Outpatient management of uncomplicated enteric fever: A case series of 93 patients from the Hospital of Tropical Diseases, London.

OBJECTIVES: Enteric fever is predominantly managed as an outpatient condition in endemic settings but there is little evidence to support this approach in non-endemic settings. This study aims to review the outcomes of outpatients treated for enteric fever at the Hospital of Tropical Diseases in London, UK. METHODS: We conducted a retrospective analysis of all patients with confirmed enteric fever between August 2009 and September 2020. Demographic, clinical, laboratory and microbiological data were collected and compared between the inpatient and outpatient populations. Outcomes investigated were complicated enteric fever, treatment failure and relapse. RESULTS: Overall, 93 patients (59% male, median age 31) were identified with blood and/or stool culture confirmed enteric fever and 49 (53%) of these were managed as outpatients. The commonest empirical treatment for outpatients was azithromycin (70%) and for inpatients was ceftriaxone (84%). Outpatients were more likely than inpatients to receive only one antibiotic (57% vs 19%, p < 0.01) and receive a shorter duration of antibiotics (median 7 vs 11 days, p <0.01). There were no cases of complicated disease or relapse in either the inpatient or outpatient groups. There was one treatment failure in the outpatient group. Azithromycin was well-tolerated with no reported side effects. CONCLUSIONS: Our findings suggest that outpatient management of uncomplicated imported enteric fever is safe and effective with the use of oral azithromycin. Careful monitoring of patients is recommended as treatment failure can occur.

British infection association guidelines for the diagnosis and management of enteric fever in England.

Enteric fever (EF) is an infection caused by the bacteria called Salmonella Typhi or Paratyphi. Infection is acquired through swallowing contaminated food or water. Most EF in England occurs in people returning from South Asia and other places where EF is common; catching EF in England is rare. The main symptom is fever, but stomach pain, diarrhoea, muscle aches, rash and other symptoms may occur. EF is diagnosed by culturing the bacteria from blood and/or stool in a microbiology laboratory. EF usually responds well to antibiotic treatment. Depending on how unwell the individual is, antibiotics may be administered by mouth or by injection. Over the past several years, there has been an overall increase in resistance to antibiotics used to treat enteric fever, in all endemic areas. Additionally, since 2016, there has been an ongoing outbreak of drug-resistant EF in Pakistan. This infection is called extensively drug-resistant, or XDR, EF and only responds to a limited number of antibiotics. Occasionally individuals develop complications of EF including confusion, bleeding, a hole in the gut or an infection of the bones or elsewhere. Some people may continue to carry the bacteria in their stool for a longtime following treatment for the initial illness. These people may need treatment with a longer course of antibiotics to eradicate infection. Travellers can reduce their risk of acquiring EF by following safe food and water practices and by receiving the vaccine at least a few weeks before travel. These guidelines aim to help doctors do the correct tests and treat patients for enteric fever in England but may also be useful to doctors and public health professionals in other similar countries.

Proteus mirabilis - a rare cause of non-HACEK Gram-negative infective endocarditis.

Infective endocarditis caused by Proteus mirabilis is strikingly rare. Here, we describe the case of an 86-year old man with five recurrent septic episodes over a period of three months associated with Proteus mirabilis bacteraemia secondary to underlying Proteus endocarditis. The final diagnosis was made based on clinical findings, blood culture results and transoesophageal echocardiogram. The patient was treated medically with 6 weeks of ceftriaxone and long-term oral ciprofloxacin. On completion of intravenous therapy the patient remained well. We performed a literature review and found this to be only the fourth confirmed case of Proteus mirabilis endocarditis successfully treated with antibiotic therapy alone. This case highlights an important but rare cause of endocarditis, reinforcing the need to consider this diagnosis in recurrent Gram-negative bacteraemia even if by an atypical organism.

Neisseria meningitidis serogroup C sepsis and septic arthritis in an HIV-positive man.

A patient with well-controlled HIV-1 infection presented with fever and rigors, a widespread maculopapular rash, and severe generalised arthralgia. Sepsis of unknown aetiology was diagnosed, and treatment with broad-spectrum antimicrobials commenced. Following initial clinical improvement, a right knee septic arthritis developed. Microscopy and culture of the joint aspirate were negative for organisms but 16S rDNA PCR identified Neisseria meningitidis DNA, subsequently verified as capsular genogroup C, thus confirming a diagnosis of disseminated meningococcal sepsis with secondary septic arthritis.

