Vancomycin minimum inhibitory concentration, host comorbidities and mortality in Staphylococcus aureus bacteraemia.

We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30-day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality.

Dissemination and genetic context analysis of bla(VIM-6) among Pseudomonas aeruginosa isolates in Asian-Pacific Nations.

VIM-6, previously reported in two strains from Singapore recovered in 2000, was detected in 16 isolates collected in 2006 in India (12 isolates), Indonesia (two), Korea and the Philippines (one each). High genetic variability was observed among VIM-6-producing isolates (12 ribotypes and 11 pulsed-field gel electrophoresis types), but clones were observed in India and Indonesia; bla(VIM-6)-carrying integrons of 3.9 kb and 5 kb were detected, and two of five Indian hospitals yielded isolates with both integrons. These two integrons, bla(VIM-6) was located in the first position, followed by bla(OXA-10) and aacA4. The 5-kb integrons also harboured aadA1 and a 331-bp open reading frame encoding a putative efflux pump.

Antimicrobial activities of garenoxacin (BMS 284756) against Asia-Pacific region clinical isolates from the SENTRY program, 1999 to 2001.

Between 1999 and 2001, 16,731 isolates from the Asia-Pacific Region were tested in the SENTRY Program for susceptibility to six fluoroquinolones including garenoxacin. Garenoxacin was four- to eightfold less active against Enterobacteriaceae than ciprofloxacin, although both drugs inhibited similar percentages at 1 microg/ml. Garenoxacin was more active against gram-positive species than all other fluoroquinolones except gemifloxacin. For Staphylococcus aureus, oxacillin resistance was high in many participating countries (Japan, 67%; Taiwan, 60%; Hong Kong, 55%; Singapore, 52%), with corresponding high levels of ciprofloxacin resistance (57 to 99%) in oxacillin-resistant S. aureus (ORSA). Of the ciprofloxacin-resistant ORSA isolates, the garenoxacin MIC was >4 microg/ml for only 9% of them. For Streptococcus pneumoniae, penicillin nonsusceptibility and macrolide resistance were high in many countries. No relationship was seen between penicillin and garenoxacin susceptibility, with all isolates being susceptible at <2 microg/ml. There was, however, a partial correlation between ciprofloxacin and garenoxacin MICs. For ciprofloxacin-resistant isolates for which garenoxacin MICs were 0.25 to 1 microg/liter, mutations in both the ParC and GyrA regions of the quinolone resistance-determining region could be demonstrated. No mutations conferring high-level resistance were detected. Garenoxacin shows useful activity against a wide range of organisms from the Asia-Pacific region. In particular, it has good activity against S. aureus and S. pneumoniae, although there is evidence that low-level resistance is present in those organisms with ciprofloxacin resistance.

Prevalence of extended-spectrum beta-lactamase-producing Enterobacter cloacae in the Asia-Pacific region: results from the SENTRY Antimicrobial Surveillance Program, 1998 to 2001.

Enterobacter cloacae strains from hospitalized patients with a range of infections were collected by 17 laboratories in the Asia-Pacific region and South Africa. Isolates for which ceftriaxone MICs were above 1 microg/ml and/or ceftazidime MICs were above 2 microg/ml, as well as 46 strains for which ceftriaxone and/or ceftazidime MICs were at or below these values, were screened for levels of extended-spectrum beta-lactamase (ESBL) production through the use of broth microdilution for the detection of clavulanate enhancement of the activity of ceftriaxone, ceftazidime, and cefepime. Of the isolates examined, ceftriaxone and/or ceftazidime had elevated MICs for 44%, of which 36% were ESBL positive. ESBL-positive strains were commonly susceptible to piperacillin-tazobactam and more frequently resistant to several other antimicrobials studied. A cefepime MIC above 0.25 microg/ml had the highest sensitivity (100%) and specificity (74%) for predicting the presence of an ESBL.

