Summary
Infectious diseases are conditions with significant consequences in terms of public health while associated mortality, morbidity, and complications can be prevented. Disease severity and duration can be shortened by means of rational antimicrobial therapy. It is important to obey main rational antibiotic use rules ie. to collect and examine appropriate culture specimens before treatment, identify potential microbial agents, consider the pharmacological properties of the antibiotic, determine whether combined antibiotics are indicated, review the host factors and indications for antibiotic therapy modification, and monitor response to antibiotic therapy while planning antibiotic therapy. Once correct diagnosis has been made, the correct antibiotic must be administered via the correct route, at an effective dose, at optimum intervals, and for an appropriate length of time for rational antimicrobial therapy. However, knowledge concerning the optimal duration of treatment is limited. Patients generally receive antibiotic therapy for 10-14 days. Prolonged treatment is also common. Duration of antimicrobial therapy may be a confusing issue for clinicians due to problems of resistance and toxicity. A healthy bacterial ecosystem (i.e. a normal flora) is essential to remain healthy. Antibiotic use can alter the normal bacterial flora in humans, which generally leads to the emergence of multidrug-resistant (MDR) bacteria and side effects such as diarrhea. Infections caused by MDR bacteria result in increased disease and mortality rates and extended hospital stays, as well as increased costs. Studies aimed at shortening the duration of treatment have reported that a 3-5 day treatment period in some of the community-acquired infections and one-week period in some of the nosocomial infections may be sufficient. Based on the patients" individual characteristics and clinical responses to treatment, short-term antibiotic therapy may be administered in selected patient groups both in community-acquired and healthcare-associated infections. Rational antibiotic therapy, together with observation of response to treatment and optimal treatment durations (which remain to be determined) can prevent adverse outcomes associated with long-term antibiotic use such as antibiotic-related side effects and development of MDR bacteria.
References
1Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165-228.
2Barlam TF, Cosgrove SE, Abbo LM, MacDougall C, Schuetz AN, Septimus EJ, Srinivasan A, Dellit TH, Falck-Ytter YT, Fishman NO, Hamilton CW, Jenkins TC, Lipsett PA, Malani PN, May LS, Moran GJ, Neuhauser MM, Newland JG, Ohl CA, Samore MH, Seo SK, Trivedi KK. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62:51-77.
3World Health Organization (WHO). The Rational Use of Drugs: Report of Conference of Experts on Nairobi, Kenya, 25-29 November 1985. Last accessed date: 2 July 2017. Available from: http://www.who.int
4Rogawski ET, Platts-Mills JA, Seidman JC, John S, Mahfuz M, Ulak M, Shrestha SK, Soofi SB, Yori PP, Mduma E, Svensen E, Ahmed T, Lima AA, Bhutta ZA, Kosek MN, Lang DR, Gottlieb M, Zaidi AK, Kang G, Bessong PO, Houpt ER, Guerrant RL. Use of antibiotics in children younger than two years in eight countries: a prospective cohort study. Bull World Health Organ. 2017;95:49-61.
5Ulusal Antibakteriyel İlaç Tüketim Sürveyansı - 2011. Sağlık Bakanlığı Yayın No: 995. TİTCK Yayın No: 001. Ankara-2015. ISBN: 978-975-590-540-2. Last accessed date: 2 July 2017 Available from: http://www.akilciilac.gov.tr/wpcontent/ uploads/2015/06/svy.pdf
6Versporten A, Bolokhovets G, Ghazaryan L, Abilova V, Pyshnik G, Spasojevic T, Korinteli I, Raka L, Kambaralieva B, Cizmovic L, Carp A, Radonjic V, Maqsudova N, Celik HD, Payerl-Pal M, Pedersen HB, Sautenkova N, Goossens H; WHO/Europe-ESAC Project Group. Antibiotic use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe. Lancet Infect Dis. 2014;14:381-7.
7Le Grand A, Hogerzeil HV, Haaijer-Ruskamp FM. Intervention research in rational use of drugs: a review. Health Policy Plan. 1999;14:89-102.
8American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital acquired ventilatorassociated and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.
9Martin-Loeches I, Torres A. A week seems to be weak: tailoring duration of antibiotic treatment in Gram-negative ventilator-associated pneumonia. Crit Care. 2013;17:106.
10Martinez JL. General principles of antibiotic resistance in bacteria. Drug Discov Today Technol. 2014;11:33-9.
11Niederman MS. Principles of appropriate antibiotic use. Int J Antimicrob Agents. 2005;26(Suppl 3):170-5.
