Clarence J. Fernandes

In Vitro Activities of Ertapenem (MK-0826) against Recent Clinical Bacteria Collected in Europe and Australia

ABSTRACT Ertapenem (MK-0826, L-749,345) is a 1-β-methyl carbapenem with a long serum half-life. Its in vitro activity was determined by broth microdilution against 3,478 bacteria from 12 centers in Europe and Australia, with imipenem, cefepime, ceftriaxone, and piperacillin-tazobactam used as comparators. Ertapenem was the most active agent tested against members of the familyEnterobacteriaceae, with MICs at which 90% of isolates are inhibited (MIC90s) of ≤1 μg/ml for all species. Ertapenem also was more active than imipenem against fastidious gram-negative bacteria and Moraxella spp.; on the other hand, ertapenem was slightly less active than imipenem against streptococci, methicillin-susceptible staphylococci, and anaerobes, but its MIC90s for these groups remained ≤0.5 μg/ml.Acinetobacter spp. and Pseudomonas aeruginosawere also much less susceptible to ertapenem than imipenem, and mostEnterococcus faecalis strains were resistant. Ertapenem resistance, based on a provisional NCCLS MIC breakpoint of ≥16 μg/ml, was seen in only 3 of 1,611 strains of the familyEnterobacteriaceae tested, all of them Enterobacter aerogenes. Resistance was also seen in 2 of 135 anaerobes, comprising 1 Bacteroides fragilis strain and 1Clostridium difficile strain. Ertapenem breakpoints for streptococci have not been established, but an unofficial susceptibility breakpoint of ≤2 μg/ml was adopted for clinical trials to generate corresponding clinical response data for isolates for which MICs were as high as 2 μg/ml. Of 234 Streptococcus pneumoniae strains tested, 2 required ertapenem MICs of 2 μg/ml and one required an MIC of 4 μg/ml, among 67 non-Streptococcus pyogenes, non-Streptococcus pneumoniae streptococci, single isolates required ertapenem MICs of 2 and 16 μg/ml. These streptococci also had diminished susceptibilities to other β-lactams, including imipenem as well as ertapenem. The Etest and disk diffusion gave susceptibility test results in good agreement with those of the broth microdilution method for ertapenem.

Evaluation of the MRSA-Screen Test in Detecting Oxacillin Resistance in Community and Hospital Isolates of Staphylococcus Aureus

Summary The MRSA‐Screen Test (Denka Seiken Co., Japan), a latex agglutination test to detect penicillin‐binding protein 2a, was compared with PCR for the detection of oxacillin resistance in Staphylococcus aureus. A total of 77 oxacillin‐sensitive and 269 oxacillin‐resistant (ORSA) isolates were evaluated. Of the ORSA isolates, 186 were nonmultiresistant (NORSA), defined as being resistant to two or fewer antibiotics other than‐lactams. Eighty‐three were multiresistant ORSA (MORSA) strains. If PCR is considered the gold standard test, then the sensitivity, specificity, positive and negative predictive values of the MRSA‐Screen Test were 100, 99, 99 and 100%, respectively. The endpoint was hard to read with NORSA strains that took longer than 60 s to react. MORSA strains took a median 12 s (range 5‐60 s) to give a positive reaction with the MRSA‐Screen Test, whereas NORSA strains took a median 30 s (range 5‐180 s), a difference which was significantly different (P < 0.0001, two‐tailed Mann‐Whitney unpaired two sample test). NORSA strains had an MIC 50 of 128 mg/l and MIC 90 of 256 mg/l, whereas MORSA strains had an MIC 50 and MIC 90 of > 256 mg/l. The time that the MRSA‐Screen Test took to agglutinate with ORSA strains correlated weakly with the MIC (r 2 = 0.26). Detection of methicillin resistance cost AUD

A Randomised Comparative Study of Once-Daily Ceftriaxone and 6-Hourly Flucloxacillin in the Treatment of Moderate to Severe Cellulitis

9 per isolate with the MRSA‐Screen Test, compared with AUD

In vitro studies of ciprofloxacin and survey of resistance patterns in current isolates

13 per isolate with mec A PCR. The MRSA‐Screen Test gave excellent sensitivity and specificity, and was quicker and cheaper than PCR. The full 3 min should be allowed to elapse before calling a test negative. Organisms giving indeterminate reactions should be tested for the mec A gene by PCR.