Antimicrobial resistance trends in community-acquired respiratory tract pathogens in the Western Pacific Region and South Africa: report from the SENTRY antimicrobial surveillance program, (1998-1999) including an in vitro evaluation of BMS284756.

From 1998 to 1999, a large number of community-acquired respiratory tract isolates of Streptococcus pneumoniae (n=566), Haemophilus influenzae (n=513) and Moraxella catarrhalis (n=228) were collected from 15 centres in Australia, Hong Kong, Japan, China, the Philippines, Singapore, South Africa and Taiwan through the SENTRY Antimicrobial Surveillance Program. Isolates were tested against 26 antimicrobial agents using the NCCLS-recommended methods. Overall, 40% of S. pneumoniae isolates were resistant to penicillin with 18% of strains having high-level resistance (MIC > or =2 mg/l). Rates of erythromycin and clindamycin resistance were 41 and 23%, respectively. Penicillin-resistant strains showed high rates of resistance to other antimicrobial agents: 96% to trimethoprim-sulphamethoxazole (TMP-SMX), 84% to tetracycline and 81% to erythromycin. A significant proportion of penicillin-susceptible strains was also resistant to erythromycin (21%), tetracycline (29%) and TMP-SMZ (26%). Small numbers of strains were resistant to levofloxacin (0.7%), trovafloxacin (0.4%) and grepafloxacin (1.3%) where as all strains remained uniformly susceptible to quinupristin/dalfopristin and BMS284756 (MIC(90), 0.06 mg/l), a new desfluoroquinolone. beta-lactamases were, produced by 20% H. influenzae isolates and only rare strains showed intrinsic resistance to amoxycillin. Other beta-lactam agents showed good activity with rates of resistance less than 2% and all isolates showed susceptibility to cefixime, ceftibuten, cefepime and cefotaxime. Rates of resistance to tetracycline and chloramphenicol were also relatively low at 3%. The majority (98%) of M. catarrhalis isolates was found to be beta-lactamase-positive and resistant to penicillins, however, resistance to erythromycin and tetracycline was also low at 1.8%. Both H. influenzae and M. catarrhalis isolates were uniformly susceptible to the new desfluoroquinolone and tested fluoroquinolones.

A simple method for the assay of colistin in human plasma, using pre-column derivatization with 9-fluorenylmethyl chloroformate in solid-phase extraction cartridges and reversed-phase high-performance liquid chromatography.

A simple, selective and sensitive high-performance liquid chromatographic (HPLC) method is described for the determination of colistin in human plasma. Derivatization with 9-fluorenylmethyl chloroformate was performed in the same solid-phase extraction C18 cartridge used for sample pre-treatment, followed by reversed-phase HPLC with fluorimetric detection. Quantification was achieved using the ratio of the summed peak areas of colistin A and B derivatives to that of the derivative of netilmicin (internal standard). Linear calibration curves were obtained within the concentrations of colistin sulfate from 0.10 to 4.0 mg/l in plasma. Accuracy was within 10% and reproducibility (RSD) was less than 10%.

Post-antibiotic growth suppression of linezolid against Gram-positive bacteria.

The in vitro post-antibiotic effects (PAEs) of eight different concentrations of linezolid against Gram-positive cocci were investigated and the results analysed using the sigmoid E(max) model for mathematically modelling the PAE. Mean maximal linezolid PAEs against strains of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium and Streptococcus pneumoniae were 2.2, 1.8, 2.8, 2.0 and 3.0 h, respectively. Resistance to methicillin (for the staphylococci), vancomycin (for the enterococci) and penicillin (for the pneumococci) had no effect on the duration of the PAE. Results of PAE testing support twice-daily dosing of linezolid in humans.

Multicentre study of the in vitro activity of cefepime, a broad-spectrum cephalosporin, compared to other broad-spectrum agents.

