demand-driven interventions, establish more active partnerships with women and young people, and root accountability for the results of RMNCA health efforts in affected communities. More lives can be saved more readily if humanitarian, development, and RMNCA health communities come together and support each other to work in more complementary ways. Cooperation between and across different areas of expertise, actors, and systems currently working in parallel is vital to bridge gaps and maximise opportunities for sustained impact in the interests of those most at risk in fragile and humanitarian settings. This approach could deliver a new reality for every woman and every child everywhere in every setting. It is imperative that the Sustainable Development Goals and the next Every Woman Every Child global strategy include clear measures to better support countries and the international community to uphold fundamental human rights across the life course in every setting. This would be an important step towards maximising the opportunities for sustained impact on the health and wellbeing of women, newborn babies, children, and young people whose human rights oblige this of us, and whose potential contribution to their communities’ and countries’ resilience, response, and recovery from emergencies and crises will surely reward such effort. The next Every Woman Every Child strategy will help accelerate efforts to implement the Abu Dhabi Declaration.

*Sarah Zeid, Flavia Bustreo, Maha Taysir Barakat, Peter Maurer, Kate Gilmore Partnership on Maternal, Newborn and Child Health, Geneva 1211, Switzerland (SZ); World Health Organization, Geneva, Switzerland (FB), Health Authority Abu Dhabi, Abu Dhabi, United Arab Emirates (MTB); International Committee of the Red Cross, Geneva, Switzerland (PM); and United Nations Population Fund, New York, USA (KG) [email protected] We declare no competing interests. © 2015. World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. 1







Organisation for Economic Co-operation and Development. States of fragility 2015: meeting post-2015 ambitions. Paris: Organisation for Economic Co-operation and Development, 2015. WHO, UNICEF, UNFPA, World Bank, United Nations Population Division. Trends in maternal mortality: 1990 to 2013. Estimates by WHO, UNICEF, UNFPA, World Bank and United Nations Population Division. Geneva: World Health Organization, 2014. UNICEF, WHO, World Bank, UN, UN Inter-agency Group for Child Mortality Estimation. Levels and trends in child mortality report 2014: estimates developed by the UN Inter-agency Group for Child Mortality Estimation. New York: United Nations Children’s Fund, 2014. Plan International. Because I am a girl: the state of the world’s girls 2013. In double jeopardy: adolescent girls and disasters. Surrey, UK: Plan International, 2013. Oestergaard MZ, Inoue M, Yoshida S, et al, on behalf of the United Nations Inter-agency Group for Child Mortality Estimation and the Child Health Epidemiology Reference Group. Neonatal mortality levels for 193 countries in 2009 with trends since 1990: a systematic analysis of progress, projections, and priorities. PLoS Med 2011, 8: e1001080. The Abu Dhabi Declaration. February, 2015. http://www. Feb_2015_7.pdf (accessed April 27, 2015). Lewis J. Continuum or contiguum? Development for survival and vulnerability reduction. Fifth European Sociological Association Conference 2001; Helsinki, Finland; Aug 28–Sept 1, 2001. 250 (abstr). http://www. contiguum.pdf (accessed April 27, 2015).

A new ASPECT for complicated urinary tract infections Published Online April 28, 2015 S0140-6736(14)62482-X See Articles page 1949


Complicated urinary-tract infections are a major cause of bacteraemia and are associated with high mortality rates of 20–40% among critically ill patients worldwide.1,2 Antibacterials with broad-spectrum activity, especially against uropathogenic Gramnegative bacteria, are often used as empirical treatment for complicated urinary-tract infections.3 The increasing prevalence of multidrug-resistant Enterobacteriaceae spp and Pseudomonas aeruginosa among urinary isolates, however, has led to major challenges in the selection of effective antibiotic treatments. For example, the fluoroquinolones comprise a class of antibacterials that have excellent bioavailability and broad-spectrum

