LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring.

BACKGROUND: Linezolid is a broad-spectrum antimicrobial with limited use due to toxicity. This study aimed to evaluate linezolid toxicity in a large multicentre cohort. Secondary objectives were to identify factors contributing to toxicity, including the impact of therapeutic drug monitoring (TDM). METHODS: Patients administered linezolid between January 2017 and December 2019 were retrospectively reviewed. Data were collected on patient characteristics, linezolid therapy and outcomes. Descriptive statistics were performed on all patients, and statistical comparisons were undertaken between those who did and did not experience linezolid toxicity. A multivariable logistic regression model was constructed to identify any covariates that correlated with toxicity. RESULTS: Linezolid was administered to 1050 patients; of these, 381 did not meet the inclusion criteria and 47 were excluded as therapy ceased for non-toxicity reasons. There were 105 of 622 (16.9%) patients assessed to have linezolid toxicity. Patients who experienced toxicity displayed a higher baseline creatinine (96.5 µmol/L vs. 79 µmol/L; P = 0.025), lower baseline platelet count (225 × 109/L vs. 278.5 × 109/L; P = 0.002) and received a longer course (median 21 vs. 14 days; P < 0.001) than those who did not. Linezolid TDM was performed in 144 patients (23%). Multivariable logistic regression demonstrated that TDM-guided appropriate dose adjustment significantly reduced the odds of linezolid toxicity (aOR = 0.45; 95% CI 0.21-0.96; P = 0.038) and a treatment duration > 28 days was no longer significantly associated with toxicity. CONCLUSIONS: This study confirmed that linezolid treatment-limiting toxicity remains a problem and suggests that TDM-guided dose optimisation may reduce the risk of toxicity and facilitate prolonged courses beyond 28 days.

Carbon emissions and hospital pathology stewardship: a retrospective cohort analysis.

BACKGROUND: As healthcare is responsible for 7% of Australia's carbon emissions, it was recognised that a policy implemented at St George Hospital, Sydney, to reduce non-urgent pathology testing to 2 days per week and, on other days only if essential, would also result in a reduction in carbon emissions. The aim of the study was to measure the impact of this intervention on pathology collections and associated carbon emissions and pathology costs. AIMS: To measure the impact of an intervention to reduce unnecessary testing on pathology collections and associated carbon emissions and pathology costs. METHODS: The difference in the number of pathology collections, carbon dioxide equivalents (CO2 e) for five common blood tests and pathology cost per admission were compared between a 6-month reference period and 6-month intervention period. CO2 e were estimated from published pathology CO2 e impacts. Cost was derived from pathology billing records. Outcomes were modelled using multivariable negative binomial, generalised linear and logistic regression. RESULTS: In total, 24 585 pathology collections in 5695 patients were identified. In adjusted analysis, the rate of collections was lower during the intervention period (rate ratio 0.90; 95% confidence interval (CI), 0.86-0.95; P < 0.001). This resulted in a reduction of 53 g CO2 e (95% CI, 24-83 g; P < 0.001) and $22 (95% CI, $9-$34; P = 0.001) in pathology fees per admission. The intervention was estimated to have saved 132 kg CO2 e (95% CI, 59-205 kg) and $53 573 (95% CI, 22 076-85 096). CONCLUSIONS: Reduction in unnecessary hospital pathology collections was associated with both carbon emission and cost savings. Pathology stewardship warrants further study as a potentially scalable, cost-effective and incentivising pathway to lowering healthcare associated greenhouse gas emissions.

Maintenance of broad neutralizing antibodies and memory B cells 1 year post-infection is predicted by SARS-CoV-2-specific CD4+ T cell responses.

Understanding the long-term maintenance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity is critical for predicting protection against reinfection. In an age- and gender-matched cohort of 24 participants, the association of disease severity and early immune responses on the maintenance of humoral immunity 12 months post-infection is examined. All severely affected participants maintain a stable subset of SARS-CoV-2 receptor-binding domain (RBD)-specific memory B cells (MBCs) and good neutralizing antibody breadth against the majority of the variants of concern, including the Delta variant. Modeling these immune responses against vaccine efficacy data indicate a 45%-76% protection against symptomatic infection (variant dependent). Overall, these findings indicate durable humoral responses in most participants after infection, reasonable protection against reinfection, and implicate baseline antigen-specific CD4+ T cell responses as a predictor of maintenance of antibody neutralization breadth and RBD-specific MBC levels at 12 months post-infection.