The in vitro activity of cefepime was compared to that of a range of other broad-spectrum agents, using a gradient diffusion MIC method, against 995 recent clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, other nonfermentative gram-negative bacilli, staphylococci (except oxacillin-resistant Staphylococcus aureus), streptococci, enterococci, and aerobic gram-positive bacilli. Cefepime had excellent activity against Enterobacteriaceae, including eight presumptive extended-spectrum beta-lactamase producers and 33 stably derepressed mutants of natural cephalosporinases. Activity against Pseudomonas aeruginosa was similar to ceftazidime and superior to cefpirome. Its activity against gram-positive cocci was also good, being more active against staphylococci and only slightly less active against streptococci than ceftriaxone. Cefepime maintained activity against bacteria resistant to aminoglycosides and ciprofloxacin. Enterococci, Bacillus species, Burkholderia cepacia and Stenotrophomonas maltophilia were predicably resistant. Cefepime has a spectrum of activity almost as broad as that of the carbapenems.

Antibiotic resistance in Streptococcus pneumoniae.

Resistance to penicillin and other antibiotics in Streptococcus pneumoniae has emerged in Australia and around the world in the past decade, and appears to be worsening (e.g., rates of penicillin resistance in Australia rose from 1% in 1989 to 25% in 1997). In Australia, the only oral antibiotic able to treat respiratory infections caused by some multiresistant strains is high-dose amoxycillin. If these strains increase in prevalence, then treatment failures for relatively minor infections (e.g., otitis media) are likely to become common, resulting in repeat antibiotic courses or hospitalisation for parenteral therapy. Therapy for meningitis caused by penicillin-sensitive pneumococcal strains remains high-dose benzylpenicillin, but empirical treatment while awaiting culture and sensitivity results is problematic; neither penicillin nor third-generation cephalosporins cover all strains. Therefore, many authorities recommend vancomycin, usually combined with a third-generation cephalosporin, for treating presumptive or proven pneumococcal meningitis pending penicillin-susceptibility results. As almost all readily available oral antibiotics in Australia select for resistant strains of pneumococci, multiresistant strains will increase in prevalence unless unnecessary antibiotic use and prescription volumes are reduced substantially in the next few years.

Genetic characterization of vanG, a novel vancomycin resistance locus of Enterococcus faecalis.

Enterococcus faecalis strain WCH9 displays a moderate level of resistance to vancomycin (MIC = 16 microgram/ml) and full susceptibility to teicoplanin but is negative by PCR analysis using primers specific for all known enterococcal vancomycin resistance genotypes (vanA, vanB, vanC, vanD, and vanE). We have isolated and sequenced a novel putative vancomycin resistance locus (designated vanG), which contains seven open reading frames, from this strain. These are organized differently from those of all the other enterococcal van loci, and, furthermore, the individual vanG gene products exhibit less than 50% amino acid sequence identity to other van gene products.

The impact of penicillin resistance on the outcome of invasive Streptococcus pneumoniae infection in children.

BACKGROUND: Invasive infections caused by Streptococcus pneumoniae with reduced susceptibility to penicillin are increasing in prevalence in Australia. AIMS: To determine the impact of reduced susceptibility of S. pneumoniae to penicillin on morbidity, mortality and treatment of invasive infection. METHODS: Retrospective case note review of children with invasive S. pneumoniae infection over a 26 month period. Penicillin minimum inhibitory concentrations (MIC) were determined by E test. Primary clinical outcome measures included days to defervescence, duration of hospital stay, complication rates and mortality. The secondary outcome of financial cost was examined. Comparisons between outcomes of patients with infections caused by susceptible and non-susceptible strains were performed with Student's t test, Pearson chi2, Mann-Whitney U tests and multiple logistic regression. RESULTS: Sixty-eight episodes of invasive pneumococcal disease were reviewed: 14 isolates (21.1%) had reduced susceptibility or resistance to penicillin (PNSSP, MIC 0.125 mg/L-1.5 mg/L). Ten patients had meningitis, 21 had pneumonia, 22 had bacteraemia with another focus and 15 had bacteraemia without an obvious focus. PNSSP were more common in patients with meningitis and pneumonia. No patients died. Overall, patients with infections caused by PNSSP had significantly longer hospitalisation and longer time to defervescence. Complication rates were not significantly different between groups. Outcome differences were no longer significant when meningitis patients were excluded from the analysis. The PNSSP group received more expensive intravenous antibiotics and their infections were significantly more costly to treat. CONCLUSIONS: Infections with penicillin non-susceptible S. pneumoniae are associated with higher morbidity than infections with penicillin susceptible strains, and treatment of these infections is more expensive, due to higher drug costs and longer hospital stay.

