When and what to test for: A cost-effectiveness analysis of febrile illness test-and-treat strategies in the era of responsible antibiotic use

Autoři: Anthony Zhenhuan Zhang aff001;  Diana Negoescu aff001;  Claudia Munoz-Zanzi aff002
Působiště autorů: College of Science and Engineering, Industrial and System Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America aff001;  School of Public Health, Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota, United States of America aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227409



Febrile illness caused by viral and bacterial diseases (e.g., dengue and leptospirosis) often have similar symptoms and are difficult to differentiate without diagnostic tests. If not treated appropriately, patients may experience serious complications. The question of what diagnostic tests to make available to providers in order to inform antibiotic therapy remains an open problem for health services facing limited resources.

Methods and findings

We formulated the problem of minimizing the weighted average of antibiotic underuse and overuse to inform the optimal diagnostic test and antibiotic treatment options for given occurrence probabilities of several bacterial and viral infections. We modeled the weight of antibiotic overuse as a monetary penalty per unnecessarily administered course, which we varied in both the base case and sensitivity analysis. Detailed Markov cohort models of febrile illness progression were used to estimate the weight of antibiotic underuse. The model accounted for multiple infections simultaneously and incorporated test, treatment, and other direct and indirect costs, as well as the effect of delays in seeking care and test turnaround times. We used the Markov models to numerically estimate disability-adjusted life years (DALYs), pre-penalty costs, and likelihood of antibiotics overuse per patient for fifteen different strategies in two example settings in Thailand, one with a higher probability of bacterial infections (Northern Thailand, Scenario A) and one with a higher probability of viral infections (Bangkok, Scenario B). We found that empirical antibiotic treatment to all patients always incurs the lowest pre-penalty cost (Scenario A: $47.5/patient, $100.6/patient, $149.5/patient for patients seeking care on day one, day four, and day ten respectively; Scenario B: $94.1/patient, $108.7/patient, $122.1/patient on day one, day four, and day ten respectively), and the lowest DALYs, (Scenario A: 0.2 DALYs/patient, 0.9 DALYs/patient, 1.7 DALYs/patient on day one, day four, and day ten, respectively; Scenario B: 0.5 DALYs/patient, 0.7 DALYs/patient, 0.9 DALYs/patient on day one, day four, and day ten, respectively). However, such strategy resulted in the highest proportion of antibiotic overuse per patient (Scenario A: 38.1%, 19.3%, 7.5% on day one, day four, and day ten, respectively; Scenario B: 82.9%, 42.1%, 16.3% on day one, day four, and day ten, respectively). Consequently, empirical antibiotic treatment became suboptimal with antibiotic overuse penalties above $12,800/course, $18,400/course, $23,900/course for patients presenting on day one, day four, and day ten in Scenario A and above $1,100/course, $1,500/course, $1,600/course for patients presenting on day one, day four, and day ten in Scenario B.


Empirical antibiotic treatment to all patients provided the best outcomes if antibiotic overuse was not the primary concern or if presenting with viral disease (such as dengue) was unlikely. Empirical antibiotic treatment to severe patients only was in most cases not beneficial. Otherwise, strategies involving diagnostic tests became optimal. In particular, our results indicated that single test strategies (bacterial RDT or viral PCR) were optimal in regions with a greater probability of presenting with viral infection. PCR-led strategies (e.g., parallel bacterial PCR, or multiplex PCR) are robust under parameter uncertainty (e.g., with uncertain disease occurrence probabilities).

Klíčová slova:

Antibiotics – Bacterial diseases – Bacterial pathogens – Diagnostic medicine – Monetary policy – Polymerase chain reaction – Typhus – Leptospirosis


1. Suttinont C, Losuwanaluk K, Niwatayakul K, Hoontrakul S, Intaranongpai W, Silpasakorn S, et al. Causes of acute, undifferentiated, febrile illness in rural Thailand: results of a prospective observational study. Annals of Tropical Medicine & Parasitology. 2006;100(4):363–70. doi: 10.1179/136485906X112158 16762116

2. Katz AR, Ansdell VE, Effler PV, Middleton CR, Sasaki DM. Assessment of the Clinical Presentation and Treatment of 353 Cases of Laboratory-Confirmed Leptospirosis in Hawaii, 1974–1998. Clinical Infectious Diseases. 2001;33(11):1834–41. doi: 10.1086/324084 11692294

3. World Health Organization. Dengue and severe dengue: World Health Organization. Regional Office for the Eastern Mediterranean; 2014 [cited 2019 June 28]. Available from: https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue.