Cluster of invasive Mycobacteria chimaera infections following cardiac surgery demonstrating novel clinical features and risks of aortic valve replacement.

There is a global outbreak of infections due to Mycobacterium chimaera associated with cardiac surgery. The most serious infections involve prosthetic material implantation, and all have followed surgical procedures involving cardiopulmonary bypass. We describe a cluster of four cases following cardiac surgery at a tertiary referral centre in Sydney, Australia. We report novel clinical findings, including haemolysis and kidney rupture possibly related to immune reconstitution inflammatory syndrome. The positive effect of corticosteroids on haemodynamic function in two cases and the failure of currently recommended antimicrobial therapy to sterilise prosthetic valve material in the absence of surgery despite months of treatment are also critically examined. Positron emission tomography was positive in two cases despite normal transoesophageal echocardiograms. The proportion of cases with M. chimaera infection after aortic valve replacement (4/890, 0.45%; 95% confidence interval 0.18-1.15%) was significantly higher than after all other cardiothoracic surgical procedures (0/2433, 0%; 95% confidence interval 0-0.16%).

Sustained multimodal antimicrobial stewardship in an Australian tertiary intensive care unit from 2008-2015: an interrupted time-series analysis.

The long-term outcomes and sustainability of antimicrobial stewardship (AMS) in the intensive care unit (ICU) require evaluation. This study analysed the effect of a multimodal ICU AMS introduced in a 15-bed medical-surgical tertiary Australian adult ICU in November 2008, using interrupted time-series analysis of antibiotic usage, Gram-negative resistance and cost from November 2005 to October 2015, including national ICU average usage as a control. Overall ICU mortality, 30-day blood stream infection (BSI) mortality and length of stay (LOS) were compared over the same period. There were 2512 patients admitted to ICU before and 6435 after AMS intervention. Post-AMS there was a reduction in the trend of aminoglycoside usage both absolute from 63.3 DDD/1000 occupied bed days (OBD)/month (-1.1; 95% confidence interval [CI] -2.2, -0.1; P = 0.033) and relative to the national trend (-1.3; 95%CI -2.4, -0.3; P = 0.016). Vancomycin usage increased both absolute from 161.2 DDD/1000 OBD/month (1.8; 95%CI 0.03, 3.6; P = 0.046) and relative to the national trend (1.8; 95%CI -0.3, 3.9; P = 0.092). There were sustained post-AMS downward trends in carbapenem, antipseudomonal penicillin, third-generation cephalosporin and fluoroquinolone use that did not reach statistical significance. Post-AMS, antipseudomonal penicillin resistance declined (-12.8%; 95%CI -24.9, -0.6; P = 0.040). Antimicrobial acquisition costs declined by AUD$0.5/OBD/month (95%CI -1.1, 0.1; P = 0.096). Over the study period, severity-adjusted ICU mortality declined from 12.9% to 10.4%; risk ratio (RR) 0.92 (95%CI 0.82, 1.03) and BSI 30-day mortality from 37.9% to 26.3%; RR, 0.76 (95%CI 0.56, 1.03). Median ICU LOS for ICU survivors increased from 2.3 to 2.6 days. Multimodal AMS sustainably embedded in ICU was associated with reductions in broad-spectrum Gram-negative antibiotic use, overall antibiotic costs and Gram-negative resistance, without adverse clinical impact.

Cervicitis: a prospective observational study of empiric azithromycin treatment in women with cervicitis and non-specific cervicitis.

