Matthew Scarborough

The diagnosis and management of acute bacterial meningitis in resource-poor settings

Acute bacterial meningitis is more common in resource-poor than resource-rich settings. Survival is dependent on rapid diagnosis and early treatment, both of which are difficult to achieve when laboratory support and antibiotics are scarce. Diagnostic algorithms that use basic clinic and laboratory features to distinguish bacterial meningitis from other diseases can be useful. Analysis of the CSF is essential, and simple techniques can enhance the yield of diagnostic microbiology. Penicillin-resistant and chloramphenicol-resistant bacteria are a considerable threat in resource-poor settings that go undetected if CSF and blood can not be cultured. Generic formulations of ceftriaxone are becoming more affordable and available, and are effective against meningitis caused by penicillin-resistant or chloramphenicol-resistant bacteria. However, infection with Streptococcus pneumoniae with reduced susceptibility to ceftriaxone is reported increasingly, and alternatives are either too expensive (eg, vancomycin) or can not be widely recommended (eg, rifampicin, which is the key drug to treat tuberculosis) in resource-poor settings. Additionally, improved access to affordable antibiotics will not overcome the problems of poor access to hospitals and the fatal consequences of delayed treatment. The future rests with the provision of effective conjugate vaccines against S pneumoniae, Haemophilus influenzae, and Neisseria meningitides to children in the poorest regions of the world.

Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial

BACKGROUND Southern Africa has a high incidence of bacterial meningitis in adults, often associated with HIV co-infection. Mortality exceeds 50%, even with appropriate antibiotic therapy, and is not improved with corticosteroids. Glycerol adjuvant therapy reduces long-term morbidity in bacterial meningitis in children, and its use is being promoted. We aimed to assess the effectiveness of glycerol as an adjuvant therapy for adults with bacterial meningitis in Africa. METHODS The study was done in two phases. First, in an open-label dose-finding study, 45 adult patients with symptoms, signs, and cerebrospinal fluid findings consistent with bacterial meningitis received either 50 mL, 75 mL, or 100 mL of glycerol four times a day for 4 days. We then did a randomised, double-blind, placebo-controlled trial of oral glycerol in adults with bacterial meningitis. Patients with clinical and cerebrospinal fluid findings suggestive of bacterial meningitis were randomly assigned in blocks of 12 by use of a random number list produced by an independent statistician to receive either glycerol or an equivalent volume of sugar solution. Glycerol and placebo were indistinguishable by colour or taste. The primary outcome was mortality at 40 days, with secondary outcomes including disability and mortality restricted to pneumococcal disease. All patients were analysed for the primary outcome excluding those who were lost to follow-up. This trial is registered at controlled-trials.com, number ISRCTN70121840. FINDINGS 75 mL glycerol four times a day was the highest tolerated dose, and was used for the main study. 265 patients were assigned treatment: 137 glycerol and 128 placebo. The trial was stopped early on the advice of the data and safety monitoring board after a planned interim analysis. By day 40, 61 (49%) of 125 patients in the placebo group and 86 (63%) of 136 in the glycerol group had died (adjusted odds ratio 2.4, 95% CI 1.3-4.2, p=0.003). There was no benefit from glycerol for death and disability by day 40, and glycerol did not improve death and disability by day 40 or death at day 40 in patients with proven bacterial disease or pneumococcal disease. Two serious adverse events occurred that were possibly due to the study drug. INTERPRETATION Oral glycerol therapy cannot be recommended as an adjuvant therapy in adults with bacterial meningitis in resource-poor settings with a high HIV prevalence. FUNDING Meningitis Research Foundation.