12Kollef MH. Optimizing antibiotic therapy in the intensive care unit setting. Crit Care. 2001;5:189-95.
13Centers for Disease Control and Prevention (CDC). Core elements of hospital antibiotic stewardship programs. Last accessed date: 2 July 2017. Available from: https://www.cdc.gov/antibiotic-use/healthcare/implementation/ core-elements.html
14Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis. 2001;33:757-62.
15Devrim İ, Gülfidan G, Oruç Y, Yaşar N, Sorguç Y, Ayhan FY, Bayram N, Ünal N. Point-Prevalence Study Relating to Antibiotic Usage in Dr. Behçet Uz Children Hospital; Comparison of 2008 and 2012 Data. J Pediatr Inf. 2012;6:46-9.
16Pigrau-Serrallach C, Rodríguez-Pardo D. Bone and joint tuberculosis. Eur Spine J. 2013;22(Suppl 4):556-66.
17Colmenero JD, Jime´nez-Mejias ME, Reguera JM, Palomino-Nicas J, Ruiz- Mesa JD, Marquez-Rivas J, Lozano A, Pachon J. Tuberculous vertebral osteomyelitis in the new millennium: still a diagnostic and therapeutic challenge. Eur J Clin Microbiol Infect Dis. 2004;23:477-83.
18Neu HC, Howrey SP. Testing the physician"s knowledge of antibiotic use: selfassessment and learning via videotape. N Engl J Med. 1975;293:1291-5.
19Holubar M, Deresinsky S. Antimicrobial stewardship in hospital settings. Last accessed date: 30.05.2018 Available from: https://www.uptodate.com/ contents/antimicrobial-stewardship-in-hospital-settings
20Avkan-Oğuz V, Baykam N, Sökmen S, Güner R, Agalar F, Alp E, Doğrul A, Turhan Ö, Ağalar C, Kurtaran B, Geçim İE, Özaras R, Yılmaz G, Akbulut A, Koksal İ. Recommendations for intra-abdominal infections consensus report. Ulus Cerrahi Derg. 2016;32:306-21.
21Ariza J, Bosilkovski M, Cascio A, Colmenero JD, Corbel MJ, Falagas ME, Memish ZA, Roushan MR, Rubinstein E, Sipsas NV, Solera J, Young EJ, Pappas G; International Society of Chemotherapy; Institute of Continuing Medical Education of Ioannina. Perspectives for the Treatment of Brucellosis in the 21st Century: The Ioannina Recommendations. PLoS Med. 2007;4:e317.
22Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O"Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63:e147.
23Lepper MH, Dowling HF. Treatment of pneumococcic meningitis with penicillin compared with penicillin plus aureomycin; studies including observations on an apparent antagonism between penicillin and aureomycin. AMA Arch Intern Med. 1951;88:489-94.
24Mathies AW Jr, Leedom JM, Ivler D, Wehrle PF, Portnoy B. Antibiotic antagonism in bacterial meningitis. Antimicrob Agents Chemother (Bethesda). 1967;7:218-24.
25Eliopoulos GM, Moellering RC. Principles of Anti-infective Therapy. In: Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas and Bennett"s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia: 2015;17:224-33.
26Sande MA, Overton JW. In vivo antagonism between gentamicin and chloramphenicol in neutropenic mice. J Infect Dis. 1973;128:247-50.
27McLaughlin JE, Reeves DS. Clinical and laboratory evidence for inactivation of gentamicin by carbenicillin. Lancet. 1971;1:261-4.
28White DG, Shao S, Sudler R, Ayers S, Friedman S, Chen S, McDermott PF, McDermott S, Wagner DD, Meng J. The isolation of antibiotic-resistant Salmonella from retail ground meats. N Engl J Med. 2001;345:1147-54.
29Sorensen TL, Blom M, Monnet DL, Frimoldt-Moller N, Poulsen RL, Espersen F. Transient carriage after ingestion of antibiotic-resistant Enterococcus faecium from chicken and pork. N Engl J Med. 2001;345:1161-6.
30McDonald LC, Rossiter S, Mackinson C, Wang YY, Johnson S, Sullivan M, Sokolow R, DeBess E, Gilbert L, Benson JA, Hill B, Angulo FJ. Quinupristindalfopristin- resistant Enterococcus faecium on chicken and in human stool specimens. N Engl J Med. 2001;345:1155-60.
31Akıcı A, Uğurlu MÜ, Gönüllü N, Oktay Ş, Kalaça S. Pratisyen Hekimlerin Akılcı İlaç Kullanımı Konusunda Bilgi ve Tutumlarının Değerlendirilmesi. Sted. 2002;11:253-6.