Postantibiotic suppression of growth of erythromycin A-susceptible and -resistant gram-positive bacteria by the ketolides telithromycin (HMR 3647) and HMR 3004.

We investigated the in vitro postantibiotic effects (PAEs) of the ketolides telithromycin (HMR 3647) and HMR 3004 and analyzed the results using the sigmoid E(max) model. Mean maximum telithromycin PAEs against erythromycin A-susceptible strains of Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae were 3. 7, 8.9, and 9.7 h, respectively, while maximum PAEs for erythromycin A-resistant strains were much shorter. Mean maximum HMR 3004 PAEs were 3.2 to 4.4 h for all species.

Methicillin-resistant Staphylococcal aureus evolution in Australia over 35 years.

Australia has a long association methicillin-resistant Staphylococcus aureus (MRSA). Its unique geographic and demographic features have led to the emergence and spread of three types of MRSA over 35 years. Classical multiresistant hospital-acquired MRSA were first noted in Australia in 1965. By the end of the 1970s, strains of this type of MRSA were well established in the complex tertiary care hospitals in the capital cities on the eastern seaboard of mainland Australia. Characterized by resistance to beta-lactams, erythromycin, tetracycline, gentamicin, and trimethoprim-sulfamethoxazole, these strains have persisted and diversified genetically and have acquired a variety of new resistances. They have proven pathogenicity and are a prominent cause of hospital infection in the endemic institutions. More recently they have become endemic in some central state tertiary care hospitals. Community-acquired strains of MRSA first appeared in the north of Western Australia in the mid-1980s. Strains have subsequently appeared in the south of the state and in the two adjacent central states, and are more frequently isolated from Aboriginal patients. Although harboring few or no additional resistances apart from resistance to beta-lactams initially, these strains are also accumulating additional resistances. A different variety of community-acquired MRSA has recently been noted in eastern Australia. It has a similar antibiogram to the western strains, but an entirely different epidemiology, resembling that currently being experienced in parts of New Zealand, and associated with patients of south Pacific island origin.

The clinical efficacy of continuous-infusion flucloxacillin in serious staphylococcal sepsis.

Since the efficacy of beta-lactams against pathogens such as methicillin-susceptible Staphylococcus aureus (MSSA) is related to the time for which serum drug concentrations exceed the MIC for the pathogen, administration of anti-staphylococcal beta-lactams by continuous infusion may provide a more suitable means of drug delivery than intermittent dosing. To assess the clinical efficacy of continuous-infusion therapy, we reviewed the outcomes for 20 consecutive patients with proven serious MSSA sepsis (three with endocarditis, ten osteomyelitis, one endocarditis plus osteomyelitis and six deep abscess) treated with continuous-infusion flucloxacillin (8-12 g/day). Patients initially receiving routine intermittent-dose flucloxacillin therapy were changed to continuous-infusion flucloxacillin (mean duration 29 days; range 4-60 days) for completion of their treatment course. In the majority of cases this was given at home. Serum flucloxacillin concentrations during continuous-infusion flucloxacillin 12 g/day were 11.5->40 mg/L (ten patients) and those during continuous-infusion flucloxacillin 8 g/day were 8->40 mg/L (five patients), these concentrations being well above the expected MIC of flucloxacillin for MSSA. Continuous-infusion flucloxacillin was well tolerated by most patients, and 14/17 patients (82%) who completed their course of continuous-infusion flucloxacillin were judged clinically and microbiologically cured at long-term follow-up (mean 67 weeks; range 4-152 weeks). These preliminary data suggest that, following initial intermittent-dose flucloxacillin therapy, continuous-infusion flucloxacillin is an effective treatment option for serious MSSA sepsis, and forms a feasible and possibly preferable alternative to glycopeptides when considering home-based parenteral therapy for these infections. Further studies are needed to identify whether continuous-infusion flucloxacillin can entirely replace intermittent-dose therapy for such infections.

