Candidaemia and a risk predictive model for overall mortality: a prospective multicentre study.

BACKGROUND: Candidaemia is associated with high mortality. Variables associated with mortality have been published previously, but not developed into a risk predictive model for mortality. We sought to describe the current epidemiology of candidaemia in Australia, analyse predictors of 30-day all-cause mortality, and develop and validate a mortality risk predictive model. METHODS: Adults with candidaemia were studied prospectively over 12 months at eight institutions. Clinical and laboratory variables at time of blood culture-positivity were subject to multivariate analysis for association with 30-day all-cause mortality. A predictive score for mortality was examined by area under receiver operator characteristic curves and a historical data set was used for validation. RESULTS: The median age of 133 patients with candidaemia was 62 years; 76 (57%) were male and 57 (43%) were female. Co-morbidities included underlying haematologic malignancy (n = 20; 15%), and solid organ malignancy in (n = 25; 19%); 55 (41%) were in an intensive care unit (ICU). Non-albicans Candida spp. accounted for 61% of cases (81/133). All-cause 30-day mortality was 31%. A gastrointestinal or unknown source was associated with higher overall mortality than an intravascular or urologic source (p < 0.01). A risk predictive score based on age > 65 years, ICU admission, chronic organ dysfunction, preceding surgery within 30 days, haematological malignancy, source of candidaemia and antibiotic therapy for ≥10 days stratified patients into < 20% or ≥ 20% predicted mortality. The model retained accuracy when validated against a historical dataset (n = 741). CONCLUSIONS: Mortality in patients with candidaemia remains high. A simple mortality risk predictive score stratifying patients with candidaemia into < 20% and ≥ 20% 30-day mortality is presented. This model uses information available at time of candidaemia diagnosis is easy to incorporate into decision support systems. Further validation of this model is warranted.

Pulmonary Cryptococcosis.

Inhalation of Cryptococcus into the respiratory system is the main route of acquisition of human infection, yet pulmonary cryptococcosis goes mostly unrecognized by many clinicians. This delay in diagnosis, or misdiagnosis, of lung infections is due in part to frequently subtle clinical manifestations such as a subacute or chronic cough, a broad differential of diagnostic possibilities for associated pulmonary masses (cryptococcomas) and, on occasion, negative respiratory tract cultures. Hematogenous dissemination from the lung can result in protean manifestations, the most severe of which is meningoencephalitis. There are few clinical studies of pulmonary cryptococcosis and its pathogenesis is poorly understood. The main purpose of this review is to describe the epidemiology, clinical presentation, diagnosis, and treatment of pulmonary cryptococcosis to increase clinician's awareness of this diagnostic possibility and to enhance clinical management. Useful pointers to the approach and management of pulmonary cryptococcosis and the implications of disseminated disease are included, together with recommendations for future research.

Support for the EUCAST and revised CLSI fluconazole clinical breakpoints by Sensititre® YeastOne® for Candida albicans: a prospective observational cohort study.

OBJECTIVES: Species-specific clinical breakpoints (CBPs) for Candida spp. were established following consideration of clinical outcomes in patients with oesophageal candidiasis. We sought to further determine the validity of the current CBPs based on data from a prospective candidaemia study. PATIENTS AND METHODS: All Candida albicans candidaemia episodes in patients enrolled in the Australian Candidaemia Study and who were treated with fluconazole monotherapy were included. Fluconazole MICs were established using Sensititre(®) YeastOne(®). RESULTS: Two hundred and seventeen evaluable episodes were identified, 93.5% of which occurred in adult patients. Fluconazole was commenced within 72 h of blood culture positivity in 96.3% (209/217) of episodes. Fluconazole doses were appropriate in 89.9% (195/217) of episodes and the median duration of therapy was 14 days (IQR 8-21 days) for the whole cohort. The all-cause 30 day mortality was 19.8% (43/217), with 37.2% (16/43) of deaths attributed to candidaemia. Classification and regression tree (CART) analysis identified a fluconazole MIC target of ≥2 mg/L for infection-related mortality and ≥4 mg/L for overall 30 day mortality. Overall mortality was no different in episodes with isolates above or below the identified MIC target, although there was a trend towards significance (P = 0.051). On univariate analysis, infection-related mortality was significantly increased in C. albicans episodes with an MIC ≥2 mg/L compared with those below this MIC target (20.6% versus 4.9%; P = 0.001). This target remained an independent predictor of infection-related mortality (OR 8.2; 95% CI 2.3-29.7; P = 0.001). CONCLUSIONS: We observed a direct relationship between infection-related mortality and rising fluconazole MIC for C. albicans candidaemia; overall, the data support the EUCAST and revised CLSI fluconazole clinical breakpoints.