A case of carbapenemase-producing Klebsiella pneumoniae in Australia

SummaryIn a study comparing flucloxacillin (1g every 6 hours intravenously), as standard treatment for moderate to severe cellulitis, with ceftriaxone (1g once daily intravenously), ceftriaxone was found to be an effective alternative to flucloxacillin without the associated risk of serious cholestatic hepatitis.Forty-seven evaluable patients, 24 in the ceftriaxone group and 23 in the flucloxacillin group, were evaluated in this prospective randomised study examining clinical efficacy, safety and duration of hospitalisation. 22 of 23 (96%) patients in the ceftriaxone group achieved clinical success (clinical cure and improvement), while 16 of 22 (70%) flucloxacillin patients were considered a clinical success (clinical cure and improvement). Baseline bacteriology was not performed in the single patient who did not respond to ceftriaxone, while 5 of the 6 patients who did not respond to flucloxacillin had a negative baseline culture. The remaining flucloxacillin failure was infected with Staphylococcus aureus, which persisted at the post-treatment evaluation. All other pathogens isolated at baseline in both treatment arms were eradicated at the post-treatment bacteriological evaluation.No serious or unexpected adverse events were reported in either group. Because it requires only once-daily administration, ceftriaxone made it possible for some patients to be treated as outpatients, resulting in an average reduction of 3.04 hospital bed-days, while at the same time being as efficacious as flucloxacillin.

In vitro antibacterial activity of beta-lactams and non-beta-lactams against Streptococcus pneumoniae isolates from Sydney, Australia

We studied the activity of ciprofloxacin and other antibiotics against both routine and multiresistant (multi-R) clinical isolates. Ciprofloxacin inhibited more than 98% of most species of Enterobacteriaceae at a concentration of 2 micrograms/ml. Only Acinetobacter calcoaceticus, and to a much lesser degree, Providencia and Serratia, were resistant. Most Pseudomonas aeruginosa isolates were susceptible. Only 1% of staphylococci were resistant; the test panel included 1200 MRSA. For most species of streptococci, the MIC90 was 1 microgram/ml; for enterococci, it was 2 micrograms/ml. We also surveyed resistance in our current isolates. Resistance to ciprofloxacin has increased in A. calcoaceticus and Providencia, and in Streptococcus pneumoniae and group B streptococci. Ciprofloxacin-resistant isolates tended to show increased resistance to other antibiotics, including aminoglycosides and, later, cephalosporins.

In vitro Activity of A-56619 and A-56620 against Multi-Resistant and Routine Clinical Isolates

Sir, A 64-year-old man was hospitalised during a holiday in Greece and on return was admitted to a Sydney hospital. An open lung biopsy confirmed Mycobacterium tuberculosis. The patient later presented with an aorto-oesophageal fistula which required emergency stenting. Following radical aortic resection the patient developed sepsis and died. Operative specimens grew Klebsiella resistant to meropenem. The isolate tested positive for a Klebsiella pneumoniae carbapenemase (KPC). This case is the first known isolation of a KPC-producing organism from an Australian hospital. In December 2008, the patient was hospitalised for recurrent epididymo-orchitis. He was noted to be hypotensive and Synacthen stimulation testing confirmed the diagnosis of Addison’s disease. Computed tomography (CT) scanning of the chest, abdomen and pelvis showed left-sided adrenal calcification and an 8 mm saccular thoracic aortic aneurysm with luminal ulceration proximal to the aneurysm. These changes were thought to be in keeping with atherosclerotic disease. The patient underwent elective percutaneous endoluminal stent insertion in July 2009. Two months later the patient travelled to Greece. He was unwell during the holiday and was twice admitted to Greek hospitals, including an admission to an intensive care unit (ICU). The discharge diagnosis was ‘Addisonian crisis’ but the inciting event was unclear. In October 2009, 2 weeks after returning to Australia, the patient remained unwell and was admitted to our institution for the first time with fevers, lethargy, anorexia and breathlessness. CT scans of the chest showed bilateral, symmetrical, peri-hilar, ground-glass infiltrates. Given the history of recent travel and the outbreak of H1N1 influenza at the time, a presumptive diagnosis of influenza pneumonitis was made. He was intubated, ventilated and treated with oseltamivir. Vancomycin, meropenem and azithromycin were added to cover hospital-acquired and atypical pathogens. Although the patient showed early improvement, his fevers persisted and he required re-intubation and re-admission to ICU on three further occasions. The radiological changes progressed to more confluent consolidation. After several weeks in hospital with poor response to broad-spectrum antimicrobial therapy, an open lung biopsy was performed. Pathology showed multiple caseating granulomas with numerous acid fast bacilli. The patient was commenced on standard four drug therapy with rifampicin, isoniazid, pyrazinamide and ethambutol. Culture of tissue subsequently grew pan-susceptible Mycobacterium tuberculosis. The patient was discharged to a rehabilitation facility, but was re-admitted 4 weeks later with persistent fever, anorexia and weight loss, despite therapy. He had developed a recurrent pleural effusion with consolidation of the left lower lobe. Diagnostic thoracocentesis showed 2þ acid fast bacilli on smear, but mycobacterial culture remained sterile. The patient was again discharged home to continue his anti-tuberculous therapy.