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.

What is the role for Xpert® MTB/RIF in high-resource settings? Experience from a central London hospital.

The role of Xpert(®) MTB/RIF for tuberculosis (TB) diagnosis remains to be clearly delineated in high-resource settings. At a London hospital, we evaluated a policy of selective assay use, with testing restricted to defined sub-groups of patients. Management was directly influenced in 30% of patients studied, including 'ruling-in' a TB diagnosis (leading to initiation of treatment for TB or for potential multidrug-resistant TB); negative assay results also helped support decisions for cessation of empirical anti-tuberculosis treatment or the safe initiation of other treatments such as immunosuppressant drugs. The benefits and pitfalls of this assay's use within high-resource settings are discussed.

A cross-sectional study of Mycoplasma genitalium infection and correlates in women undergoing population-based screening or clinic-based testing for Chlamydia infection in London.

OBJECTIVE: To determine Mycoplasma genitalium infection and correlates among young women undergoing population-based screening or clinic-based testing for Chlamydia infection. DESIGN: Cross-sectional study. SETTING: National Chlamydia Screening Programme (NCSP) and two London sexually transmitted infection (STI) clinics. PARTICIPANTS: 2441 women aged 15-64 years who participated in the NCSP and 2172 women who attended two London STI clinics over a 4-month period in 2009. OUTCOME MEASURES: (1) M genitalium prevalence in defined populations (%). (2) Age-adjusted ORs (aORs) for correlates of M genitalium infection. RESULTS: The overall frequency of M genitalium and Chlamydia trachomatis was 3% and 5.4%, respectively. Co-infection was relatively uncommon (0.5% of all women); however 9% of women with C trachomatis also had M genitalium infection. M genitalium was more frequently detected in swab than urine samples (3.9 vs 1.3%, p<0.001) with a significantly higher mean bacterial load (p ≤ 0.001). Among NCSP participants, M genitalium was significantly more likely to be diagnosed in women of black/black British ethnicity (aOR 2.3, 95% CI 1.2 to 4.5, p=0.01). M genitalium and C trachomatis and were both significantly associated with multiple sexual partners in the past year (aOR 2.4, 95% CI 1.3 to 4.4, p=0.01 and aOR 2.0, 95% CI 1.4 to 2.8, p<0.01). Among STI clinic attendees, M genitalium was more common in women who were less than 25 years in age. CONCLUSIONS: M genitalium is a relatively common infection among young women in London. It is significantly more likely to be detected in vulvovaginal swabs than in urine samples. Co-infection with Chlamydia is uncommon. The clinical effectiveness of testing and treatment strategies for M genitalium needs further investigation.

Comparison of two interferon-gamma release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB) in testing for latent tuberculosis infection among HIV-infected adults.

There is currently no 'gold standard' for diagnosis of latent tuberculosis infection (LTBI), and both the tuberculin skin test and interferon-gamma release assays (IGRAs) are used for diagnosis; the latter have a higher sensitivity than tuberculin skin tests for diagnosis of LTBI in HIV-infected individuals with lower CD4 counts. No evidence base exists for selection of IGRA methodology to identify LTBI among human immunodeficiency virus-infected patients in the UK. We prospectively evaluated two commercially available IGRA methods (QuantiFERON-TB Gold In Tube [QFG] and T-SPOT.TB) for testing LTBI among HIV-infected patients potentially nosocomially exposed to an HIV-infected patient with 'smear-positive' pulmonary tuberculosis. Among the exposed patients median CD4 count was 550 cells/µL; 105 (90%) of 117 were receiving antiretroviral therapy, of who 104 (99%) had an undetectable plasma HIV load. IGRAs were positive in 12 patients (10.3%); QFG positive in 11 (9.4%) and T-SPOT.TB positive in six (5.1%); both IGRAs were positive in five patients (4.3%). There was one indeterminate QFG and one borderline T-SPOT.TB result. Concordance between the two IGRAs was moderate (κ = 0.56, 95% confidence interval = 0.27-0.85). IGRAs were positive in only 4 (29%) of 14 patients with previous culture-proven tuberculosis. No patient developed tuberculosis during 20 months of follow-up.

Development and evaluation of a real-time PCR assay for detection of Pneumocystis jirovecii DNA in bronchoalveolar lavage fluid of HIV-infected patients.