32World Health Organization (WHO). WHO Policy perspectives on medicines. Promoting rational use of medicines: core components. Geneva, Sep 2002. Last available date: 1 July 2017. Available from: www.who.com
33Le Grand A, Hogerzeil HV, Haaijer-Ruskamp FM. Intervention research in rational use of drugs: a review. Health Policy Plan. 1999;14:89-102.
34Baron S. Medical Microbiology. 4th edition. Chapter 6 Normal Flora. University of Texas Medical Branch at Galveston; 1996. Last accessed date: 2 July 2017 Available from: https://www.ncbi.nlm.nih.gov/books/NBK7617
35Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012;13:260-70.
36Falagas ME, Rafailidis PI, Makris GC. Bacterial interference for the prevention and treatment of infections. Int J Antimicrob Agents. 2008;31:518-22.
37Brook I. Bacterial interference. Crit Rev Microbiol. 1999;25:155-72.
38Wooley RE, Brown J, Gibbs PS, Nolan LK, Turner KR. Effect of Normal Intestinal Flora of Chickens on Colonization by Virulent Colicin V-Producing, Avirulent, and Mutant Colicin V-Producing Avian Escherichia coli. Avian Dis. 1994;38:141-5.
39Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol. 2015;21:8787-803.
40Doron S, Davidson LE. Antimicrobial Stewardship Mayo Clin Proc. 2011;86:1113-23.
41Leung E, Weil DE, Raviglione M, Nakatani H; World Health Organization World Health Day Antimicrobial Resistance Technical Working Group. The WHO policy package to combat antimicrobial resistance. Bull World Health Organ. 2011;89:390-2.
42Jernberg C, Löfmark S, Edlund C, Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010;156:3216-23.
43Rafii F, Sutherland JB, Cerniglia CE. Effects of treatment with antimicrobial agents on the human colonic microflora. Ther Clin Risk Manag. 2008;4:1343-58.
44Al-Nassir WN, Sethi AK, Li Y, Pultz MJ, Riggs MM, Donskey CJ. Both oral metronidazole and oral vancomycin promote persistent overgrowth of vancomycin-resistant enterococci during treatment of Clostridium difficileassociated disease. Antimicrob Agents Chemother. 2008;52:2403-6.
45De La Cochetière MF, Durand T, Lepage P, Bourreille A, Galmiche JP, Doré J. Resilience of the dominant human fecal microbiota upon short-course antibiotic challenge. J Clin Microbiol. 2005;43:5588-92.
46Edlund C, Nord CE. Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections. J Antimicrob Chemother. 2000;46(Suppl 1):41-8.
47Friedrich MJ. Unraveling the influence of gut microbes on the mind. JAMA;2015;313:1699-701.
48Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O"Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of Adults With Hospital-acquired and Ventilatorassociated Pneumonia: Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:61-111.
49Yilmaz G, Saylan S, Aksoy F, Köksal İ. Individualized Antibiotic Therapy in Patients with Ventilator-Associated Pneumonia. J Med Microbiol. 2017;66:78-82.
50Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):27-72.
51Sener B. Collateral Damage and Antibiotic Resistance. ANKEM Derg. 2011;26:288-92.
52Peltola H, Vuori-Holopainen E, Kallio MJ; SE-TU Study Group. Succesful shortening from seven to four days of parenteral beta-lactam treatment for common chilhood infections: A prospective and randomized study. Int J Infect Dis. 2001;5:3-8.
53Schrag SJ, Peña C, Fernández J, Sánchez J, Gómez V, Pérez E, Feris JM, Besser RE. Effect of short-course, high dose amoxicillin therapy on resistant pneumococcal carriage: A randomised trial. JAMA. 2001;286:49-56.
54Dunbar LM, Khashab MM, Kahn JB, Zadeikis N, Xiang JX, Tennenberg AM. Efficacy of 750 mg, 5 day levofloxacin in the treatment of communityacquired pneumonia caused by atypical pathogens. Curr Med Res Opin. 2004;20:555-63.
55Kıter G. Azithromycin in the treatment of adults with mild to moderate community-acquired pneumonia: A study of efficacy and tolerability. Meandros Med Dent J. 2000;1:11-5.
56Socan M. Treatment of atypical pneumonia with azithromycin: comparison of a 5-day and a 3-day course. J Chemother. 1998;10:64-8.