antimicrobial activity against most uropathogenic Gram-negative bacteria, including Enterobacteriaceae spp and P aeruginosa. More than 35% of urinary isolates of Escherichia coli collected from patients admitted to hospital in countries across the world, however, are resistant to fluoroquinolones.4 Furthermore, resistance to fluoroquinolones is especially high (more than 50%) among E coli that produce extended-spectrum β-lactamases (ESBL).4 Thus, there is an urgent need for the development of new antibacterials to treat complicated urinary-tract infections. Ceftolozane-tazobactam is a novel combination drug that includes a cephalosporin-β-lactamase inhibitor Vol 385 May 16, 2015

with potent activity against multidrug-resistant Gramnegative bacteria, including most ESBL-producing Enterobacteriaceae spp and carbapenem-resistant P aeruginosa.5 A phase 2 clinical trial has shown similar safety and efficacy for ceftolozane alone and ceftazidime in the treatment of complicated urinary-tract infections.6 In The Lancet, Florian Wagenlehner and colleagues7 report their safety and efficacy findings for ceftolozanetazobactam compared with levofloxacin, assessed in the ASPECT-cUTI clinical programme. This large, international, multicentre, double-blind, randomised, controlled, phase 3 clinical trial was done in 1083 hospital inpatients with complicated lower-urinary-tract infections or pyelonephritis, in 209 centres in 25 countries. Patients were randomly assigned to receive either intravenous 1·5 g ceftolozane-tazobactam every 8 h or intravenous 750 mg levofloxacin every 24 h, both for 7 days. The results confirmed the non-inferiority of ceftolozane-tazobactam to levofloxacin in the microbiological modified intention-to-treat population of patients who showed growth of one or two uropathogens of at least 10⁵ colony-forming units per mL in urine culture (306 [76·9%] of 398 patients vs 275 [68·4%] of 402 patients, 95% CI 2·3–14·6) and the per-protocol population (284 [83·3%] of 341 patients vs 266 [75·4%] of 353 patients, 2·0–14·0). Adverse event profiles did not differ significantly between treatment groups. Importantly, ceftolozane-tazobactam was superior to levofloxacin in patients with infections caused by ESBL-producing (38 [62·3%] of 61 patients vs 20 [35·1%] of 57 patients) or levofloxacin-resistant bacteria (60 [60·0%] of 100 patients vs 44 [39·3%] of 112 patients). These results suggest that ceftolozanetazobactam could be a useful new treatment option for patients with complicated urinary-tract infections, especially those caused by multidrug-resistant Gramnegative bacteria. We congratulate Wagenlehner and colleagues for completing this much anticipated and rigorous clinical trial. Looking ahead, several important features of the clinical use of ceftolozane-tazobactam should be assessed further. First, ceftolozane-tazobactam is primarily excreted in the urine and dose adjustment is required in patients with moderate to severe impairment of renal function.8 In Wagenlehner and colleagues’ study,7 patients with severe renal impairment, including those with estimated creatinine clearance of less than Vol 385 May 16, 2015

Dr P Marazzi/Science Photo Library


0·5 mL/s per m², requirement for peritoneal dialysis, haemodialysis or haemofiltration, and oliguria, were excluded. As patients with complicated urinary-tract infections are prone to develop acute renal impairment, the safety and optimum dosing regimen of ceftolozanetazobactam in this subgroup require investigation. Second, there remains no evidence-based consensus on the duration of therapy for complicated urinarytract infections. The efficacy of the 7 day regimen used by Wagenlehner and colleagues should be compared with alternative regimens, such as those extended to 14 days or beyond.9 Third, since ceftolozanetazobactam has potent activity against P aeruginosa, including multidrug-resistant isolates, whether this drug would be useful to treat nosocomial complicated urinary-tract infections, which are commonly caused by P aeruginosa, should be determined.10 Fourth, clinicians should be aware of the limited activity of ceftolozanetazobactam against other important uropathogenic bacteria, including enterococci and carbapenemaseproducing Enterobacteriaceae spp, such as those producing Klebsiella pneumoniae carbapenemases and metallo-β-lactamases.10 Therefore, urine culture to determine the identity and drug susceptibility of the causative organisms in patients who are not responsive to empirical treatment with ceftolozane-tazobactam remains important. Finally, the judicious use of this new antibacterial and continuous surveillance for emerging resistance towards it in different parts of the world are necessary to extend its usefulness as we await the next novel broad-spectrum agent becoming available. 1921


