Laurence John

Multidrug-resistant tuberculosis (MDR-TB) treatment in the UK: a study of injectable use and toxicity in practice

BACKGROUND Multidrug-resistant tuberculosis (MDR-TB) is an increasing challenge to health services globally. Although new drugs are in development, current guidelines still recommend prolonged use of injectable antimicrobials (usually amikacin, kanamycin or capreomycin). The evidence base to inform treatment and monitoring strategies is very limited. METHODS We conducted a retrospective study of patients initiating injectable antimicrobials for MDR-TB treatment in five UK centres between January 2004 and December 2009. (i) Current treatment and monitoring strategies were reviewed. (ii) The incidence of ototoxicity (defined both clinically and on audiological testing) and factors associated with ototoxicity were investigated using logistic regression. RESULTS (i) The choice of injectable antimicrobial varied. Of 50 MDR-TB patients, 29/50 (58%) received amikacin, 11/50 (22%) received capreomycin and 10/50 (20%) received streptomycin or a combination; reflecting a difference in policy between centres. Only 21/50 (42%) patients received baseline screening by audiogram within 2 weeks of starting treatment and 16/50 (32%) then had monthly audiograms, with the majority screened more infrequently and 12/50 (24%) receiving no screening. (ii) Of the 50 patients, 14 (28%) experienced ototoxicity, with 9/50 (18%) left with long-term hearing loss. Increased age (P = 0.02), use of amikacin (P = 0.02) and decreased renal function (P = 0.01) were significantly associated with ototoxicity. CONCLUSIONS There is local variation in both the choice of injectable agent and in ototoxicity screening practices. Long-term morbidity from injectable treatment is significant even in this well-resourced setting, and the data suggest capreomycin might be associated with less ototoxicity when compared with amikacin. There is a need for more high-quality clinical data to inform future guidelines for treatment and monitoring.

A trial of caspofungin salvage treatment in PCP pneumonia

Pneumocystis jirovecii pneumonia (PCP) remains a major cause of mortality in patients with HIV; we read with enormous interest the recent PCP mortality prediction rule stratifying 451 patients by mortality at the time of illness presentation.1 The first-line treatment for this infection, cotrimoxazole, is associated with a number of adverse effects, including rash, leucopenia, thrombocytopenia and interstitial nephritis.2 Therefore, treatment with cotrimoxazole significantly adds to the morbidity associated with this condition and we note in this study that this was the main treatment used. One of the identifying characteristics of P jirovecii is the presence of (1,3)-β-d-glucan in its cell wall.3 As the cell wall of this organism does not contain ergosterol (the target of azoles and polyenes), echinocandins, which target the synthesis of (1,3)-β-d-glucan, are likely to be the only effective antifungals for PCP.4 Caspofungin was the first echinocandin licensed for empiric antifungal treatment in candidiasis and aspergillosis. In animal …

Reversing the tide of the UK tuberculosis epidemic

1suggest that a quality-assured, primary care based screening programme for latent tuberculosis infection for individuals aged 16–35 years, who entered the UK in the past 5 years from a country with a tuberculosis incidence of 150 cases per 100 000 population or higher, could provide a solution to the UK tuberculosis epidemic. We are strongly supportive of such a primary care led initiative.

International spread of MDR TB from Tugela Ferry, South Africa.

We describe a death associated with multidrug-resistant tuberculosis and HIV infection outside Africa that can be linked to Tugela Ferry (KwaZulu-Natal, South Africa), the town most closely associated with the regional epidemic of drug-resistant tuberculosis. This case underscores the international relevance of this regional epidemic, particularly among health care workers.

Diagnosis and treatment strategies of tuberculous intestinal perforations: a case series.

Gastrointestinal tuberculosis (TB) may result in intestinal obstruction and perforation, even after antituberculous therapy has been initiated. Despite surgical intervention tuberculous perforation has a high complication and mortality rate, and it is difficult to predict the subgroup of patients with abdominal TB who progress to perforation. In this study, we retrospectively investigated the clinical features that may predict disease progression in patients in our institution who presented abdominal TB over a 5-year period between January 2006 and August 2011, as well as describe an unreported method of managing tuberculous intestinal perforations when resection with end-to-end anastomosis is unfeasible. Six out of 91 patients (6.6%) with abdominal TB developed perforations. Factors linked with increased complications and mortality were age, comorbidities, multiple perforations and length of time between onset of abdominal symptoms and perforation. Four patients (66.7%) had long histories of abdominal symptoms before perforation. Three patients were receiving or had completed antituberculous therapy before developing perforation. Five patients were managed surgically, two underwent laparostomy as both primary closure and end-to-end anastomosis were deemed too risky. Mortality following perforation was 17%. Patients with prolonged abdominal symptoms, even after antituberculous therapy, should raise suspicion for subacute intestinal obstruction. This should be recognized early and surgical intervention considered in order to prevent mortality secondary to perforation. Laparostomy may be an alternative when resection and end-to-end anastomosis is not possible.