Consensus guidelines for the treatment of yeast infections in the haematology, oncology and intensive care setting, 2014.

Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et al. appearing elsewhere in this supplement).

Key lessons from the COVID-19 public health response in Australia.

Australia avoided the worst effects of the COVID-19 pandemic, but still experienced many negative impacts. Reflecting on lessons from Australia's public health response, an Australian expert panel composed of relevant discipline experts identified the following key lessons: 1) movement restrictions were effective, but their implementation requires careful consideration of adverse impacts, 2) disease modelling was valuable, but its limitations should be acknowledged, 3) the absence of timely national data requires re-assessment of national surveillance structures, 4) the utility of advanced pathogen genomics and novel vaccine technology was clearly demonstrated, 5) decision-making that is evidence informed and consultative is essential to maintain trust, 6) major system weaknesses in the residential aged-care sector require fixing, 7) adequate infection prevention and control frameworks are critically important, 8) the interests and needs of young people should not be compromised, 9) epidemics should be recognised as a 'standing threat', 10) regional and global solidarity is important. It should be acknowledged that we were unable to capture all relevant nuances and context specific differences. However, the intent of this review of Australia's public health response is to critically reflect on key lessons learnt and to encourage constructive national discussion in countries across the Western Pacific Region.

Evaluation of a clinical scoring system and directed laboratory testing for respiratory virus infection in hematopoietic stem cell transplant recipients.

A simple clinical screening (CS) tool for respiratory virus (RV) infection was introduced and evaluated in a single hematology ward, as part of a strategy to reduce nosocomial RV infection. Up to 6 clinical symptoms or signs were scored and a predefined threshold score of ≥ 2 prompted paired nose/throat swab (NTS) collection for RV testing. The criterion standard for RV infection was positive immunofluorescence (IF) or polymerase chain reaction (PCR) for 7 and 15 viruses, respectively. The tool was shown to be most beneficial at excluding infection at a threshold score of 1 (negative predictive value [NPV] 89%, [95% confidence interval 78-96%], sensitivity 85% [70-94%], specificity 35% [27-43%]), compared with a score of 2 (NPV 85% [76-91%], sensitivity 63% [46-77%], specificity 57% [48-65%]) at a prevalence of 22%. The tool's ability to diagnose infection was limited (positive predictive value 27% and 29% at thresholds 1 and 2). The sensitivity of IF compared with PCR was 45% for the 7 viruses common to both, and 23% for the extended virus panel detected by PCR. An algorithm incorporating CS, paired NTS collection at a threshold of 1 symptom or sign, and sensitive testing including PCR can guide infection control measures in hospitalized hematopoietic stem cell transplant recipients.

Detection of occult Scedosporium species in respiratory tract specimens from patients with cystic fibrosis by use of selective media.

Respiratory samples from cystic fibrosis outpatients were cultured on Sabouraud's dextrose agar (SABD) containing antibiotics, Mycosel, and Scedosporium-selective medium (SceSel+). Thirty-two (14.7%) of 218 specimens from 11/69 (15.9%) patients yielded a Scedosporium sp., most frequently Scedosporium aurantiacum (17/218). Scedosporium was recovered on SceSel+, Mycosel, and SABD from 90.6%, 50.0%, and 46.9% of the specimens tested, respectively.

Chitotriosidase and gene therapy for fungal infections.

Chitotriosidase secreted by activated human macrophages has been implicated in the defence against chitin-bearing pathogens. The antifungal properties of human chitotriosidase were investigated here following retroviral vector-mediated gene transfer of the open reading frame of the chitotriosidase gene into Chinese hamster ovary cells. A chitinase assay confirmed that the engineered cells secreted recombinant chitotriosidase constitutively. Two dimensional gel electrophoresis and western blotting indicated that the recombinant protein is the major, chitin-binding, fifty kilodalton isoform. Culture medium conditioned by the transduced cells inhibited growth of isolates of Aspergillus niger, Candida albicans and Cryptococcus neoformans. Furthermore, longevity was significantly increased in a mouse model of cryptococcosis when cells transduced with the chitotriosidase gene and encapsulated in alginate microspheres were implanted subcutaneously in the animals. Engraftment of microcapsules containing cells transduced with the chitotriosidase gene has the potential to combat infections caused by chitinous pathogens through the prolonged delivery of recombinant chitotriosidase.

Pathways to COVID-19 'community protection'.