57Schönwald S, Kuzman I, Oreskovic K, Burek V, Skerk V, Car V, Bozinović D, Culig J, Radosević S. Azithromycin: single 1.5 g dose in the treatment of patients with atypical pneumonia syndrome--a randomized study. Infection. 1999;27:198-202.
58Hoepelman IM, Möllers MJ, van Schie MH, Greefhorst AP, Schlösser NJ, Sinninghe Damsté EJ, van de Moosdijk CN, Dalinghaus WH, Eland ME, Mol SJ, Rozenberg-Arska M. A short (3 day) course of azithromycin tablets versus a 10-day course of amoxycillin-clavulanic acid in the treatment of adults with lower respiratory tract infections and effects on long term outcome. Int J Antimicrob Agents. 1997;9:141-6.
59Tellier G, Niederman MS, Nusrat R, Patel M, Lavin B. Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of chlarithromycin twice daily in patients with mild to moderate community-acquired pneumonia. J Antimicrob Chemother. 2004;54:515-23.
60Li JZ, Winston LG, Moore DH, Bent S. Efficacy of short course antibiotic regimens for community-acquired pneumonia: A meta-analysis. Am J Med. 2007;120:783-90.
61El Moussaoui R, de Borgie CA, van den Broek P, Hustinx WN, Bresser P, van den Berk GE, Poley JW, van den Berg B, Krouwels FH, Bonten MJ, Weenink C, Bossuyt PM, Speelman P, Opmeer BC, Prins JM. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ. 2006;332:1355.
62Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C, Le Jeune I, Macfarlane JT, Read RC, Roberts HJ, Levy ML, Wani M, Woodhead MA; Pneumonia Guidelines Committee of the BTS Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 2009;64(Suppl 3):1-55.
63Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, Kaplan SL, Mace SE, McCracken GH Jr, Moore MR, St Peter SD, Stockwell JA, Swanson JT; Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53:25-76.
64Capelastegui A, Espana Yandiola PP, Quintana JM, Bilbao A, Diez R, Pascual S, Pulido E, Egurrola M. Predictors of short-term rehospitalization following discharge of patients hospitalized with community-acquired pneumonia. Chest. 2009;136:1079-85.
65Jasti H, Mortensen EM, Obrosky DS, Kapoor WN, Fine MJ. Causes and risk factors for rehospitalization of patients hospitalized with communityacquired pneumonia. Clin Infect Dis. 2008;46:550-6.
66Klompas M. Nosocomial pneumoniae. In: Mandell GL, Bennett JE, Dolin R (eds). Mandell, Douglas and Bennett"s Principles and Practice of Infectious Diseases. 8th edition. Philadelphia: 2015;303:3325-33.
67Fishman JA. Nosocomial pneumoniae. In: Grippi MA, Elias JA, Fishman JA, Kotloff RM, Pack AI, Senior RM, Siegel MD (eds). Fishman"s pulmonary diseases and disorders 4th ed. New York: Mc Graw-Hill Companies, 2008:2273-90.
68Martin-Loeches I, Torres A. A week seems to be weak: tailoring duration of antibiotic treatment in Gram-negative ventilator-associated pneumonia. Crit Care. 2013;17:106.
69Silva CD, Silva Júnior M. Strategies for appropriate antibiotic use in intensive care unit. Einstein (Sao Paulo). 2015;13:448-53.
70Klompas M, Li L, Menchaca JT, Gruber S; Centers for Disease Control and Prevention Epicenters Program. Ultra-Short-Course Antibiotics for Patients With Suspected Ventilator-Associated Pneumonia but Minimal and Stable Ventilator Settings. Clin Infect Dis. 2017;64:870-6.
71Rhee C. Using Procalcitonin to Guide Antibiotic Therapy. Open Forum Infect Dis. 2016;4:ofw249.
72Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, Marsch S, Azzola A, Rakic J, Mueller B, Tamm M. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J. 2009;34:1364-75.
73Sandberg T, Skoog G, Hermansson AB, Kahlmeter G, Kuylenstierna N, Lannergård A, Otto G, Settergren B, Ekman GS. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, openlabel and double-blind, placebo-controlled, non-inferiority trial. Lancet. 2012;380:484-90.
74Peterson J, Kaul S, Khashab M, Fisher AC, Kahn JB. A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology. 2008;71:17-22.
75Jarrell AS, Wood GC, Ponnapula S, Magnotti LJ, Croce MA, Swanson JM, Boucher BA, Fabian TC. Short-duration treatment for catheter-associated urinary tract infections in critically ill trauma patients. J Trauma Acute Care Surg. 2015;79:649-53.