Treatment with 1 G azithromycin was observed prospectively in 130 women with cervicitis (>30 polymorphonuclear leucocytes/high-powered field) enrolled in a cervicitis aetiology study of 558 women at three sexually transmitted infection clinics in Sydney, Australia. Two overlapping groups of women with cervicitis were considered: 'cervicitis group 1' (n = 116) excluded women with Trichomonas vaginalis and a subgroup of this, 'cervicitis group 2' (non-specific cervicitis) (n = 96) further excluded women with Neisseria gonorrhoea, Chlamydia trachomatis and Mycoplasma genitalium at enrolment. Testing for Chlamydia trachomatis, Mycoplasma genitalium and Trichomonas vaginalis was by PCR and Neisseria gonorrhoea by PCR and culture. Treatment outcomes were cervicitis or vaginal symptoms at follow-up. Effect on cervicitis at follow-up was also assessed after additional reported partner treatment. In 'cervicitis group 1' where prevalence of Mycoplasma genitalium and/or Chlamydia trachomatis was 23/116 (19.8%), azithromycin reduced cervicitis at follow-up (RR = 0.62 (95% CI 0.39-0.97) p = 0.035), but there was no significant effect in non-specific cervicitis ('cervicitis group 2') (RR = 0.60 (95% CI 0.35-1.01) p = 0.056). Empiric treatment did not reduce vaginal symptoms at follow-up in either group. No effect of empiric partner treatment was seen. The conclusion was that empiric azithromycin treatment of cervicitis reduces cervicitis at follow-up in populations with high prevalence of Chlamydia trachomatis and/or Mycoplasma genitalium. There are no benefits of empiric azithromycin for non-specific cervicitis or empiric partner treatment.

Cervicitis aetiology and case definition: a study in Australian women attending sexually transmitted infection clinics.

OBJECTIVES: Studies examining cervicitis aetiology and prevalence lack comparability due to varying criteria for cervicitis. We aimed to outline cervicitis associations and suggest a best case definition. METHODS: A cross-sectional study of 558 women at three sexually transmitted infection clinics in Sydney, Australia, 2006-2010, examined pathogen and behavioural associations of cervicitis using three cervicitis definitions: 'microscopy' (>30 pmnl/hpf (polymorphonuclear leucocytes per high-powered field on cervical Gram stain)), 'cervical discharge' (yellow and/or mucopurulent cervical discharge) or 'micro+cervical discharge' (combined 'microscopy' and 'cervical discharge'). RESULTS: Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV) and Neisseria gonorrhoeae (NG) had the strongest associations with cervicitis definitions 'micro+cervical discharge': CT adjusted prevalence ratio (APR)=2.13 (95% CI 1.38 to 3.30) p=0.0006, MG APR=2.21 (1.33 to 3.69) p=0.002, TV APR=2.37 (1.44 to 3.90) p=0.0007 NG PR=4.42 (3.79 to 5.15) p<0.0001 and 'cervical discharge': CT APR=1.90 (1.25 to 2.89) p=0.003, MG APR=1.93 (1.17 to 3.19) p=0.011, TV APR=2.02 (1.24 to 3.31) p=0.005 NG PR=3.88 (3.36 to 4.48) p<0.0001. Condom use for vaginal sex 'always/sometimes' reduced cervicitis risk: ('micro+cervical discharge') APR=0.69 (0.51 to 0.93) p=0.016. Combined population attributable risk % (PAR%) of these four pathogens was only 18.0% with a protective PAR% of condoms of 25.7%. Exposures not associated with cervicitis included bacterial vaginosis, Mycoplasma hominis, Ureaplasma urealyticum, herpes simplex virus 1&2, cytomegalovirus, Candida, age, smoking and hormonal contraception. CONCLUSIONS: Cervicitis was associated with CT, MG, TV and NG with combined PAR% of these pathogens only 18% in this setting, suggesting other factors are involved. Condoms significantly reduced cervicitis risk. Cervicitis definitions with best clinical utility and pathogen prediction were 'cervical discharge' and 'micro+cervical discharge'.

Pyelonephritis: what are the present day causative organisms and antibiotic susceptibilities?

