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0training in women with prolapse. In addition to the effectiveness of muscle training, the trial also shows the potential for prevention of prolapse symptoms through lifelong attention to pelvic floor muscle exercise, and possibly intentional use of muscles to protect the pelvic floor during physical strain, such as that inflicted by heavy lifting. The results of this trial should encourage clinicians to refer women to physiotherapists, and to other health-care professionals who can implement behavioural and physical therapies for prolapse in a range of health-care settings.
Kathryn L Burgio
University of Alabama at Birmingham and the Birmingham/ Atlanta Geriatric Research, Education, and Clinical Center, Birmingham, AL 35244, USA kburgio@uabmc.edu
I declare that I have no conflicts of interest.
1 Hendrix SL, Clark A, Nygaard I, Aragaki A, Barnabei V, McTiernan A. Pelvic organ prolapse in the Women's Health Initiative: gravity and gravidity. Am J Obstet Gynecol 2002; 186: 1160-66.
2 Bergstrom JO, Colling JC, Clark AL. Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol 1997; 89: 501-06.
3 Burgio KL, Goode PS, Johnson TM, et al. Behavioral versus drug treatment for overactive bladder in men: the male overactive bladder treatment in veterans (MOTIVE) trial. J Am Geriatr Soc 2011; 59: 2209-16.
4 Johnson TM, Markland AD, Goode PS, et al. Efficacy of adding behavioral treatment or antimuscarinic drug therapy to alpha-blocker therapy in men with nocturia. Br J Urol Int 2013; 110: 100-08.
5 Moore K, Dumoulin C, Bradley C, et al. Adult conservative management.
In Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence, 5th International Consultation on Incontinence. Plymbridge: Health Publications, 2013: 1101-27.
6 Gormley EA, Lightner DJ, Burgio KL, et al, American Urological Association, Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. J Urol 2012;
188: 2455-63.
7 Brœkken IH, Majida M, Engh ME, B0 K. Can pelvic floor muscle training reverse pelvic organ prolapse and reduce prolapse symptoms? An assessor-blinded, randomized, controlled trial. Am J Obstet Gynecol 2010;
203: 170.e1-e7.
8 Kashyap R, Jain V, Singh A. Comparative effect of 2 packages of pelvic floor muscle training on the clinical course of stage I-III pelvic organ prolapse. Int J Gynaecol Obstet 2013; 121: 69-73.
9 Hagen S, Stark D, Glazener C, et al, on behalf of the POPPY Trial Collaborators. Individualised pelvic floor muscle training in women with pelvic organ prolapse (POPPY): a multicentre randomised controlled trial. Lancet 2013; published online Nov 28. http://dx.doi.org/10.1016/ S0140-6736(13)61977-7.
10 Bo K. Pelvic floor muscle training is effective in treatment of female stress urinary incontinence, but how does it work?
Int Urogynecol J Pelvic Flood Dysfunct 2004; 15: 76-84.
11 Hagen S, Glazener C, Cook J, Herbison P, Toozs-Hobson P. Further properties of the pelvic organ prolapse symptom score: minimally important change and test-retest reliability. Neurourol Urodyn 2010; 29: 1055-56.
12 Ellerkmann RM, Cundiff GW, Melick CF, Nihira MA, Leffler K, Bent AE. Correlation of symptoms with location and severity of pelvic organ prolapse. Am J Obstet Gynecol 2001; 185: 1332-37.
13 Mouritsen OL, Larsen JP. Symptoms, bother and POPQ in women referred with pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct 2003;
14: 122-27.
Melioidosis: refining management ofa tropical time bomb
Burkholderia pseudomallei
Published Online November 25, 2013 http://dx.doi.org/10.10l6/ S0140-6736(13)62143-1 See Articles page 807 Copyright © Fisher et al. Open Access article distributed under the terms of CC BY
Melioidosis, dubbed the Vietnamese time bomb1 after reports of lengthy disease latency in war veterans, is caused by Burkholderia pseudomallei and manifests as acute, subacute, or chronic disease. Bacteraemic disease especially when associated with pneumonia is the most lethal form, especially if associated with septic shock, but infection with or without abscess formation can occur in any organ system. Although most presentations occur soon after exposure, the organism's ability to evade host immune mechanisms and to survive and multiply in phagocytes2 gives rise to latency—latency of up to 62 years has been reported.3 Seroprevalence rates vary widely but are highest in northeast Thailand, where most children show evidence of exposure.4 It remains unclear how many of those with serological evidence of exposure harbour latent B pseudomallei with the potential for subsequent activation. Several risk factors cause some people to have an increased risk of melioidosis, with diabetes being the most common.5
For those with culture-confirmed melioidosis, treatment recommendations include an initial intensive intravenous course of at least 10 days with ceftazidime or a carbapenem.5 This course is followed by a so-called oral eradication phase of at least 3 months. The initial clinical response might indicate a need to modify the duration of the intensive phase, but the optimum antibiotic regimen and duration for eradication are uncertain. Recurrent melioidosis was noted in 13% of patients treated in Australia,6 but its prevalence has fallen over the past decade, possibly attributed to improved compliance, choice, and dosing of antibiotic regimens.7 Higher rates of recurrence in Thailand have been associated with inadequate duration of treatment.8 In The Lancet, Ploenchan Chetchotisakd and colleagues present findings from the MERTH trial,9 in which they enrolled 626 patients with melioidosis, randomly allocating them to receive trimethoprim-sulfamethoxazole alone (the recommended regimen in Australia) or trimethoprim-sulfamethoxazole
plus doxycycline (the recommended regimen in Thailand). During follow-up, they recorded no between-group difference in the occurrence of culture-positive recurrent cases (16 in the single-drug group, 21 in the combination group; hazard ratio 0-81, 95% CI 0-42-1-55), suggesting non-inferiority of the single-drug treatment (p=0-01). Furthermore, toxicity was higher in the combination group.