76Lieberthal AS, Carroll AE, Chonmaitree T, Ganiats TG, Hoberman A, Jackson MA, Joffe MD, Miller DT, Rosenfeld MD, Sevilla XD, Schwartz RH, Thomas PA, Tunkel DE. The diagnosis and management of acute otitis media. Pediatrics. 2013;131:964-99.
77Hoberman A, Paradise JL, Rockette HE, Kearney DH, Bhatnagar S, Shape TR, Martin JM, Kurs-Lasky M, Copelli SJ, Colborn K, Block SL, Labella JJ, Lynch TG, Cohen NL, Haralam M, Pope MA, Nagg JP, Green MD, Shaikh N. Shortened antimicrobial treatment for acute otitis media in young children. N Engl J Med. 2016;375:2446-56.
78Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, Wincott JL, Sitar DS, Klassen TP, Moffatt ME. Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis. JAMA. 1998;279:1736-42.
79Smith SE, Rumbaugh KA, May AK. Evaluation of a Short Course of Antimicrobial Therapy for Complicated Intra-Abdominal Infections in Critically Ill Surgical Patients. Surg Infect (Larchmt). 2017;18:742-50.
80Celestin AR, Odom SR, Angelidou K, Evans SR, Coimbra R, Guidry CA, Cuschieri J, Banton KL, O"Neill PJ, Askari R, Namias N, Duane TM, Claridge JA, Dellinger EP, Sawyer RA, Cook CH. Novel Method Suggests Global Superiority of Short-Duration Antibiotics for Intra-abdominal Infections. Clin Infect Dis. 2017;16;65:1577-9.
81Hewlett AL, Rupp ME. New Developments in the Prevention of Intravascular Catheter Associated Infections. Infect Dis Clin North Am. 2012;26:1-11.
82Pagani JL, Eggimann P. Management of catheter-related infection. Expert Rev Anti Infect Ther. 2008;6:31-7.
83Carek PJ, Dickerson LM, Sack JL. Diagnosis and management of osteomyelitis. Am Fam Physician. 2001;63:2413-20.
84Swiontkowski MF, Hanel DP, Vedder NB, Schwappach JR. A comparison of short- and long-term intravenous antibiotic therapy in the postoperative management of adult osteomyelitis. J Bone Joint Surg Br. 1999;81:1046-50.
85Bernard L, Dinh A, Ghout I, Simo D, Zeller V, Issartel B, Le Moing V, Belmatoug N, Lesprit P, Bru JP, Therby A, Bouhour D, Dénes E, Debard A, Chirouze C, Fèvre K, Dupon M, Aegerter P, Mulleman D; Duration of Treatment for Spondylodiscitis (DTS) study group. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet. 2015;385:875-82.
86Rod-Fleury T, Dunkel N, Assal M, Rohner P, Tahintzi P, Bernard L, Hoffmeyer P, Lew D, Uçkay I. Duration of post-surgical antibiotic therapy for adult chronic osteomyelitis: a single-centre experience. Int Orthop. 2011;35:1725-31.
87Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis. 2005;9:127-38.
88Hanssen AD, Rand JA. Evaluation and treatment of infection at the site of a total hip or knee arthroplasty. Instr Course Lect. 1999;48:111-22.
89Salvati EA, Gonzalez Della Valle A, Masri BA, Duncan CP. The infected total hip arthroplasty. Instr Course Lect. 2003;52:223-45.
90Hsieh PH, Shih CH, Chang YH, Lee MS, Shih HN, Yang WE. Two-stage revision hip arthroplasty for infection: comparison between the interim use of antibiotic-loaded cement beads and a spacer prosthesis. J Bone Joint Surg. 2004;86:1989-97.
91Masri BA, Duncan CP, Beauchamp CP. Long-term elution of antibiotics from bone-cement: an in vivo study using the prosthesis of antibiotic-loaded acrylic cement (PROSTALAC) system. J Arthroplasty. 1998;13:331-8.
92Hsieh PH, Chang YH, Chen SH, Ueng SW, Shih CH. High concentration and bioactivity of vancomycin and aztreonam eluted from Simplex cement spacers in two-stage revision of infected hip implants: a study of 46 patients at an average follow-up of 107 days. J Orthop Res. 2006;24:1615-21.
93Stockley I, Mockford BJ, Hoad-Reddick A, Norman P. The use of twostage exchange arthroplasty with depot antibiotics in the absence oflong-term antibiotic therapy in infected total hip replacement. J Bone Joint Surg Br. 2008;90:145-8.