AIM: Infections of the lower urinary tract and acute pyelonephritis are commonly encountered in clinical practice. Widespread usage of antibiotics and changing susceptibility profiles of uropathogens requires regular review of treatment guidelines to meet these challenges. We aimed to better understand the prevalence of uropathogens and emerging antibiotic resistance in patients with pyelonephritis requiring hospital admission. METHODS: In this single centre, 12-year retrospective observational study, we reviewed case notes and urine culture results of 249 patients admitted with acute pyelonephritis under the care of the nephrology department, along with 46,660 urine samples with positive isolates from the emergency department (ED) during the same period. The prevalence of uropathogens, their antibiotic susceptibilities and emerging resistance patterns to commonly used antibiotics were studied. Antibiotic susceptibilities were also reviewed in line with the currently recommended national guidelines for empiric therapy. RESULTS: We found the most prevalent uropathogen to be Escherichia coli. Approximately 50% of E. coli infections were resistant to ampicillin. First and third generation cephalosporin resistance was <5%, however, the latter has increased over the last decade and is more prevalent in the elderly. Enterococcus faecalis was associated with less than 10% of cases of lower urinary tract infections and no case of pyelonephritis. CONCLUSION: Antibiotic resistance of uropathogens to commonly used antibiotics is increasing with time and there is a need for hospitals to review their recommended guidelines for empiric therapy in line with local patterns of uropathogens and antibiotic susceptibilities.

What proportion of sexually transmissible infections and HIV are diagnosed in New South Wales' public sexual health services compared with other services?

BACKGROUND: In New South Wales (NSW), publicly funded sexual health services (PFSHSs) target the populations at greatest risk for important sexually transmissible infections (STIs) and so may make a large contribution to the diagnosis of notifiable STIs. We aimed to determine the proportions of STIs diagnosed in PFSHSs and notified to the NSW Ministry of Health in 2009, and describe geographical variations. METHODS: The number of notifiable STIs (infectious syphilis, gonorrhoea, HIV and chlamydia) diagnosed in 2009 was obtained for each Area Health Service (AHS) and each PFSHS. The proportion of diagnoses made by PFSHSs was calculated at the state and AHS level according to five geographical regions: inner and outer metropolitan, regional, rural and remote. RESULTS: The overall proportions of diagnoses made by NSW PFSHSs were syphilis, 25%; gonorrhoea, 25%; HIV, 21%; and chlamydia, 14%. Within each zone, the proportions of these STIs were (respectively): (i) inner metropolitan: 32%, 26%, 21% and 13%; (ii) outer metropolitan: 41%, 24%, 43% and 9%; (iii) regional: 62%, 15%, 23% and 10%; (iv) rural: 8%, 29%, <5% and 20%; and (v) remote: <5%, 43%, <5% and 29%. There was considerable variation in proportions of STIs between and within AHSs (<5-100%). CONCLUSIONS: NSW PFSHSs contribute a large proportion of diagnoses for syphilis, gonorrhoea and HIV, but less so for chlamydia. Across AHSs and zones, there was considerable variation in the proportions. These data support the role of PFSHS in identifying and managing important STIs in high-risk populations.

Pharyngeal Gonorrhoea in Women: An Important Reservoir for Increasing Neisseria gonorrhoea Prevalence in Urban Australian Heterosexuals?

We aim to characterize sexual behavioral aspects of heterosexual Neisseria gonorrhoea (NG) acquisition in two Sexually Transmitted Diseases clinics in Sydney, Australia, in 2008-2012. Of 167 NG cases, 102 were heterosexually acquired with a trend of increasing NG prevalence in heterosexuals from 1.1% (95% CI 0.6-2.1) in 2008 to 3.0% (95% CI 2.0-4.0) in 2012 (P = 0.027). Of heterosexual male cases, unprotected fellatio was the likely sexual activity for NG acquisition in 21/69 (30.4%) and commercial sex work (CSW) contact the likely source in 28/69 (40.6%). NG prevalence overall in CSW (2.2%) was not significantly higher than in non-CSW (1.2%) (P = 0.15), but in 2012 there was a significant increase in NG prevalence in CSW (8.6%) compared to non-CSW (1.6%) (P < 0.001). Pharyngeal NG was found in 9/33 (27.3%) female cases. Decreased susceptibility to ceftriaxone (MIC ≥ 0.03 mg/L) occurred in 2.5% NG isolates, none heterosexually acquired. All were azithromycin susceptible. A significant trend of increasing prevalence of heterosexual gonorrhoea in an urban Australian STD clinic setting is reported. We advocate maintenance of NG screening in women, including pharyngeal screening in all women with partner change who report fellatio, as pharyngeal NG may be an important reservoir for heterosexual transmission. Outreach to CSW should be enhanced.

