocarditis. The influence of preoperative antimicrobial treatment on culture, Gram stain, and histopathological examination findings for resected valve specimens was examined. When valves were removed before the end of treatment, organisms were seen on the Gram stain of ground valve material performed in the microbiology laboratory and on Gram-stained histopathological sections in 231 (81%) of 285 and 140 (67%) of 208 specimens, respectively (P=.0007). Gram-positive cocci were either cultured from or observed in excised valve tissue in 42 (67%) of 63 episodes involving negative preoperative blood cultures. Positive Gram stain results for microbiological specimens should be reintroduced into the definite pathological criteria for infective endocarditis. When deciding on how long to continue antimicrobial therapy after valve replacement for endocarditis, valve culture results should be the only laboratory finding taken into account, because it takes months for dead bacteria to be removed from sterile vegetations.