*Jasper Fuk-Woo Chan, Kwok-Yung Yuen State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China [email protected]



JF-WC has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma Hong Kong. K-YY declares no competing interests. 1

2 3



To KK, Lo WU, Chan JF, Tse H, Cheng VC, Ho PL. Clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity. Int J Infect Dis 2013; 17: e120–24. Wagenlehner FM, Pilatz A, Naber KG, Weidner W. Therapeutic challenges of urosepsis. Eur J Clin Invest 2008; 38 (suppl 2): 45–49. Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010; 50: 625–63. Hoban DJ, Nicolle LE, Hawser S, Bouchillon S, Badal R. Antimicrobial susceptibility of global inpatient urinary tract isolates of Escherichia coli: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) program: 2009–2010. Diagn Microbiol Infect Dis 2011; 70: 507–11. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane–tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Hospitals (2011–2012). Antimicrob Agents Chemother 2013; 57: 6305–10.




Umeh O, Cebrik D, Friedland I. A double-blind, randomized, phase 2 study to compare the safety and efficacy of intravenous CXA-101 (CXA) and intravenous ceftazidime (CTZ) in complicated urinary tract infection (cUTI). 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; Boston, MA, USA; Sept 12–15, 2010. Abstract number L1-361A. Wagenlehner FM, Obiamiwe U, Steenbergen J, Yuan G, Diaruiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015; published online April 28. Wooley M, Miller B, Krishna G, Hershberger E, Chandorkar G. Impact of renal function on the pharmacokinetics and safety of ceftolozane– tazobactam. Antimicrob Agents Chemother 2014; 58: 2249–55. Sandberg T, Skoog G, Hermansson AB, Kahlmeter G. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet 2012; 380: 484–90. Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs 2014; 74: 31–51.

Alain Pol, ISM/Science Photo Library

Renal denervation superior to drug therapy in hypertension

Published Online January 26, 2015 S0140-6736(14)62050-X See Articles page 1957


Despite widespread use of conventional antihypertensive therapy, which effectively reduces blood pressure in most hypertensive patients, a failure to attain target blood pressure levels in about 10% of patients with arterial hypertension suggests a deficit in present strategies, leaving this patient cohort at high risk of cardiovascular and renal disease.1 Although mechanisms underlying the pathogenesis of arterial hypertension are complex and multifactorial, augmented sympathetic activation crucially contributes to hypertension and its adverse effects. Moreover, high levels of muscle sympathetic nerve activity predominantly feature in patients with resistant hypertension despite multidrug treatment.2,3 Renal denervation is a recent development in the management of drug-resistant hypertension that opposes sympathetic activity. Renal denervation has substantial clinical and pathophysiological relevance and a favourable safety profile, resulting in a sustained reduction in blood pressure and sympathetic nerve activity.2–7 Accordingly, since the proof-of-concept study of renal denervation,5 many patients with resistant hypertension and at high risk of cardiovascular and renal disease who underwent renal denervation have

benefited from improved blood pressure control along with attenuation of hypertension-induced end organ damage. Although expectations were high for the randomised controlled Symplicity HTN-3 study,8 surprisingly the trial did not meet its primary (mean change in office systolic blood pressure from baseline to 6 months in the renal denervation group, compared with the sham-treated control group) or secondary (change in ambulatory blood pressure at 6 months) efficacy endpoints as a result of several confirmed study design issues.9 Although the study included a sham procedure, limitations of Symplicity HTN-3 included ineffective or inconsistent renal denervation associated with interventionalists inexperienced in the renal denervation procedure, medication changes both between screening visits and before assessment of 6 month endpoints (in about 40% of patients), variable drug adherence, and an absence of validated tests to confirm renal denervation. These limitations provide a probable explanation for the absence of a significant difference in systolic blood pressure between renal denervation and sham-procedure groups. Despite these study design issues, the reporting of Symplicity HTN-3 has halted renal denervation and further neuroscience research into uncontrolled blood pressure. Vol 385 May 16, 2015

A new ASPECT for complicated urinary tract infections.

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