Trichomonas vaginalis: underdiagnosis in urban Australia could facilitate re-emergence.

OBJECTIVES: Trichomonas vaginalis (TV) has a low profile in urban sexually transmitted infection (STI) clinics in many developed countries. The objective of this study was to determine the true prevalence of TV in an Australian urban sexual health setting using sensitive molecular diagnostic techniques. METHODS: A cross-sectional study investigating the aetiology of cervicitis in women attending two urban sexual health clinics in Sydney, Australia, enrolled 356 consecutive eligible women from 2006 to 2008. The diagnostic yield from the standard clinical practice of discretionary high vaginal wet preparation microscopy in women with suspicious vaginal discharge was compared with universal use of nested PCR for TV of cervical samples. RESULTS: TV was detected by PCR in 17/356 women (4.8%, 95% CI 2.8 to 7.5%), whereas only four cases (1.1%, 95% CI 0.3 to 2.8%) were detected by discretionary wet preparation microscopy. Eleven of the 17 women (p=0.003) were of culturally and linguistically diverse background. Additionally, cervicitis was found to be significantly associated with TV, RR 1.66 (1.14 to 2.42), p=0.034. CONCLUSIONS: Traditional TV-detection methods underestimate TV prevalence in urban Australia. The TV prevalence of 4.8% by PCR testing in this study exceeds previously reported urban Australian TV rates of <1%. An increase in trichomoniasis-associated adverse reproductive outcomes and enhanced HIV transmission poses a salient public health threat. Accordingly, TV warrants a higher profile in urban STI clinic settings in developed countries, and we suggest that priority be given to development of standardised molecular TV detection techniques and that these become part of routine STI testing.

Primary health care providers surveyed commonly misinterpret 'first void urine' for chlamydia screening.

An open question survey of general practitioners (GP) and hospital emergency department (ED) doctors revealed that the term 'FVU' (first void urine) used for urine chlamydia testing, is ambiguous, potentially leading to incorrect urine sample collection and barriers to effective screening. The results of this survey indicate that only 4.3% (95% confidence interval [CI] 0.5-14.5%) of GP and 6.9% (95% CI 0.9-22.8%) of ED doctors respectively, correctly interpreted the meaning of FVU. The majority of clinicians surveyed misunderstood 'FVU' to require the first urine void of the day, accounting for 68.1% (95% CI 52.9-80.9%) of GP responses and 37.9% (95% CI 20.7-57.7%) of ED doctors responses. This highlights the need for clarification and standardisation of terminology used in urine chlamydia screening for health care providers, in order to optimise strategies for diagnosis and control of the ongoing chlamydia epidemic.

Dapsone hypersensitivity syndrome causing disseminated intravascular coagulation.

Dapsone hypersensitivity syndrome is an idiosyncratic reaction to this drug and can present with different clinical manifestations of varying severity. We describe a patient with disseminated intravascular coagulation (DIC) as an adverse reaction to dapsone. To the best of our knowledge, this is the first time it has been described in the literature. She presented with fever, rash and abdominal pain; she also had marked eosinophilia and features suggestive of oxidative haemolysis. Her course was complicated by DIC, splenic infarction and gastrointestinal bleeding. Extensive investigations did not reveal any alternative aetiology. She was initially treated with supportive measures and folic acid; steroids were administered later, following clinical deterioration. There was gradual improvement and the steroids were tapered. The patient recovered fully and remains well; her underlying chronic dermatologic condition is under satisfactory control with other medications.