The study's power calculations probably did not take into account the high rate of re-infection by a different genotype from the initial infection, rather than true relapse. Of recurrences with paired isolate typing undertaken (29 [78%] of 37 patients with culture-confirmed recurrent melioidosis), 15 (52%) were due to a different genotype, which is much higher than previous reports—in a study of 921 patients in which detailed typing was used to characterise paired isolates from relapse cases, 26% were shown to be new infections.10 It is tempting to postulate that at least some of these re-infections were actually recurrence from an original polyclonal infection, but the pronounced difference in median time to re-presentation of 7 months (for relapse) versus 29 months (for reinfection) suggests otherwise. Previous work has also shown polyclonal infection to be a rare occurrence, happening in only 1-5% of patients.11 Despite this unexpected finding, even a subgroup analysis of same-genotype relapses lends support to the investigators' conclusions.
MERTH had a treatment duration longer than generally recommended—20 weeks. Advocates of combination antibiotics for 3 months might therefore remain unconvinced without further research clarifying the optimum duration. However, several points support the study's findings. Doxycycline might antagonise the effects of trimethoprim-sulfamethoxazole in vitro.12 Also, doxycycline mono-therapy is associated with high rates of relapse.13 For many years, single-drug treatment with trimethoprim-sulfamethoxazole has been used effectively as eradication treatment in Australia.6 In view of the extended duration of eradication treatment necessary, compliance might be hampered by adverse events as reported in the combination treatment group in this trial. Patients in this group had a 40% rate of switching to second-line regimens due to adverse events.
B pseudomallei is an environmental saprophyte found in the soil and fresh surface water of tropical
regions. Clinical trials in such settings are often difficult, meaning that conditions of treatment are necessarily real-world. Melioidosis endemicity has been reported in dozens of tropical regions and cases are also imported to non-tropical areas, but numbers are generally small. Adequately powered clinical trials can be done only in highly endemic areas such as Thailand, with support from international organisations experienced in clinical trials. It is a disease of major public health importance in northeast Thailand, and is possibly the third most common cause of death due to an infection after HIV and tuberculosis, accounting for roughly 20% of community-acquired bacteraemia.5 The findings of MERTH should prompt a change in standard recommendations for the eradication treatment phase of melioidosis toward trimethoprim-sulfamethoxazole alone. However, many questions about optimum doses and duration remain, with some even suggesting that an extended intravenous phase might decrease the rate of relapse. Because B pseudomallei has such complex interactions with host immunity resulting in latency, diverse presentations, and high risk of disease relapse, future treatment guidelines might be equally complex and possibly stratified, related to disease site and severity, as well as host factors and initial treatment response.
*Dale A Fisher, Patrick N A Harris
Department of Medicine, National University Hospital, and Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore mdcfda@nus.edu.sg
We declare that we have no conflicts of interest.
1 Time Magazine. Diseases: Viet nam's time bomb. Time Feb 10, 1967. http:// content.time.com/time/magazine/article/0,9171,840848,00.html (accessed Oct 23, 2013).
2 Jones AL, Beveridge TJ, Woods DE. Intracellular survival of Burkholderia pseudomallei. Infect Immun 1996; 64: 782-90.
3 Ngauy V, Lemeshev Y, Sadkowski L, Crawford G. Cutaneous melioidosis in a man who was taken as a prisoner of war by the Japanese during World War II. J Clin Microbiol 2005; 43: 970-72.
4 Wuthiekanun V, Chierakul W, Langa S, et al. Development of antibodies to Burkholderia pseudomallei during childhood in melioidosis-endemic northeast Thailand. Am J Trop Med Hyg 2006; 74: 1074-75.
