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Appendix

Olesen SW, Barnett ML, MacFadden DR, et al. Trends in outpatient prescribing practice among US older adults, 2011-2015: an observational study.

Appendix Table 1. Dosage form codes for oral and injected drugs.

Appendix Table 2: Antibiotic generic names.

Appendix Table 3. Trends in study population characteristics.

Appendix Table 4. Patterns and trends in overall antibiotic use by demography and geography.

Appendix Table 5. Trends in use of ciprofloxacin, metronidazole, and levofloxacin for gastrointestinal conditions.

Appendix Table 6. Trends in use of ciprofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole for genitourinary conditions.

Appendix Table 7. Trends in use of cephalexin, trimethoprim/sulfamethoxazole, and ciprofloxacin for skin, cutaneous, and mucosal conditions.

Appendix Methods.

1 Appendix Table 1. Dosage form codes for oral and injected drugs. Part D Events were filtered for oral and injected drugs using the values in this table. Dosage code Dosage form CA CAPSULE CE CAPSULE,DELAYED RELEASE (ENTERIC COATED) CJ CAPSULE,EXTENDED RELEASE MULTIPHASE 24HR HH AMPUL (ML) HK IV SOLUTION, PIGGYBACK PREMIX FROZEN(ML) HM INTRAVENOUS SOLUTION HP INTRAVENOUS SOLUTION, PIGGYBACK (ML) HQ DISPOSABLE SYRINGE (ML) HQ SYRINGE (ML) HS VIAL (SDV,MDV OR ADDITIVE) (EA) HS VIAL (EA) HV VIAL (SDV,MDV OR ADDITIVE) (ML) HV VIAL (ML) IF VIAL WITH THREADED PORT (EA) IG VIAL WITH THREADED PORT (ML) IM CAPSULE,IMMEDIATE, DELAY RELEASE,BIPHASE PD SUSPENSION, RECONSTITUTED, ORAL (ML) PI SOLUTION, RECONSTITUTED, ORAL PP PACKET (EA) QI SUSPENSION, EXTENDED RELEASE, RECONST. RG SUSPENSION, MICROCAPSULE RECONSTITUTED RH DROPS, VISCOUS (ML) SC SUSPENSION, ORAL (FINAL DOSE FORM) SJ SOLUTION, ORAL ST SYRUP TA TABLET TC TABLET, CHEWABLE TE TABLET, DELAYED RELEASE (ENTERIC COATED) TM TABLET, EXTENDED RELEASE 12 HR TS TABLET, EXTENDED RELEASE UP TABLET,EXTENDED RELEASE MULTIPHASE 24 HR ZD COMBINATION PACKAGE (EA)

2 Appendix Table 2. Antibiotic generic names. Part D Events were filtered for using the generic names in this table. Generic name Antibiotic AMIKACIN SULFATE amikacin amoxicillin AMOXICILLIN/ CLAV amoxicillin/clavulanate ampicillin AMPICILLIN SODIUM/ NA ampicillin AMPICILLIN TRIHYDRATE ampicillin AZITHROMYCIN azithromycin aztreonam AZTREONAM LYSINE aztreonam AZTREONAM/DEXTROSE-WATER aztreonam bacitracin BACITRACIN/ B SULFATE bacitracin BEDAQUILINE FUMARATE bedaquiline BESIFLOXACIN HCL besifloxacin BESIFLOXACIN HYDROCHLORIDE besifloxacin BISMUTH SAL/METRONID/TETRACYC metronidazole/tetracycline BISMUTH/METRONID/TETRACYCLINE metronidazole/tetracycline CAPREOMYCIN SULFATE capreomycin cefaclor cefadroxil CEFADROXIL HYDRATE cefadroxil SODIUM cefazolin CEFAZOLIN SODIUM/DEXTROSE,ISO cefazolin cefdinir PIVOXIL cefditoren HCL cefepime cefixime SODIUM cefotaxime DISODIUM cefotetan SODIUM cefoxitin CEFOXITIN SODIUM/DEXTROSE,ISO cefoxitin PROXETIL cefpodoxime cefprozil ACETATE ceftaroline ceftazidime CEFTAZIDIME IN DEXTROSE5%WATER ceftazidime CEFTAZIDIME NA/DEXTROSE,ISO ceftazidime CEFTAZIDIME PENTAHYDRATE ceftazidime CEFTAZIDIME PENTAHYDRATE/D5W ceftazidime DIHYDRATE ceftibuten SODIUM ceftriaxone AXETIL cefuroxime