Prioritizing echocardiography in Staphylococcus aureus bacteraemia

OBJECTIVES Infective endocarditis (IE) is a severe complication in Staphylococcus aureus bacteraemia (SAB) and recent guidelines from the BSAC recommend all patients undergo echocardiography. We assessed the use of echocardiography at a major tertiary referral centre and sought to identify those patients most likely to have positive findings. METHODS We retrospectively evaluated all cases of SAB at Oxford University Hospitals NHS Trust between September 2006 and August 2011. RESULTS Three-hundred-and-six out of 668 patients with SAB underwent cardiac imaging on average 9.8 ± 1.3 days from the first culture. Thirty-one patients (10.1%) had echocardiographic evidence of IE. Risk factors for observing evidence of IE on scanning included the presence of prosthetic heart valves (32% versus 4%, P < 0.001) or cardiac rhythm management (CRM) devices (16% versus 3%, P < 0.004). On excluding patients with prosthetic valves or CRM devices from the analysis, no patient with a line-related bacteraemia and only one patient (an intravenous drug user) with no/mild regurgitation on transthoracic echocardiography had echo evidence of IE. CONCLUSIONS We propose that the use of scarce echocardiography resources could be prioritized. Patients with prosthetic heart valves or a CRM device should receive early cardiological input and transoesophageal echocardiography. In patients with a clearly defined line-related bacteraemia who do not have a prosthetic valve or CRM device or clinical features of IE, response to treatment could be closely monitored and imaging deferred. Patients without a line-related infection or prosthetic valve/device could receive a transthoracic echocardiogram as a screening tool.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial

BackgroundStaphylococcus aureus bacteraemia is a common and serious infection, with an associated mortality of ~25%. Once in the blood, S. aureus can disseminate to infect almost any organ, but bones, joints and heart valves are most frequently affected. Despite the infection’s severity, the evidence guiding optimal antibiotic therapy is weak: fewer than 1,500 patients have been included in 16 randomised controlled trials investigating S. aureus bacteraemia treatment. It is uncertain which antibiotics are most effective, their route of administration and duration, and whether antibiotic combinations are better than single agents. We hypothesise that adjunctive rifampicin, given in combination with a standard first-line antibiotic, will enhance killing of S. aureus early in the treatment course, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Our aim is to determine whether adjunctive rifampicin reduces all-cause mortality within 14 days and bacteriological failure or death within 12 weeks from randomisation.MethodsWe will perform a parallel group, randomised (1:1), blinded, placebo-controlled trial in NHS hospitals across the UK. Adults (≥18 years) with S. aureus (meticillin-susceptible or resistant) grown from at least one blood culture who have received ≤96 h of active antibiotic therapy for the current infection and do not have contraindications to the use of rifampicin will be eligible for inclusion. Participants will be randomised to adjunctive rifampicin (600-900mg/day; orally or intravenously) or placebo for the first 14 days of therapy in combination with standard single-agent antibiotic therapy. The co-primary outcome measures will be all-cause mortality up to 14 days from randomisation and bacteriological failure/death (all-cause) up to 12 weeks from randomisation. 940 patients will be recruited, providing >80% power to detect 45% and 30% reductions in the two co-primary endpoints of death by 14 days and bacteriological failure/death by 12 weeks respectively.DiscussionThis pragmatic trial addresses the long-standing hypothesis that adjunctive rifampicin improves outcome from S. aureus bacteraemia through enhanced early bacterial killing. If proven correct, it will provide a paradigm through which further improvements in outcome from S. aureus bacteraemia can be explored.Trial registrationCurrent Controlled Trial ISRCTN 37666216

High mortality amongst adolescents and adults with bacterial meningitis in sub-Saharan Africa: an analysis of 715 cases from Malawi.

Mortality from bacterial meningitis in African adults is significantly higher than those in better resourced settings and adjunctive therapeutic interventions such as dexamethasone and glycerol have been shown to be ineffective. We conducted a study analysing data from clinical trials of bacterial meningitis in Blantyre, Malawi to investigate the clinical parameters associated with this high mortality. Methods We searched for all clinical trials undertaken in Blantyre investigating bacterial meningitis from 1990 to the current time and combined the data from all included trial datasets into one database. We used logistic regression to relate individual clinical parameters to mortality. Adults with community acquired bacterial meningitis were included if the CSF culture isolate was consistent with meningitis or if the CSF white cell count was >100 cells/mm3 (>50% neutrophils) in HIV negative participants and >5 cells/mm3 in HIV positive participants. Outcome was measured by mortality at discharge from hospital (after 10 days of antibiotic therapy) and community follow up (day 40). Results Seven hundred and fifteen episodes of bacterial meningitis were evaluated. The mortality rate was 45% at day 10 and 54% at day 40. The most common pathogens were S.pneumoniae (84% of positive CSF isolates) and N.meningitidis (4%). 607/694 (87%) participants tested were HIV antibody positive. Treatment delays within the hospital system were marked. The median presenting GCS was 12/15, 17% had GCS<8 and 44.9% had a seizure during the illness. Coma, seizures, tachycardia and anaemia were all significantly associated with mortality on multivariate analysis. HIV status and pneumococcal culture positivity in the CSF were not associated with mortality. Adults with community acquired bacterial meningitis in Malawi present with a severe clinical phenotype. Predictors of high mortality are different to those seen in Western settings. Optimising in-hospital care and minimising treatment delays presents an opportunity to improve outcomes considerably.

Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of 100 cases.

AIMS Chronic osteomyelitis may recur if dead space management, after excision of infected bone, is inadequate. This study describes the results of a strategy for the management of deep bone infection and evaluates a new antibiotic-loaded biocomposite in the eradication of infection from bone defects. PATIENTS AND METHODS We report a prospective study of 100 patients with chronic osteomyelitis, in 105 bones. Osteomyelitis followed injury or surgery in 81 patients. Nine had concomitant septic arthritis. 80 patients had comorbidities (Cierny-Mader (C-M) Class B hosts). Ten had infected nonunions. All patients were treated by a multidisciplinary team with a single-stage protocol including debridement, multiple sampling, culture-specific systemic antibiotics, stabilisation, dead space filling with the biocomposite and primary skin closure. RESULTS Patients were followed up for a mean of 19.5 months (12 to 34). Infection was eradicated in 96 patients with a single procedure and all four recurrences were successfully managed with repeat surgery. Adverse events were uncommon, with three fractures, six wound leaks and three unrelated deaths. Outcome was not dependant on C-M host class, microbial culture, wound leakage or presence of nonunion. CONCLUSION This single-stage protocol, facilitated by the absorbable local antibiotic, is effective in the treatment of chronic osteomyelitis. It offers a more patient-friendly treatment compared with other published treatment options. Cite this article: Bone Joint J 2016;98-B:1289-96.

Gram-negative bacteraemia; a multi-centre prospective evaluation of empiric antibiotic therapy and outcome in English acute hospitals

Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin-tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35-1.94 and adjusted OR 0.92; 95% CI 0.50-1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors.

Serial measurement of the C-reactive protein is a poor predictor of treatment outcome in prosthetic joint infection

OBJECTIVES Prosthetic joint infection is usually treated using surgery and antibiotics. The response to the treatment regimen is often evaluated using serial monitoring of plasma C-reactive protein (CRP) concentrations. In order to examine how useful this monitoring is, we calculated the sensitivity and specificity of CRP concentrations for predicting treatment failure. PATIENTS AND METHODS We examined 3732 CRP measurements from 260 patients who were treated by either two-stage revision or debridement and retention. We tested the association between CRP concentration and outcome using logistic regression models, and assessed sensitivity and specificity by using receiver operator curves. RESULTS The areas under receiver operator curves for CRP concentrations predicting outcome ranged from 0.55 to 0.65. CONCLUSIONS CRP concentrations did not accurately predict treatment failure. Serial monitoring may not be of benefit.

Sensitivity and specificity of an index for the diagnosis of TB meningitis in patients in an urban teaching hospital in Malawi

Tuberculous (TB) meningitis is difficult to diagnose and has a high mortality rate, particularly when presentation is delayed. A diagnostic index developed in Vietnam, an area of low‐HIV seroprevalence, has been proposed as a means to differentiate TB meningitis from acute bacterial meningitis using clinical and laboratory features. We applied this index over a 4‐month period to adults presenting with meningitis to an urban teaching hospital in Malawi, where HIV seroprevalence is 70% among medical inpatients. Eighty‐five consecutive eligible patients were studied. Nine had TB meningitis, 64 bacterial meningitis and 12 cryptococcal meningitis. The sensitivity of the diagnostic index for predicting TB meningitis was 78%, with a specificity of 43%, too low to be used in the diagnosis of TB meningitis in this setting. This finding is likely to be generalizable to other southern African countries with similarly high‐HIV seroprevalences.

Persistence of Pneumolysin in the Cerebrospinal Fluid of Patients With Pneumococcal Meningitis Is Associated With Mortality

Poor prognosis in Pneumococcal meningitis may be associated with high pneumolysin levels in cerebrospinal fluid (CSF). In patient samples we showed that pneumolysin levels in CSF remained high after 48 hours in nonsurvivors of meningitis compared with survivors. Selective antipneumolysin treatment may present a novel therapeutic option.