Current features of infective endocarditis in elderly patients: results of the International Collaboration on Endocarditis Prospective Cohort Study.

BACKGROUND: Elderly patients are emerging as a population at high risk for infective endocarditis (IE). However, adequately sized prospective studies on the features of IE in elderly patients are lacking. METHODS: In this multinational, prospective, observational cohort study within the International Collaboration on Endocarditis, 2759 consecutive patients were enrolled from June 15, 2000, to December 1, 2005; 1056 patients with IE 65 years or older were compared with 1703 patients younger than 65 years. Risk factors, predisposing conditions, origin, clinical features, course, and outcome of IE were comprehensively analyzed. RESULTS: Elderly patients reported more frequently a hospitalization or an invasive procedure before IE onset. Diabetes mellitus and genitourinary and gastrointestinal cancer were the major predisposing conditions. Blood culture yield was higher among elderly patients with IE. The leading causative organism was Staphylococcus aureus, with a higher rate of methicillin resistance. Streptococcus bovis and enterococci were also significantly more prevalent. The clinical presentation of elderly patients with IE was remarkable for lower rates of embolism, immune-mediated phenomena, or septic complications. At both echocardiography and surgery, fewer vegetations and more abscesses were found, and the gain in the diagnostic yield of transesophageal echocardiography was significantly larger. Significantly fewer elderly patients underwent cardiac surgery (38.9% vs 53.5%; P < .001). Elderly patients with IE showed a higher rate of in-hospital death (24.9% vs 12.8%; P < .001), and age older than 65 years was an independent predictor of mortality. CONCLUSIONS: In this large prospective study, increasing age emerges as a major determinant of the clinical characteristics of IE. Lower rates of surgical treatment and high mortality are the most prominent features of elderly patients with IE. Efforts should be made to prevent health care-associated acquisition and improve outcomes in this major subgroup of patients with IE.

Cervicitis: a review.

PURPOSE OF REVIEW: Sexually transmitted infections impact significantly on global health. Whereas Chlamydia, Neisseria gonorrhoea and syphilis have been extensively examined, there remains a paucity of knowledge of nonchlamydial and nongonococcal cervicitis, an arguably more prevalent but poorly characterized condition with uncertain clinical implications. With increasing application of molecular diagnostic methods for the detection of sexually transmitted infections and a growing body of literature on cervicitis, a review is timely. RECENT FINDINGS: The number of putative aetiological agents implicated in cervicitis is growing and includes Mycoplasma genitalium, herpes simplex virus, cytomegalovirus, bacterial vaginosis and Trichomonas. The potential role of cervicitis in HIV transmission has been highlighted. Increasing broad-spectrum antibiotic usage with associated emergence of antimicrobial resistance reinforces the need for targeted antibiotic therapies, including the management of cervicitis. SUMMARY: As our understanding of the aetiology and significance of cervicitis, particularly nonspecific cervicitis, improves, management will be refined. Advances in molecular diagnostic testing will facilitate this process, but urinary nucleic acid amplification testing should not replace clinical examination while cervicitis prevalence and significance is not yet established. A standardized approach to cervicitis research, particularly with consensus of case definition, may facilitate outcomes that can be more generally applied in clinical practice.

Hemopoietic cells with features of the mast cell and basophil lineages and their potential role in allergy.

Human mast cells (MCs) and basophils play a key role in the pathogenesis of allergic disorders, not only by producing inflammatory and fibrogenic mediators, but also by directly and indirectly secreting various cytokines and chemokines. Although mast cells and basophils have differences in many properties, recent evidence suggests that human MCs and basophils may be derived from a common progenitor, and their contents and phenotypes may be reversibly altered in a variety of allergic disorders. The study of FcetaRI signalling of mast cell and basophils offers new opportunities for therapeutic interventions based on the specific inhibition of the earliest events in allergic diseases. This article reviews the origin, differentiation, morphology and phenotypic properties of MCs and basophils, focussing particularly on the possible pathogenic role of MCs and basophils in allergy and biochemical targets for therapeutic interventions in allergic diseases.