To date, no country has reached a natural COVID-19 epidemic peak and observed peaks essentially reflect the effectiveness of 'lockdown' measures. The major challenge is finding a responsible way out of 'lockdown', given that SARS- CoV-2 is now an established global pathogen. Acknowledging limitations in our knowledge regarding the sufficiency and durability of immune responses following natural SARS Cov-2 infection, we discuss three pathways to 'community protection'. Uncontrolled epidemic spread (route 1; R0>2) has been associated with overwhelmed health care systems and high death rates, especially in the vulnerable. Controlled epidemic spread (route 2; effective R0 1-2) can be achieved with limited or strict control of social mixing; strict control will be necessary to ensure that only low-risk individuals become infected, without spill-over to vulnerable groups during their period of infectiousness. It has been demonstrated that local epidemic elimination (route 3; effective R0<1) can be achieved through prolonged 'lock down', supplemented by early active case finding with quarantine of close contacts to ensure rapid termination of transmission chains within the community. Although universal availability of a safe and effective vaccine remains the preferred 'exit strategy', this may be hard to achieve and alternative options must be considered with careful consideration of all adverse outcomes - including health, social and economic consequences.

Candidemia following solid organ transplantation in the era of antifungal prophylaxis: the Australian experience.

Solid organ transplant (SOT) recipients have high rates of invasive fungal infections, with Candida species the most commonly isolated fungi. The aim of this study was to identify differences between incidence rates, risk factors, clinical presentations, and outcomes of candidemia in SOT recipients and non-SOT patients. Data from the multicenter prospective Australian Candidaemia Study were examined. From August 2001 to July 2004, 24 episodes (2.2%; 24/1068) of candidemia were identified in SOT recipients. During this period, the numbers of transplanted organs included liver (n=455), kidney (n=1605), single lung (n=57), bilateral lung (n=183), heart and lung (n=18), heart (n=157), and pancreas (n=62). The overall annual estimated incidence of candidemia in SOT recipients was higher (3 per 1000 transplant admissions) than in non-SOT patients (incidence 0.21 per 1000 admissions; P<0.001). The incidence and timing of candidemia post transplant was influenced by the transplanted organ type, with the majority of episodes (n=14, 54%) occurring >6 months after renal transplantation. Risk factors for candidemia in the month preceding diagnosis were similar to non-SOT recipients except for corticosteroid therapy (P<0.001). Antifungal prophylaxis did not select for more resistant or non-albicans Candida species in the SOT group. The 30-day all-cause mortality was similar to non-SOT patients with candidemia and remains high at 21%. All deaths in SOT recipients occurred early (within 5 days of diagnosis), underlining a need for better diagnostic tests, targeted prevention, and early treatment strategies.

Recommendations for the treatment of established fungal infections.

Evidence-based guidelines for the treatment of established fungal infections in the adult haematology/oncology setting were developed by a national consensus working group representing clinicians, pharmacists and microbiologists. These updated guidelines replace the previous guidelines published in the Internal Medicine Journal by Slavin et al. in 2004. The guidelines are pathogen-specific and cover the treatment of the most common fungal infections including candidiasis, aspergillosis, cryptococcosis, zygomycosis, fusariosis, scedosporiosis, and dermatophytosis. Recommendations are provided for management of refractory disease or salvage therapies, and special sites of infections such as the cerebral nervous system and the eye. Because of the widespread use newer broad-spectrum triazoles in prophylaxis and empiric therapy, these guidelines should be implemented in concert with the updated prophylaxis and empiric therapy guidelines published by this group.

Identification of genetic markers of resistance to echinocandins, azoles and 5-fluorocytosine in Candida glabrata by next-generation sequencing: a feasibility study.

OBJECTIVES: Multi-antifungal drug resistance in Candida glabrata is increasing. We examined the feasibility of next-generation sequencing (NGS) to investigate the presence of antifungal drug resistance markers in C. glabrata. METHODS: The antifungal susceptibility of 12 clinical isolates and one ATCC strain of C. glabrata was determined using the Sensititre YeastOne® YO10 assay. These included three isolate pairs where the second isolate of each pair had developed a rise in drug MICs. Single nucleotide polymorphisms (SNPs) in genes known to be linked to echinocandin, azole and 5-fluorocytosine resistance were analysed in all isolates through NGS. RESULTS: High-quality non-synonymous SNPs in antifungal resistance genes such as FKS1, FKS2, CgCDR1, CgPDR1 and FCY2 were identified. For two of three isolate pairs, there was a >60-fold rise in MICs to all echinocandins in the second isolate from each pair; one echinocandin-resistant isolate harboured a mutation in FKS1 (S629P) and the other in FKS2 (S663P). Of the third pair, both the 5-fluorocytosine-susceptible, and resistant isolates had a mutation in FCY2 (A237T). SNPs in CgPDR1 were found in pan-azole-resistant isolates. SNPs in other genes linked to azole resistance (CgCDR1, ERG9 and CgFLR1) were present in both azole-susceptible and azole-resistant isolates. SNPs were also identified in Candida adhesin genes EPA1, EPA6, PWP2 and PWP5 but their presence was not associated with higher drug MICs. CONCLUSIONS: Genome-wide analysis of antifungal resistance markers was feasible and simultaneously revealed mutation patterns of genes implicated in resistance to different antifungal drug classes.

Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients.

BACKGROUND: Invasive fungal infections, important causes of morbidity and mortality in critically ill patients, may be preventable with the prophylactic administration of antifungal agents. OBJECTIVES: This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005), and EMBASE (1980 to week 36, 2005). We also handsearched reference lists, abstracts of conference proceedings and scientific meetings (1998 to 2004), and contacted authors of included studies and pharmaceutical manufacturers. SELECTION CRITERIA: We included randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen in non-neutropenic critically ill adult patients. DATA COLLECTION AND ANALYSIS: Two authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We resolved differences by discussion. We synthesized data using the random effects model and expressed results as relative risk with 95% confidence intervals. MAIN RESULTS: We included 12 unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a nonabsorbable agent) involving 1606 randomized patients. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by about 25% (relative risk 0.76, 95% confidence interval 0.59 to 0.97) and invasive fungal infections by about 50% (relative risk 0.46, 95% confidence interval 0.31 to 0.68). We identified no significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or C. krusei, although the confidence intervals of the summary effect measures were wide. Adverse effects were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics. AUTHORS' CONCLUSIONS: Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.

Cathelicidins in the Tasmanian devil (Sarcophilus harrisii).

Tasmanian devil joeys, like other marsupials, are born at a very early stage of development, prior to the development of their adaptive immune system, yet survive in a pathogen-laden pouch and burrow. Antimicrobial peptides, called cathelicidins, which provide innate immune protection during early life, are expressed in the pouch lining, skin and milk of devil dams. These peptides are active against pathogens identified in the pouch microbiome. Of the six characterised cathelicidins, Saha-CATH5 and 6 have broad-spectrum antibacterial activity and are capable of killing problematic human pathogens including methicillin-resistant S. aureus and vancomycin-resistant E. faecalis, while Saha-CATH3 is active against fungi. Saha-CATH5 and 6 were toxic to human A549 cells at 500 µg/mL, which is over seven times the concentration required to kill pathogens. The remaining devil cathelicidins were not active against tested bacterial or fungal strains, but are widely expressed throughout the body, such as in immune tissues, in digestive, respiratory and reproductive tracts, and in the milk and pouch, which indicates that they are likely also important components of the devil immune system. Our results suggest cathelicidins play a role in protecting naive young during pouch life by passive immune transfer in the milk and may modulate pouch microbe populations to reduce potential pathogens.

Mucormycosis in Australia: contemporary epidemiology and outcomes.

Mucormycosis is the second most common cause of invasive mould infection and causes disease in diverse hosts, including those who are immuno-competent. We conducted a multicentre retrospective study of proven and probable cases of mucormycosis diagnosed between 2004-2012 to determine the epidemiology and outcome determinants in Australia. Seventy-four cases were identified (63 proven, 11 probable). The majority (54.1%) were caused by Rhizopus spp. Patients who sustained trauma were more likely to have non-Rhizopus infections relative to patients without trauma (OR 9.0, p 0.001, 95% CI 2.1-42.8). Haematological malignancy (48.6%), chemotherapy (42.9%), corticosteroids (52.7%), diabetes mellitus (27%) and trauma (22.9%) were the most common co-morbidities or risk factors. Rheumatological/autoimmune disorders occurred in nine (12.1%) instances. Eight (10.8%) cases had no underlying co-morbidity and were more likely to have associated trauma (7/8; 87.5% versus 10/66; 15.2%; p <0.001). Disseminated infection was common (39.2%). Apophysomyces spp. and Saksenaea spp. caused infection in immuno-competent hosts, most frequently associated with trauma and affected sites other than lung and sinuses. The 180-day mortality was 56.7%. The strongest predictors of mortality were rheumatological/autoimmune disorder (OR = 24.0, p 0.038 95% CI 1.2-481.4), haematological malignancy (OR = 7.7, p 0.001, 95% CI 2.3-25.2) and admission to intensive care unit (OR = 4.2, p 0.02, 95% CI 1.3-13.8). Most deaths occurred within one month. Thereafter we observed divergence in survival between the haematological and non-haematological populations (p 0.006). The mortality of mucormycosis remains particularly high in the immuno-compromised host. Underlying rheumatological/autoimmune disorders are a previously under-appreciated risk for infection and poor outcome.