4. Hotez PJ, Bottazzi ME, Strych U, Chang L-Y, Lim YAL, Goodenow MM, et al. Neglected Tropical Diseases among the Association of Southeast Asian Nations (ASEAN): Overview and Update. PLOS Neglected Tropical Diseases. 2015;9(4):e0003575. doi: 10.1371/journal.pntd.0003575 25880767

5. Dupouey J, Faucher B, Edouard S, Richet H, Kodjo A, Drancourt M, et al. Human leptospirosis: An emerging risk in Europe? Comparative Immunology, Microbiology and Infectious Diseases. 2014;37(2):77–83. doi: 10.1016/j.cimid.2013.12.002 24388481

6. Durski KN, Jancloes M, Chowdhary T, Bertherat E. A global, Multi-disciplinary, Multi-sectorial Initiative to Combat Leptospirosis: Global Leptospirosis Environmental Action Network (GLEAN). International Journal of Environmental Research and Public Health. 2014;11(6):6000–8. doi: 10.3390/ijerph110606000 24905245.

7. Prasad N, Murdoch DR, Reyburn H, Crump JA. Etiology of Severe Febrile Illness in Low- and Middle-Income Countries: A Systematic Review. PLOS ONE. 2015;10(6):e0127962. doi: 10.1371/journal.pone.0127962 26126200

8. Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global Morbidity and Mortality of Leptospirosis: A Systematic Review. PLOS Neglected Tropical Diseases. 2015;9(9):e0003898. doi: 10.1371/journal.pntd.0003898 26379143

9. Christou L. The global burden of bacterial and viral zoonotic infections. Clinical Microbiology and Infection. 2011;17(3):326–30. doi: 10.1111/j.1469-0691.2010.03441.x 21129102

10. Rowe AK, de Savigny D, Lanata CF, Victora CG. How can we achieve and maintain high-quality performance of health workers in low-resource settings? The Lancet. 2005;366(9490):1026–35. https://doi.org/10.1016/S0140-6736(05)67028-6.

11. Robinson ML, Manabe YC. Reducing Uncertainty for Acute Febrile Illness in Resource-Limited Settings: The Current Diagnostic Landscape. The American Society of Tropical Medicine and Hygiene. 2017;96(6):1285–95. doi: 10.4269/ajtmh.16-0667 28719277.

12. Crump JA, Gove S, Parry CM. Management of adolescents and adults with febrile illness in resource limited areas. BMJ. 2011;343:d4847. doi: 10.1136/bmj.d4847 21824901

13. Suputtamongkol Y, Pongtavornpinyo W, Lubell Y, Suttinont C, Hoontrakul S, Phimda K, et al. Strategies for Diagnosis and Treatment of Suspected Leptospirosis: A Cost-Benefit Analysis. PLOS Neglected Tropical Diseases. 2010;4(2):e610. doi: 10.1371/journal.pntd.0000610 20186324

14. Centers for Disease Control and Prevention. Antibiotic Resistance: A Global Threat: Centers for Disease Control and Prevention; 2019 [cited 2019 June 28]. Available from: https://www.cdc.gov/features/antibiotic-resistance-global/index.html.

15. Engemann JJ, Carmeli Y, Cosgrove SE, Fowler VG, Bronstein MZ, Trivette SL, et al. Adverse Clinical and Economic Outcomes Attributable to Methicillin Resistance among Patients with Staphylococcus aureus Surgical Site Infection. Clinical Infectious Diseases. 2003;36(5):592–8. doi: 10.1086/367653 12594640

16. World Health Organization. Drug resistance 2019 [cited 2019 June 28]. Available from: https://www.who.int/drugresistance/AMR_Emergence_Spread/en/.

17. McAdam PR, Templeton KE, Edwards GF, Holden MTG, Feil EJ, Aanensen DM, et al. Molecular tracing of the emergence, adaptation, and transmission of hospital-associated methicillin-resistant Staphylococcus aureus. Proceedings of the National Academy of Sciences. 2012;109(23):9107–12. doi: 10.1073/pnas.1202869109 22586109

18. Crump J, Newton PN, Baird SJ, Lubell Y. Febrile illness in adolescents and adults. Mental, Neurological, and Substance Use Disorders: Disease Control Priorities. 4: The International Bank for Reconstruction and Development/The World Bank; 2017.