5 Wiersinga WJ, Currie BJ, Peacock SJ. Melioidosis. N Engl J Med 2012; 367: 1035-44.
6 Currie BJ, Fisher DA, Anstey NM, Jacups SP. Melioidosis: acute and chronic disease, relapse and re-activation. Trans R SocTrop Med Hyg 2000;
94: 301-04.
7 Currie BJ, Ward L, Cheng AC. The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year Darwin prospective study. PLoS NeglTrop Dis 2010; 4: e900.
8 Limmathurotsakul D, Chaowagul W, Chierakul W, et al. Risk factors for recurrent melioidosis in northeast Thailand. Clin Infect Dis 2006;
43: 979-86.
9 Chetchotisakd P, Chierakul W, Chaowagul W, et al. Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, doubleblind, non-inferiority, randomised controlled trial. Lancet 2013; published online Nov 25. http://dx.doi.org/10.10l6/S0140-6736(13)6l951-0.
10 Maharjan B, Chantratita N, Vesaratchavest M, et al. Recurrent melioidosis in patients in northeast Thailand is frequently due to reinfection rather than relapse. J Clin Microbiol 2005; 43: 6032-34.
11 Limmathurotsakul D, Wuthiekanun V, Chantratita N, et al. Simultaneous infection with more than one strain of Burkholderia pseudomallei is uncommon in human melioidosis. J Clin Microbiol 2007; 45: 3830-32.
12 Dance DA, Wuthiekanun V, Chaowagul W, White NJ. Interactions in vitro between agents used to treat melioidosis. J Antimicrob Chemother 1989; 24: 311-16.
13 Chaowagul W, Simpson AJ, Suputtamongkol Y, Smith MD, Angus BJ, White NJ. A comparison of chloramphenicol, trimethoprim-sulfamethoxazole, and doxycycline with doxycycline alone as maintenance therapy for melioidosis. Clin Infect Dis 1999; 29: 375-80.
@ Safer countries through global health security
Published Online February 13, 2014 http://dx.doi.org/10.10l6/ S0140-6736(14)60l89-6
Countries around the world face a perfect storm of converging threats that might substantially increase the risk from infectious disease epidemics, despite improvements in technologies, communication, and some health systems. New pathogens emerge each year, some of which have high mortality and the potential for efficient transmission—eg, severe acute respiratory syndrome (SARS),1 Middle East respiratory syndrome coronavirus,2 and avian influenza A H7N9.3 Existing pathogens are becoming resistant to available antibiotics and several are now resistant to virtually all available treatment.4 There is also the potential threat of intentional release of biological agents, which can be developed or synthesised biologically and disseminated at low cost and with little scientific expertise. Moreover, the accelerated pace of globalisation amplifies these risks: a disease is just a plane trip away, and an outbreak anywhere is a threat everywhere.
One of the primary responsibilities of any government is to protect the health and safety of its people. There are three key elements of health security: prevention wherever possible, early detection, and timely and effective response. Although many countries are now better able to manage infectious disease threats than in the past, these improvements have often been small in scale and limited in scope. The International Health Regulations (IHR), revised by WHO in 2005 to more directly address new and emerging epidemic threats,5 require all 194 signatory countries to improve capacity in these and other areas as part of their commitment to protecting health.6 Yet, at least 80% of countries did not report full IHR compliance by the 2012 deadline.7
There is a perception in some quarters that tackling epidemic threats is less important than addressing
major killers, such as HIV, tuberculosis, and malaria, and that international efforts to stop outbreaks might be more in the interest of high-income than of low-income and middle-income countries.8 In fact, epidemic threats are potentially devastating to development through economic dislocation, decreased productivity, avoidable medical costs, loss of revenues from tourism and travel, and negative incentives for investment. The effective implementation of measures to ensure global health security builds a firm, broad-based public health foundation that promotes country self-sufficiency and can sustain health progress in any area in which a country decides to focus. Most fundamentally, addressing epidemic threats saves lives.
Rapid progress in health security is feasible if there is high-level political motivation, adequate investment, and technical expertise. After the devastating impact of SARS in 2003, China launched an ambitious programme to improve detection of new threats, strengthen response capacity, and report more transparently. The number of influenza surveillance laboratories grew to more than 400, the Chinese National Influenza Center was designated as the world's fifth WHO Collaborating Centre for Reference and Research on Influenza,9 the Chinese Center for Disease Control and Prevention (China CDC) was greatly strengthened with training of field epidemiologists and establishment of an Emergency Operations Centre, and mechanisms for rapid reporting to WHO were put in place. When the influenza A H7N9 virus began causing human illness in February, 2013, China was quickly able to identify and sequence the genome, and share the sequence globally within days of the first report, which enabled a rapid start on development of diagnostics and a vaccine.
Many countries have improved health security by preventing avoidable epidemics, detecting outbreaks