Multi-centre collaborative study for the in vitro evaluation of new macrolides dirithromycin and erythromycylamine

Aims: This study was undertaken to determine the antimicrobial resistance patterns of strains of Streptococcus pneumoniae from Sydney, Australia, comparing penicillin‐susceptible, ‐intermediate and ‐resistant isolates. Methods: Non‐duplicate cultures of S. pneumoniae were collected from 1 January to 31 December 2002 in the three penicillin‐susceptibility categories. Minimum inhibitory concentrations (MICs) of 19 antibacterial agents were determined by agar dilution based on the National Committee for Clinical Laboratory Standards (NCCLS) methodology. Overall for 2002, 687 non‐duplicate isolates were obtained, of which 190 (28%) were intermediate or resistant to penicillin. From this set, 183 isolates were selected for study: 88 (48%) in the penicillin‐susceptible group (MIC⩽0.06 mg/L), 25 (14%) in the penicillin‐intermediate group (MIC 0.125–1.0 mg/L) and 70 (38%) in the penicillin‐resistant group (MIC⩾2.0 mg/L). Results: Resistance to non‐beta‐lactams was more common in penicillin‐intermediate or ‐resistant strains. Multidrug resistance (resistance to ⩾2 non‐&bgr;‐lactams) was found in 3% of penicillin‐susceptible, 52% of penicillin‐intermediate and 87% of penicillin‐resistant isolates. Erythromycin resistance was seen in 22% of the penicillin‐susceptible strains but increased significantly to 60% and 89% in the penicillin‐intermediate and resistant strains, respectively. Clindamycin, tetracycline and trimethoprim/sulfamethoxazole showed similar diminished activity in penicillin‐intermediate and ‐resistant strains; 64, 84 and 91% of the penicillin‐resistant isolates were resistant to clindamycin, tetracycline and to trimethoprim/sulfamethoxazole, respectively. Chloramphenicol resistance was comparatively low level except 19% of the penicillin‐resistant strains were resistant. Ciprofloxacin MICs for 14 strains were raised (MICs 4–16 mg/L); three of these were penicillin‐susceptible, one penicillin‐intermediate and 10 penicillin‐resistant. Only one isolate was resistant to moxifloxacin and to gatifloxacin. Resistance to rifampicin, vancomycin, oritavancin, or linezolid was not detected. Twenty‐three isolates were intermediate and one resistant to quinupristin/dalfopristin – 22 of these were penicillin resistant. Conclusions: Streptococcus pneumoniae isolates from Sydney are commonly resistant to &bgr;‐lactams and available non‐&bgr;‐lactam agents, especially if they are penicillin non‐susceptible. Resistance to moxifloxacin and gatifloxacin is still rare, but some isolates were non‐susceptible to quinupristin/dalfopristin. It is important to continue to survey resistance patterns to recognise emerging resistances which affect the selection of empirical antimicrobials to treat infections with S. pneumoniae.

A national collaborative study of the in vitro activity of oral cephalosporins and loracarbef (LY 163892)

A-56619 and A-56620 are two new quinolone compounds that are currently being studied. They were found to be active against multi-resistant and routine isolates of Staphylococcus aureus, enterobacteria, aminoglycoside-sensitive and resistant strains of Pseudomonas aeruginosa. Most of the enterobacteria were inhibited by 0.5-1 mg/l of A-56620. A-56619 was less active, concentrations of 1-4 mg/l being needed for 90% inhibition. Both the compounds were active at concentrations of 0.5-1 mg/l against staphylococci, including multi-resistant S. aureus. The MIC90 for P. aeruginosa was 1-2 mg/l for A-56620 and 8 mg/l for A-56619.

Comparative Antibacterial Activities of New β-Lactam Antibiotics against Pseudomonas aeruginosa

&NA; A national study was conducted to determine the in vitro activity of 2 newer macrolides, dirithromycin and erythromycylamine compared with that of erythromycin, tetracycline and penicillin. Nineteen major teaching hospitals participated in the study. Minimal Inhibitory Concentrations (MICs) were determined by agar dilution, mostly using Iso‐Sensitest Agar and an inoculum of 104 cells per spot. 2284 clinically significant strains were isolated in late 1991 and early 1992, comprising 1736 Gram‐positive cocci, 355 Haemophilus influenzae, 97 Moraxella catarrhalis, 32 Listeria monocytogenes, 25 Neisseria meningitidis and 39 Neisseria gonorrhoeae were tested. The study indicates that dirithromycin and erythromycylamine possess antibacterial activity equivalent to that of erythromycin against most Gram‐positive cocci and M. catarrhalis. Strains resistant to erythromycin were also resistant to dirithromycin and to erythromycylamine. Tetracycline was as active as the macrolides against both penicillin‐resistant and penicillin‐susceptible strains of Staphylococcus aureus. Coagulase‐negative penicillin‐resistant staphylococci, compared with tetracycline, were relatively resistant to the macrolides. H. influenzae was less susceptible than the Gram‐positive cocci.