Open splenectomy for Varicella zoster induced spontaneous splenic rupture

Highlights • Spontaneous splenic rupture should be considered in patients presenting with peritonism without preceding trauma.• Haematological and infectious causes, including Varicella Zoster, should be sought when investigating spontaneous splenic rupture.• There is limited published guidance regarding the surgical options when faced with spontaneous splenic rupture.

Challenges in screening for latent tuberculosis in inflammatory bowel disease prior to biologic treatment: a UK cohort study

Objective The aim of this study was to determine the occurrence of latent tuberculosis infections (LTBI) and active TB in a cohort of patients with inflammatory bowel disease (IBD) treated with biologics. We also examined the effects of immunosuppressive drugs on indeterminate interferon-gamma release assays (IGRA) in LTBI screening. Design Retrospective study of patients treated with biologics between March 2007 and November 2015. Setting St Mark’s Hospital, North West London, UK. Patients 732 patients with IBD who were screened for LTBI using either tuberculin skin test or IGRA before starting a biologic treatment. Methods Retrospective case note review of all patients with IBD who were screened for LTBI prior to initiating biologics. Patients who developed active TB were identified from the London TB register. Results Of 732 patients with IBD, 31 (4.2%) were diagnosed with and treated for LTBI with no significant side effects. Six of 596 patients (1.0%) who received biologic treatment developed active TB. There was a higher proportion of indeterminate IGRA in the immunosuppressive medication group compared with the non-immunosuppressive group (33% (59/181) compared with 9% (6/66), p<0.001). The combination of steroids and thiopurines had the highest proportion of indeterminate IGRA (64%, 16/25). High and low doses of steroids were equally likely to result in an indeterminate IGRA result (67% (8/12) and 57% (4/7), respectively). Conclusions This study highlights the challenges of LTBI screening prior to commencing biologic therapy and demonstrates the risk of TB in patients who have been screened and who are receiving prolonged and continuing doses of antitumour necrosis factor.

Screening contacts of patients with extrapulmonary TB for latent TB infection

2016 TB National Institute for Health and Care Excellence (NICE) guidelines imply that contacts of extrapulmonary TB do not require screening for latent TB infection. At our high TB prevalence site, we identified 189 active cases of TB for whom there were 698 close contacts. 29.1% of the contacts of pulmonary TB and 10.7% of the contacts of extrapulmonary TB had active or latent TB infection. This supports screening contacts of extrapulmonary TB at our site and presents a way to access high-risk individuals. We propose to continue to screen the contacts of our patients with extrapulmonary TB and recommend other TB units audit their local results.

P98 Cervical TB lymphadenitis: A predominantly right-sided phenomenon due to ascending infection from the thorax

Introduction Cervical Tuberculous (TB) Lymphadenitis is the commonest presentation of extrapulmonary TB. There is however little evidence about its aetiology; consensus is divided as to whether it arises from infection via the pharyngeal lymphoid ring or from thoracic infection. Our clinical suspicions were that it is most frequently a right-sided phenomenon as a result of Mycobacterium Tuberculosis ascending the right paratracheal chain following pulmonary inoculation. Methods We explored this hypothesis by retrospectively reviewing 211 cases of cervical TB lymphadenitis diagnosed at Northwick Park Hospital in London. We assessed clinical findings, neck ultrasound findings, chest radiograph findings and explored the literature to see what other evidence exists to support or refute this hypothesis. Results Clinical assessment found that 62.1% (P < 0.0001) cases had right-sided disease, 28.9% left-sided and 9.0% bilateral. Of the 153 ultrasound scans available, 62% showed supraclavicular lymphadenitis (levels IV&V nodes) and only 9.5% submental/submandibular lymphadenitis (level I nodes). 205 chest x-rays were studied, the most frequent abnormality was lymphadenopathy (40/205), including 25 paratracheal lymphadenopathy (23/25 right-sided). Notably, 22/23 patients with right paratracheal lymphadenopathy had right-sided cervical lymphadenitis. Discussions Our findings suggest that ascending infection from the thorax via the paratracheal chain following pulmonary inoculation plays the greatest role in the aetiology of cervical lymphadenitis. We explain this using anatomical studies. Infection via the pharynx may be implicated in those exhibiting upper cervical lymphadenitis. In some low-resource setting where TB may be diagnosed on clinical grounds alone, knowledge that right-sided supraclavicular nodes are the most frequently affected may add confidence to clinical decision-making.

S2 Multi-drug Resistant Tuberculosis (MDR-TB) treatment in the UK: a survey of injectable use and toxicity in practice

Rationale Recent discoveries in human genetics have identified mitochondrial mutations which confer a high risk of sensorineural deafness in individuals exposed to aminoglycosides. Successful MDR-TB treatment often requires prolonged use of these agents. There are little data from the UK to inform the use of genetic tests within MDR-TB patients. We set out to survey MDR-TB practice in the UK with an emphasis on injectable drug use, ototoxicity and audiological monitoring practice. Methods Five centres took part in a retrospective study of patients initiating injectable treatment for MDR-TB between 1 January 2004 and 31 December 2009. Data were collected regarding patient characteristics, choice of injectable, methods and frequency of ototoxicity screening and incidence of drug-related complications. Results Treatment for 50 MDR-TB patients was reviewed. 29/50 (58%) patients received amikacin, 11/50 (22%) capreomycin, 4/50 (8%) streptomycin and 6/50 (12%) more than one injectable. Three centres used amikacin as their preferred injectable, two used capreomycin. Audiological screening for ototoxicity was variable. 21/50 (42%) patients received baseline screening within 2 weeks of starting an injectable. 16/50 (32%) patients went on to have monthly audiograms, with the majority screened more infrequently or if symptoms were reported. 12/50 (24%) patients received no screening at any point. Ototoxicity was defined as a 20 dB loss from baseline on audiogram at one test frequency, or a 10 dB loss at two adjacent frequencies, or in the absence of a baseline result, as two or more frequencies below 20 dB. If no audiograms were available, the definition was symptomatic. 14/50 (28%) of patients experienced ototoxicity, with 9/50 (18%) left with persistent hearing loss. Increased age (p=0.02), use of amikacin (p=0.02) and decreased renal function on therapy (p=0.01) were significantly associated with ototoxicity (see Abstract S2 Table 1). No centre routinely tests for mitochondrial DNA mutations.Abstract S2 Table 1 Ototoxicity (%) n=14 No Ototoxicity (%) n=36 p-Value univariate Age (years) 41.3 (SD 14.5) 31.9 (SD 11.2) 0.02 Gender  Female 4 (28.6) 16 (44.6)  Male 10 (71.4) 20 (55.6) 0.3 Ethnicity  Caucasian 4 (28.6) 6 (16.7)  Asian Indian/Pakistani 2 (14.3) 11 (30.6)  Asian Chinese 0 (0) 2 (5.6)  Asian Other 1 (7.1) 5 (13.9)  Asian African 6 (42.9) 11 (30.6)  All Other 1 (7.1) 1 (2.8) 0.57 HIV status  Positive 1 (7.1) 4 (11.1)  Negative 3 (92.9) 32 (88.9) 0.68 Amikacin at any point  Yes 13 (92.9) 21 (58.3)  No 1 (7.1) 15 (41.7) 0.02 Capreomycin at any point  Yes 2 (14.3) 15 (41.7)  No 12 (85.7) 21 (58.3) 0.07 Duration of injectable treatment (days) 123.4 (SD 62.1) 115.9 (SD 90.2) 0.77 Total dose of injectable agent (g) 96.3 (SD 54.7) 90.7 (SD 63.1) 0.78 Baseline creatinine (μmol/l) 85.9 (SD 52.8) 67.7 (SD 12.9) 0.07 Creatinine increase >44 from baseline at any point  Yes 5 (35.7) 2 (6.5)  No 9 (64.3) 29 (93.5)  Not known 0 5 0.01 Conclusions There is local variation in both choice of injectable agent and in ototoxicity screening practices between the MDR treatment centres studied. The data suggest capreomycin might be associated with less ototoxicity when compared to amikacin. There are no UK guidelines to inform best practice and better evidence, including clinical and cost-effectiveness studies, is needed to inform the implementation of current technology including genetic testing.