19. Wangrangsimakul T, Althaus T, Mukaka M, Kantipong P, Wuthiekanun V, Chierakul W, et al. Causes of acute undifferentiated fever and the utility of biomarkers in Chiangrai, northern Thailand. PLOS Neglected Tropical Diseases. 2018;12(5):e0006477. doi: 10.1371/journal.pntd.0006477 29852003

20. Lubell Y, Althaus T, Blacksell SD, Paris DH, Mayxay M, Pan-Ngum W, et al. Modelling the Impact and Cost-Effectiveness of Biomarker Tests as Compared with Pathogen-Specific Diagnostics in the Management of Undifferentiated Fever in Remote Tropical Settings. PLOS ONE. 2016;11(3):e0152420. doi: 10.1371/journal.pone.0152420 27027303

21. Luvira V, Silachamroon U, Piyaphanee W, Lawpoolsri S, Chierakul W, Leaungwutiwong P, et al. Etiologies of Acute Undifferentiated Febrile Illness in Bangkok, Thailand. The American Society of Tropical Medicine and Hygiene. 2019:tpmd180407–tpmd. doi: 10.4269/ajtmh.18-0407 30628565

22. Goris MGA, Leeflang MMG, Loden M, Wagenaar JFP, Klatser PR, Hartskeerl RA, et al. Prospective Evaluation of Three Rapid Diagnostic Tests for Diagnosis of Human Leptospirosis. PLOS Neglected Tropical Diseases. 2013;7(7):e2290. doi: 10.1371/journal.pntd.0002290 23875034

23. Hoontrakul S, Suttinont C, Losuwanaluk K, Suputtamongkol Y. Performance of SD Bioline Tsutsugamushi assays for the diagnosis of scrub typhus in Thailand. J Med Assoc Thai. 2012;95(2):S18–S22.

24. Ahmed NH, Broor S. Comparison of NS1 antigen detection ELISA, real time RT-PCR and virus isolation for rapid diagnosis of dengue infection in acute phase. Journal of Vector Borne Diseases. 2014;51(3):194. 25253212

25. Waggoner JJ, Abeynayake J, Balassiano I, Lefterova M, Sahoo MK, Liu Y, et al. Multiplex Nucleic Acid Amplification Test for Diagnosis of Dengue Fever, Malaria, and Leptospirosis. Journal of Clinical Microbiology. 2014;52(6):2011–8. doi: 10.1128/JCM.00341-14 24671788

26. Giry C, Roquebert B, Li-Pat-Yuen G, Gasque P, Jaffar-Bandjee M-C. Simultaneous detection of chikungunya virus, dengue virus and human pathogenic Leptospira genomes using a multiplex TaqMan® assay. BMC Microbiology. 2017;17(1):105. doi: 10.1186/s12866-017-1019-1 28468604

27. Worldbank. Thailand GDP per capita (2016) 2019 [cited 2019 June 28]. Available from: https://data.worldbank.org/indicator/NY.GDP.PCAP.CD?locations=TH.

28. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013;496:504. doi: 10.1038/nature12060 https://www.nature.com/articles/nature12060#supplementary-information. 23563266

29. Torgerson PR, Hagan JE, Costa F, Calcagno J, Kane M, Martinez-Silveira MS, et al. Global Burden of Leptospirosis: Estimated in Terms of Disability Adjusted Life Years. PLOS Neglected Tropical Diseases. 2015;9(10):e0004122. doi: 10.1371/journal.pntd.0004122 26431366

30. Shallcross LJ, Davies DSC. Antibiotic overuse: a key driver of antimicrobial resistance. British Journal of General Practice. 2014;64(629):604–5. doi: 10.3399/bjgp14X682561 25452508

31. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nature Reviews Microbiology. 2010;8:260. doi: 10.1038/nrmicro2319 20208551

32. Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. Pharmacy and therapeutics. 2015;40(4):277. 25859123

33. Nadjm B, Amos B, Mtove G, Ostermann J, Chonya S, Wangai H, et al. WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study. BMJ. 2010;340:c1350. doi: 10.1136/bmj.c1350 20354024

34. Tuan NM, Nhan HT, Chau NVV, Hung NT, Tuan HM, Tram TV, et al. Sensitivity and Specificity of a Novel Classifier for the Early Diagnosis of Dengue. PLOS Neglected Tropical Diseases. 2015;9(4):e0003638. doi: 10.1371/journal.pntd.0003638 25836753

35. Riediger IN, Stoddard RA, Ribeiro GS, Nakatani SM, Moreira SDR, Skraba I, et al. Rapid, actionable diagnosis of urban epidemic leptospirosis using a pathogenic Leptospira lipL32-based real-time PCR assay. PLOS Neglected Tropical Diseases. 2017;11(9):e0005940. doi: 10.1371/journal.pntd.0005940 28915243

36. Buxton MJ, Drummond MF, Van Hout BA, Prince RL, Sheldon TA, Szucs T, et al. Modelling in ecomomic evaluation: an unavoidable fact of life. Health economics. 1997;6(3):217–27. doi: 10.1002/(sici)1099-1050(199705)6:3<217::aid-hec267>3.0.co;2-w 9226140

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden