Katharina Kreitmeyri,II,VI, Ulrich Von Bothi,VI, Alenka Pecarii, Johannes P. Bordeiii

Katharina KreitmeyrI,II,VI, Ulrich von BothI,VI, Alenka PecarII, Johannes P. BordeIII, Rafael MikolajczykIV,V,VI, Johannes HuebnerI,III,VI

Pediatric Antibiotic Stewardship: Successful Interventions to Reduce Broad-Spectrum Antibiotic Use on General Pediatric Wards

Keywords: Pediatric Antibiotic Stewardship; Quality of Care, days of therapy (DoT); Antimicrobial Stewardship Program (ASP); Dosing Accuracy; Patient Safety

Acknowledgments: This work was supported by AOK Bayern - Die Gesundheitskasse. On behalf of all authors, the corresponding author states that there is no conflict of interest.

______

I Division of Pediatric Infectious Diseases, Dr. von Hauner Children's Hospital, , LMU Munich, Lindwurmstr. 4, 80337 Munich, Germany II Hospital Pharmacy, LMU Munich, Marchioninistr. 15, 81377 Munich, Germany III Division of Infectious Diseases, University Medical Center, Hugstetter Str. 55, 79106 Freiburg i. Br, Germany IV Epidemiological and Statistical Methods Research Group, Helmholtz-Center for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany V Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany VI German Center for Infection Research (DZIF)

*Corresponding Author:

Katharina Kreitmeyr ([email protected])

Division of Pediatric Infectious Diseases, Dr. von Hauner Children's Hospital, LMU Munich, Lindwurmstr. 4, 80337 Munich, Germany

1 Electronic Supplementary Material Tab. S1 Local Empiric Antibiotic Guideline, AntibiotiKARTE Check before EVERY antibiotic therapy: Is an antibiotic really necessary? Prescribe antibiotics only when a clear clinical benefit is expected. Does the patient have any allergies or signs of renal insufficiency? ALWAYS take microbiological culture BEFORE starting any antibiotic therapy! Evaluate daily: Is it possible to - stop - switch IV to PO - escalate/deescalate - define total lengths of therapy - optimize dosing according to local guidelines? Infection Empiric Antibiotic Therapy Fever of Unknown Origin (FUO) < 3 months Ampicillin 50 mg/kg tds IV PLUS Cefotaxime 50 mg/kg tds IV > 3 months Ceftriaxone1 80 mg/kg od IV (max. 4 g) Fever in Neutropenia (FIN) Piperacillin/Tazobactam2 100 mg/kg tds IV (max. 4 g/dose) if suspicion of MRSA or CVC-infection: ADD Vancomycin3 15 mg/kg tds IV (max. 650 mg/dose) Septic Shock Meropenem 20 mg/kg tds IV (max. 1 g/dose) CNS Infections Meningoencephalitis Aciclovir <1 a: 20 mg/kg tds IV, >1 a: 10 mg/kg tds IV (max. 850 mg/dose) PLUS >1 Mo.: Ceftriaxone1 80 mg/kg od IV (max. 4 g) Meningitis < 3 months Ampicillin <1 Mo.: 100 mg/kg tds IV, >1 Mo.: 100 mg/kg qds IV PLUS Cefotaxime 50 mg/kg qds IV Meningitis > 3 months Ceftriaxone1 80 mg/kg od IV (max. 4 g) Pneumonia Newborn Ampicillin 50 mg/kg tds IV PLUS Cefotaxime 50 mg/kg tds IV Community acquired (CAP) Cefuroxime 40 mg/kg tds IV 4 weeks – 6 months Community acquired (CAP) Ampicillin 50 mg/kg tds IV (max. 2 g/dose) or > 6 months Amoxicillin 30 mg/kg tds PO (max. 1.5 g/dose) Atypical Clarithromycin 7.5 mg/kg bd PO (max. 500 mg/dose) Nosocomial Piperacillin/Tazobactam2 100 mg/ kg tds IV (max. 4 g/dose) Multidrug-Resistant Bacteria History of ESBL colonisation Meropenem 15 mg/kg tds IV (max. 1 g/dose) History of MRSA colonisation include Vancomycin³ 15 mg /kg tds IV (max. 650 mg/dose) as part of empiric therapy ENT Infections Tonsillitis / Antibiotics are not the first choice! pharyngitis ONLY perform rapid strep test if min. 3 out of the following symptoms present: exudative, fever, painful cervical lymphadenopathy, no cough. ONLY in case of proven group A streptococcal infection: Penicillin V 30,000 IU/kg tds PO (max. 2 Mio. IU/dose) for 7d Epiglottitis / tracheitis >1 Mo.: Ceftriaxone1 50 mg/kg od IV (max. 4 g) Acute otitis media / acute sinusitis Antibiotics are not the first choice! Carefully evaluate using an antibiotic, because of high probability of viral origin and spontaneous recovery. First-line treatment: Analgesia, nasal decongestant. Re-evaluation after 24–48 h, if persistence of symptoms or child deteriorates: Amoxicillin 30 mg/kg tds PO (max. 1.5 g/dose) Malignant otitis externa Ceftazidime 50 mg/kg tds IV (max. 1.5 g/dose) PLUS Ciprofloxacin 15 mg /kg bd IV (max. 750 mg/dose) Urinary Tract Infections Cystitis Amoxicillin/Clavulanic acid 20/5 mg/kg tds PO (max. 1000/250 mg/dose) Pyelonephritis < 3 months Ampicillin <1 Mo.: 100 mg/kg tds IV, >1 Mo.: 100 mg/kg qds IV PLUS Cefotaxime 50 mg/kg qds IV Pyelonephritis > 3 months Piperacillin/Tazobactam2 100 mg/ kg tds IV (max. 4 g/dose) Gastrointestinal Tract Peritonitis Piperacillin/Tazobactam2 100 mg/kg tds IV (max. 4 g/dose) Skin, Soft Tissue and other Infections Osteomyelitis / Cefuroxime 50 mg/kg tds IV (max. 1.5 g/dose) septic arthritis Lymphadenitis Amoxicillin/Clavulanic acid 20/5 mg/kg tds PO (max. 1000/250 mg/dose) Cellulitis / impetigo Amoxicillin/Clavulanic acid 20/5 mg/kg tds PO (max. 1000/250 mg/dose) Cellulitis serious (with fever / fast Ampicillin/Sulbactam4 50 mg/kg tds IV (max. 4 g/dose) progress) PLUS Flucloxacillin 50 mg/kg qds IV (max. 2 g/dose) (for penicillin allergy, >1 Mo.: Clindamycin 10 mg/kg qds IV) Preseptal cellulitis Ampicillin/Sulbactam4 50 mg/kg tds IV (max. 4 g/dose) or amoxicillin/Clavulanic acid 20/5 mg/kg tds PO (max. 1000/250 mg/dose) Postseptal / periorbital cellulitis >1 Mo.: Ceftriaxone1 80 mg/kg od IV (max. 4 g) PLUS Flucloxacillin 50 mg/kg qds IV (max. 2 g/dose) Bites Amoxicillin/Clavulanic acid 20/5 mg/kg tds PO (max. 1000/250 mg/dose). (animals / human) Check need for rabies and tetanus prophylaxis!

1 Do not mix Ceftriaxone with total parenteral nutrition (TPN) / calcium-containing products; don’t use in case of hyperbilirubinemia 2 Dosing recommendations expressed as piperacillin content 3 Therapeutic Drug Monitoring recommended 4 Dosing recommendations expressed as ampicillin content od: once daily, bd: twice daily, tds: three times daily, qds: four times daily

2 Tab. S2 Antibiotic Dosing Recommendations at Dr. von Hauner Children’s Hospital Route of Single dose Daily dose Dosing interval q Maximum daily Substance administration [mg/kg] [mg/kg*d] [h] dose Amoxicillin PO 30 90 8 6 g/d Amoxicillin/Clavulansäur PO 20/5 60/15 8 2,625/375 mg/d e Ampicillin IV 50 150 8 6 g/d Ampicillin_Meningitis IV 100 300 8 15 g/d Ampicillin/Sulbactam IV 50 150 8 12 g/d Azithromycin PO/IV 10 10 24 0,5 g/d Cefazolin IV 30 90 8 8 (-12) g/d Cefotaxim IV 33 100 8 8 g/d Cefotaxim_Meningitis IV 50 200 6 12 g/d CefPOdoxim PO 5 10 12 400 mg/d Ceftazidim IV 50 150 8 6, CF: 9 g/d Ceftriaxon IV 50 50 24 2 g/d Ceftriaxon_Meningitis IV 80 80 24 4 g/d Cefuroxim PO 15 30 12 1 g/d Cefuroxim IV 40 120 8 4,5 g/d Cefuroxim_Osteomyelitis IV 50 150 8 6 g/d Ciprofloxacin PO/IV 15 30 12 1,5 g/d Clarithromycin PO 7,5 15 12 1 g/d Clindamycin PO/IV 10 40 6 1.8 (-2.7) g/d Cotrimoxazol PO 3 6 12 320 mg/d Flucloxacillin PO 33 100 8 8 g/d Flucloxacillin IV 50 200 6 12 g/d Meropenem IV 20 60 8 3 g/d Meropenem_Meningitis IV 40 120 8 6 g/d Metronidazol PO/IV 10 30 8 2 g/d Moxifloxacin IV 10 10 24 400 mg/d Penicillin G IV 75,000 IE 300,000 IE 6 24 Mio IE/d Penicillin V PO 30,000 IE 90,000 IE 8 6 Mio IE/d PipTaz IV 100 300 8 12 (-18) g/d Rifampicin PO 10 20 12 600-900 mg/d

References Dt. Gesellschaft für Pädiatrische Infektiologie, DGPI Handbuch - Infektionen bei Kindern und Jugendlichen, Stuttgart: Thieme Verlag. 2013 (6th ed.) Tschudy MK, Arcara, K.M. The Harriet Lane Handbook. Philadelphia: Elsevier Mosby. 2012 (19th ed.) Aronoff GR, Bennett W.M., Berns J.S., et al. Drug Prescribing in Renal Failure. Philadelphia: American College Of Physicians. 2007 (5th ed.) British National Formulary (BNF) for children. London: Pharmaceutical Press. 2014 Schmid I. Ambulanzmanual Pädiatrie von A-Z. Heidelberg: Springer-Verlag Berlin. 2014 (4th ed.) Bradley J, Nelson, J. Nelson's Pediatric Antimicrobial Therapy. Elk Grove Village: American Academy of Pediatrics. 2014 (20th ed.) Taketomo CK, Hodding, J.H., Kraus, D.M. Pediatric & Neonatal Dosage Handbook. Lexi-Comp, Inc. 2012 (19th ed.)

3 Tab. S3 Restricted Antibiotics Requiring Special Authorization at Dr. von Hauner Children’s Hospital Cefepime Ertapenem Rifabutin Ceftaroline Fosfomycin Streptomycin Ceftobiprole Levofloxacin Sulbactam Ceftolozane/tazobacta m Linezolid Sulfadiazine Dapsone Mezlocillin Teicoplanin Daptomycin Nitrofurantoin Tigecycline

4 Tab. S4 Comparison of Average Antibiotic Use Density Expressed as Doses per 1,000 Patient-Days (PD) during Pre-Intervention and Post-Intervention Period pre-intervention period post-intervention period Difference

PD 4,510 PD 4,456

doses doses Substance total doses/1,000 PD % total doses/1,000 PD % doses/1000 PD % J01C Penicillins 2156 478.0 38.8 2496 560.1 47.8 82.1 17.2 J01CR05 Piperacillin + BLI 1404 311.3 25.3 1384 310.6 26.5 -0.7 -0.2 J01CR01-2 Other penicillins + BLI 231 51.2 4.2 399 89.5 7.6 38.3 74.8 J01CF Beta-lactamase resistant penicillins 12 2.7 0.2 62 13.9 1.2 11.3 422.9 J01CA Penicillins with extended spectrum 463 102.7 8.3 574 128.8 11.0 26.2 25.5 J01CE Beta-lactamase sensitive penicillins 46 10.2 0.8 77 17.3 1.5 7.1 69.4 J01D Cephalosporins 1780 394.7 32.0 1130 253.6 21.6 -141.1 -35.7 J01DB 1st-generation cephalosporins 78 17.3 1.4 4 0.9 0.1 -16.4 -94.8 J01DC 2nd-generation cephalosporins 1228 272.3 22.1 778 174.6 14.9 -97.7 -35.9 J01DD 3rd-generation cephalosporins 474 105.1 8.5 348 78.1 6.7 -27.0 -25.7 J01M Fluoroquinolones 256 56.8 4.6 101 22.7 1.9 -34.1 -60.1 Ciprofloxacin 202 44.8 3.6 88 19.7 1.7 -25.0 -55.9 Levofloxacin - - - 6 1.3 0.1 1.3 - Moxifloxacin 54 12.0 1.0 7 1.6 0.1 -10.4 -86.9 J01XB Nitroimidazoles (Metronidazol) 331 73.4 6.0 151 33.9 2.9 -39.5 -53.8 J01FA Macrolides 170 37.7 3.1 243 54.5 4.7 16.8 44.7 J01XA Glycopeptides 262 58.1 4.7 357 80.1 6.8 22.0 2.1 Vancomycin 248 55.0 4.5 357 80.1 6.8 25.1 45.7 Teicoplanin 14 3.1 0.3 - - - -3.1 - J01DH Carbapenems 209 46.3 3.8 402 90.2 7.7 43.9 94.7 J01FF Lincosamides (Clindamycin) 219 48.6 3.9 241 54.1 4.6 5.5 11.4 Others 107 23.7 1.9 93 20.9 1.8 -2.9 -12.0 J01G Aminoglycosides 40 8.9 0.7 10 2.2 0.2 -6.6 -74.7 J01XB Polymyxine (Colistin) 30 6.7 0.5 - - - -6.7 - Total 5560 1232.8 100.0 5224 1172.4 100.0 -60.5 -4.9