BACKGROUND: Pneumocystis pneumonia (PCP) is conventionally diagnosed by identifying Pneumocystis jirovecii in lower respiratory tract samples using cytochemical stains. Molecular diagnosis of PCP is potentially more sensitive. METHODS: A study was undertaken to use an extensively optimised real-time polymerase chain reaction (PCR) using primers designed to hybridise with the P. jirovecii heat shock protein 70 (HSP70) gene to quantify P. jirovecii DNA in bronchoalveolar lavage (BAL) fluid from HIV-infected patients with and without PCP, and to compare this assay with conventional PCR targeting the P. jirovecii mitochondrial large subunit rRNA gene sequence (mt LSU rRNA). RESULTS: Sixty-one patients had 62 episodes of PCP (defined by detection of P. jirovecii in BAL fluid by cytochemical stains and typical clinical presentation). Quantifiable HSP70 DNA was detected in 61/62 (range approximately 13-18,608 copies/reaction; median approximately 332) and was detectable but below the limit of quantification (approximately 5 copies/reaction) in 1/62. Seventy-one other patients had 74 episodes with alternative diagnoses. Quantifiable HSP70 DNA was detectable in 6/74 (8%) episodes (range approximately 6-590 copies/reaction; median approximately 14) and detectable but below the limit of quantification in 34/74 (46%). Receiver-operator curve analysis (cut-off >10 copies/reaction) showed a clinical sensitivity of 98% (95% 91% to 100%) and specificity of 96% (95% CI 87% to 99%) for diagnosis of PCP. By contrast, clinical sensitivity of mt LSU rRNA PCR was 97% (95% CI 89% to 99%) and specificity was 68% (95% CI 56% to 78%). CONCLUSION: The HSP70 real-time PCR assay detects P. jirovecii DNA in BAL fluid and may have a diagnostic application. Quantification of P. jirovecii DNA by real-time PCR may also discriminate between colonisation with P. jirovecii and infection.

Scytalidium dimidiatum causing recalcitrant subcutaneous lesions produces melanin.

Scytalidium dimidiatum is a pigmented dematiaceous coelomycete that typically causes chronic superficial skin diseases and onychomycosis, as well as deeper infections, such as subcutaneous abscesses, mycetoma, and even fungemia in immunocompromised patients. A second species, Scytalidium hyalinum, has hyaline hyphae and arthroconidia and is considered by some authors to be an albino mutant of S. dimidiatum. This study aimed to confirm the presence of melanin or melanin-like compounds (which have been previously implicated in the virulence of other fungal pathogens) in S. dimidiatum from a patient with multiple subcutaneous nodules. Treatment of the hyphae and arthroconidia with proteolytic enzymes, denaturant, and concentrated hot acid yielded dark particles, which were stable free radicals, consistent with their identification as melanins. Extracted melanin particles from S. dimidiatum cultures were labeled by melanin-binding monoclonal antibodies (MAbs) from Sporothrix schenckii, Aspergillus fumigatus, and Cryptococcus neoformans. Lesional skin from the patient infected with S. dimidiatum contained fungal cells that were labeled by melanin-binding MAbs, and digestion of the tissue yielded dark particles that were also reactive. S. hyalinum was also subjected to the melanin extraction protocol, but no dark particles were yielded.

Mycobacterium abscessus: a cutaneous infection in a patient on renal replacement therapy.

We report a 72-year-old man on haemodialysis who presented with multiple abscesses on his lower legs. Routine bacterial culture of abscess pus was reported as 'sterile' after 48 h, leading to the suspicion of a mycobacterial infection. Skin biopsy taken for mycobacterial microscopy and culture isolated a heavy growth of Mycobacterium abscessus.

What's new in HIV

This issue goes to press as the world media turns its eyes on the World Aids Conference being held in Durban, South Africa. No doubt "the gap" in HIV care provision between developed and developing nations which the last congress in Geneva sought to bridge will seem wider than ever. Reports from the conference will follow in future issues, but in this one we focus on problems commonly faced by clinicians primarily caring for intravenous drug users. Mark Wright and Janice Main give an overview of the management of co-infection with HIV and Hepatitis C viruses, and Ray Brettle discusses the difficulties of antiretroviral selection in the context of methadone and other recreational drug use. Copyright 2000 The British Infection Society.

Induction of HIV-1-specific T cell responses by administration of cytokines in late-stage patients receiving highly active anti-retroviral therapy.