Molecular diagnostic methods for invasive fungal disease: the horizon draws nearer?

Rapid, accurate diagnostic laboratory tests are needed to improve clinical outcomes of invasive fungal disease (IFD). Traditional direct microscopy, culture and histological techniques constitute the 'gold standard' against which newer tests are judged. Molecular diagnostic methods, whether broad-range or fungal-specific, have great potential to enhance sensitivity and speed of IFD diagnosis, but have varying specificities. The use of PCR-based assays, DNA sequencing, and other molecular methods including those incorporating proteomic approaches such as matrix-assisted laser desorption ionisation-time of flight mass spectroscopy (MALDI-TOF MS) have shown promising results. These are used mainly to complement conventional methods since they require standardisation before widespread implementation can be recommended. None are incorporated into diagnostic criteria for defining IFD. Commercial assays may assist standardisation. This review provides an update of molecular-based diagnostic approaches applicable to biological specimens and fungal cultures in microbiology laboratories. We focus on the most common pathogens, Candida and Aspergillus, and the mucormycetes. The position of molecular-based approaches in the detection of azole and echinocandin antifungal resistance is also discussed.

Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.

The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19-275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.

A comparison of hospital and community-acquired infective endocarditis.

The epidemiology, clinical features, microbiology and outcome of 30 episodes of nosocomial endocarditis occurring over a 13-year period were reviewed and compared with 148 cases of community-acquired endocarditis. Twenty-eight patients (93%) had been in hospital for > 1 week and 10 patients (33%) for > 1 month when they developed endocarditis. Left-sided infection was most frequent; only 3 cases involved the tricuspid valve. Compared with community-acquired infection, patients tended to be older, had a greater incidence of congestive cardiac failure (p = 0.001) or hypotension (p = 0.0008) at presentation and were more likely to have bacteremia after an invasive procedure (83 vs 31%; p < 0.00001). Intravascular devices were the presumed source of bacteremia in 11 cases (37%); the same organism was isolated from both the blood and the suspected source of infection. Staphylococcus aureus was the most frequent causative organism, accounting for 17 episodes (57%), including 4 (13%) due to methicillin-resistant strains. Nosocomial endocarditis had a significantly higher mortality than did community-acquired infection (40 vs 18%; p = 0.02). Eight patients (27%) needed valve replacement. Proper adherence to protocols for management of intravascular devices and appropriate antimicrobial prophylaxis before procedures may have prevented endocarditis in 15 of 30 patients.

Biliary sepsis. Reviewing treatment options.

Bactobilia is a frequent accompaniment of obstruction in the biliary tract, organisms present being normal intestinal aerobes and anaerobes. Bacterial colonisation of the bile may occur asymptomatically, may predispose to infection postoperatively, or may be associated with an attack of acute cholecystitis, occurring secondary to obstruction. The choice of an antimicrobial regimen for biliary infection should take into account the expected antibiotic sensitivities of organisms colonising bile, whether biliary obstruction or bacteraemia is present, and the activity of the antibiotic in bile. Often, high biliary concentrations of an antibiotic cannot be achieved due to obstruction, and in many cases high blood and tissue concentrations are of greater importance. Surgical prophylaxis should be reserved for patients at high risk of bactobilia (e.g. the elderly), when obstruction is present, for immunosuppressed patients, and those with artificial heart valves. A single perioperative dose of a 'first' or 'second generation' cephalosporin, gentamicin, or co-trimoxazole is effective. Antibiotic therapy for acute cholecystitis should be instituted if there is evidence of systemic toxicity, when surgery is to be delayed, or in patients with identified risk factors for bactobilia. Ampicillin or a cephalosporin may be appropriate in less severe disease, while in seriously ill patients, an aminoglycoside or cephalosporin with metronidazole or clindamycin is appropriate. Oral regimens include amoxycillin, an oral cephalosporin, or co-trimoxazole, in combination with metronidazole. In acute cholangitis, systemic therapy similar to that recommended for acute cholecystitis is indicated. Patients with recurrent cholangitis may have relatively antibiotic-resistant bacteria and efforts should be made to obtain a bacteriological diagnosis. Long term suppressant therapy with oral agents such as amoxycillin, cephalexin, or co-trimoxazole may be tried.