Rapidly emerging antimicrobial resistances in Streptococcus pneumoniae in Australia. Pneumococcal Study Group.

OBJECTIVE: To examine the prevalence of resistance in Streptococcus pneumoniae to key antimicrobials in Australia during 1997. DESIGN: Prospective, Australia-wide, laboratory-based survey. SETTING: 11 microbiology laboratories from seven Australian States and Territories (five private laboratories and six public hospital laboratories) between March and November 1997. STRAINS: Up to 100 consecutive, clinically significant strains of S. pneumoniae isolated by each laboratory. MAIN OUTCOME MEASURES: Susceptibility to penicillin, amoxycillin-clavulanate, cefaclor, ceftriaxone, erythromycin, tetracycline, and sulfamethoxazole-trimethoprim (cotrimoxazole), measured by a gradient diffusion, minimum inhibitory concentration technique. RESULTS: Of 1020 strains, 16.8% had intermediate susceptibility to penicillin and 8.6% were resistant. Rates of resistance to other drugs were: amoxycillin-clavulanate, 3.1%; cefaclor, 21.4%; ceftriaxone, 3.1%; erythromycin, 15.6%; tetracycline, 15.7%; and cotrimoxazole, 33.4%. Non-invasive isolates harboured more resistances than invasive isolates, and resistance was more prevalent in isolates from children under two years. Multiple resistance was also common, with 21.2% of strains resistant to two or more classes of drug, and 9.3% of non-invasive and 1.7% of invasive isolates resistant to four classes. There were no obvious differences in resistance rates between private and public hospital laboratories. CONCLUSIONS: Rates of antimicrobial resistance are rising rapidly in S. pneumoniae in Australia. Recommendations for empiric treatment of invasive and respiratory infection need to take account of these changes.

Home-based treatment of cellulitis with twice-daily cefazolin.

OBJECTIVE: To assess the clinical outcome and pharmacokinetics of therapy with cefazolin for patients with cellulitis in a hospital-in-the-home (HIH) program. DESIGN: Observational study with outcome data compared with previously published reports of therapy for cellulitis. SETTING: A university teaching hospital and HIH unit, July 1996-December 1997. PARTICIPANTS: Patients with cellulitis were eligible for inclusion provided their medical condition was stable, they did not require surgical intervention, and their social circumstances allowed home-based therapy. INTERVENTION: Cefazolin 2 g intravenously twice daily, with regular nursing and medical assessment. MAIN OUTCOME MEASURES: Clinical efficacy; peak and trough serum concentrations of cefazolin. RESULTS: Fifty-seven patients (37 were men) with a mean age of 48 years (range, 18-90 years) had 61 episodes of moderate to severe cellulitis (41, lower limb; 17, upper limb; and three, face). They received a median of 11 doses of cefazolin (range, 3-27 doses). Clinical outcomes were: cure in 54, improvement in one, treatment failure in three, and in the remaining three episodes the outcome was indeterminate. Cefazolin concentrations were measured in 27 patients. All peak concentrations were more than 40 micrograms/mL, while trough concentrations were all above the MIC90 of the expected pathogens: median, 3.2 micrograms/mL (range: 0.4-18.5 micrograms/mL). Cefazolin was well tolerated. CONCLUSIONS: Twice-daily cefazolin 2 g intravenously is a convenient and effective option for home-based treatment of patients with cellulitis. Its clinical efficacy is comparable with other treatment regimens.