Highly active anti-retroviral therapy (HAART) is associated with reduction in the morbidity and mortality of patients with advanced HIV-1 disease. The ability of such treatment to improve immune responses against HIV-1 and opportunistic pathogens is variable and limited. Addition of cytokine immunotherapy to this treatment may improve immune responses. IL-2 with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to HIV-1+ individuals receiving HAART with undetectable viral loads, and CD4 counts < 100 cells/microl. In one patient presenting with Mycobacterium avium complex (MAC) infection, we evaluated the effect of cytokine immunotherapy on lymphocyte phenotype; plasma viral load; proliferative responses to mitogens, recall and HIV-1 antigens; cytokine production and message in response to non-specific and specific stimuli; and natural killer (NK) cell activity. Proliferation assays were performed in two similar patients. Before cytokine immunotherapy the predominant CD8+ population was mainly CD28-. No proliferation or IL-2 production was seen in response to mitogens, recall or HIV-1 antigens; and no HIV-1 peptide-specific interferon-gamma (IFN-gamma)-secreting cells were present. Low levels of IL-4 were detected in response to antigens to which patients had been exposed, associated with up-regulated expression of costimulatory molecules influenced by IL-4. Following IL-2 administration, loss of IL-4 was associated with increased NK cell activity and HIV-1 peptide-specific and non-specific IFN-gamma-producing cells. Proliferative responses associated with IL-2 production and responsiveness were only seen after subsequent concomitant administration of GM-CSF with IL-2. These changes mirrored clinical improvement. An imbalance of lymphocyte subsets may account for immune unresponsiveness when receiving HAART. Restoration of responses following immunotherapy suggests a shift towards a lymphocyte profile with anti-pathogen activity.

The role of complement, antibody, and tumor necrosis factor alpha in the killing of Plasmodium falciparum by the monocytic cell line THP-1.

Killing of Plasmodium falciparum blood forms by the differentiated human myelomonocytic THP-1Mo cell line was studied by a radiometric assay. Results showed that parasite killing was promoted by complement, antimalarial antibody, and the cytokines tumor necrosis factor alpha and gamma interferon. Differentiated THP-1Mo appears to be a useful monocytic cell line for the study of mechanisms of immunity to Plasmodium.

Antibody responses to Rhoptry-Associated Protein-1 (RAP-1) of Plasmodium falciparum parasites in humans from areas of different malaria endemicity.

Plasma IgM and IgG antibody reactivities against the recombinant Plasmodium falciparum protein, Rhoptry Associated Protein-1 (rRAP-1) were measured by ELISA in individuals from Sudan, Indonesia, Kenya and The Gambia living in areas of different malaria endemicity. IgG and IgM reactivities to rRAP-1 increased with malaria endemicity. IgG reactivities were associated with spleen rates in Indonesia with high malaria endemicity while IgM reactivities were associated with spleen rates in Kenya with low malaria endemicity. IgG and IgM reactivities to rRAP-1 increased during acute episodes of P. falciparum malaria in Sudanese adults and IgG reactivities remained high one month after treatment in all adults tested. Antibody reactivities to rRAP-1 in Gambian children in the dry season were higher in children with parasitaemia than in children without detectable parasitaemia. Antibody reactivities were not associated with protection against clinical episodes in the following rainy season but higher antibody reactivities were detectable at the end of the rainy season. There was no difference in antibody reactivity to rRAP-1 between Gambian children with mild or severe malaria.

Antiretroviral therapies in HIV-1 infection.

Recent progress in our understanding of the viral dynamics and immunobiology of HIV infection, coupled with the introduction of a new generation of antiretroviral agents, has led to significant advances in the medical management of HIV infection. Eleven antiretroviral drugs are currently licensed in the United States, and eight are licensed in Europe. These include the nucleoside reverse transcriptase inhibitors (AZT, ddI, ddC, 3TC and d4T); the non-nucleoside reverse transcriptase inhibitors (nevirapine and delavirdine) and the protease inhibitors (saquinavir, indinavir and ritonavir). This report summarises recent developments in the use of antiretroviral therapies and the main treatment strategies under evaluation in current trials. These strategies include the evaluation of novel antiretroviral agents; combinations to achieve maximal viral suppression; optimal sequencing of antiretroviral agents; and subtraction therapy. However, many important issues in the use of antiretroviral therapies remain unresolved, including the optimal role of new agents, such as protease inhibitors (PIs), and the use of triple combination therapy in initial and subsequent treatment regimens; when therapy should be changed; which alternative agents should then be used; and the most appropriate methods for monitoring the efficacy of therapy.