3 CEFUROXIME SODIUM cefuroxime CEFUROXIME SODIUM/DEXTROSE,ISO cefuroxime CEFUROXIME SODIUM/WATER cefuroxime CEPHALEXIN cephalexin CHLORAMPHENICOL NA SUCC chloramphenicol CHLORAMPHENICOL SOD SUCC chloramphenicol GLUCONATE chlorhexidine CIPROFLOXACIN ciprofloxacin CIPROFLOXACIN HCL ciprofloxacin CIPROFLOXACIN HCL/DEXAMETH ciprofloxacin CIPROFLOXACIN LACTATE ciprofloxacin CIPROFLOXACIN LACTATE/D5W ciprofloxacin CIPROFLOXACIN/CIPROFLOXA HCL ciprofloxacin CIPROFLOXACIN/HYDROCORTISONE ciprofloxacin CLARITHROMYCIN clarithromycin CLINDAMYCIN HCL clindamycin CLINDAMYCIN PALMITATE HCL clindamycin CLINDAMYCIN PHOS/BENZOYL PEROX clindamycin CLINDAMYCIN PHOS/SKIN CLNSR 19 clindamycin CLINDAMYCIN PHOSPHATE clindamycin CLINDAMYCIN PHOSPHATE/D5W clindamycin CLINDAMYCIN/BENZ PER/HYALUR NA clindamycin CLINDAMYCIN/TRETINOIN clindamycin (COLISTIMETHATE NA) colistin cycloserine daptomycin DEMECLOCYCLINE HCL demeclocycline SODIUM dicloxacillin doripenem DOXYCYCLINE CALCIUM doxycycline DOXYCYCLINE HYCLATE doxycycline DOXYCYCLINE MONOHYDRATE doxycycline SODIUM ertapenem ERY E-SUCC/SULFISOXAZOLE erythromycin/sulfisoxazole ERYTHROMYCIN BASE erythromycin ERYTHROMYCIN BASE/ETHANOL erythromycin ERYTHROMYCIN ETHYLSUCCINATE erythromycin ERYTHROMYCIN LACTOBIONATE erythromycin ERYTHROMYCIN STEARATE erythromycin ERYTHROMYCIN/BENZOYL PEROXIDE erythromycin ETHAMBUTOL HCL ethambutol ETHIONAMIDE ethionamide FIDAXOMICIN fidaxomicin TROMETHAMINE fosfomycin GATIFLOXACIN gatifloxacin

4 GEMIFLOXACIN MESYLATE gemifloxacin GENTAMICIN IN NACL, ISO-OSM gentamicin GENTAMICIN SULFATE gentamicin GENTAMICIN SULFATE/PF gentamicin GENTAMICIN/PREDNISOL AC gentamicin /CILASTATIN SODIUM imipenem isoniazid KANAMYCIN SULFATE kanamycin LANSOPRAZOLE/AMOXICILN/CLARITH clarithromycin/amoxicillin LEVOFLOXACIN levofloxacin LEVOFLOXACIN/D5W levofloxacin LEVOFLOXACIN/DEXTROSE 5%-WATER levofloxacin LINCOMYCIN HCL lincomycin LINEZOLID linezolid meropenem METRONIDAZOLE metronidazole METRONIDAZOLE/SODIUM CHLORIDE metronidazole MINOCYCLINE HCL minocycline MINOCYCLINE HCL/SKIN CL NO.4 minocycline MOXIFLOXACIN HCL moxifloxacin MOXIFLOXACIN IN NACL (ISO-OSM) moxifloxacin IN DEXTROSE,ISO-OSM nafcillin NAFCILLIN SODIUM nafcillin NAFCILLIN SODIUM/D2.4W nafcillin NEO/POLYMYX B SULF/DEXAMETH / NEOMY SULF/BACITRA/POLYMYXIN B neomycin/bacitracin/polymyxin B NEOMY SULF/BACITRAC ZN/POLY/HC neomycin/bacitracin/polymyxin B NEOMY SULF/COLIST SUL/HC/THONZ neomycin/colistin NEOMY SULF/POLYMYX B SULF/PRED neomycin/polymyxin B NEOMY SULF/POLYMYXIN B SULFATE neomycin/polymyxin B NEOMYCIN SULFATE neomycin NEOMYCIN SULFATE/FLUOCINOLONE neomycin NEOMYCIN/BACITRA/POLYMYXIN/HC neomycin/bacitracin/polymyxin B NEOMYCIN/POLYMYXIN B SULF/HC neomycin/polymyxin B NEOMYCIN/POLYMYXN B/GRAMICIDIN neomycin/polymyxin B NITROFURANTOIN nitrofurantoin NITROFURANTOIN MACROCRYSTAL nitrofurantoin NITROFURANTOIN MONOHYD/M-CRYST nitrofurantoin NORFLOXACIN norfloxacin OFLOXACIN ofloxacin OMEPRAZOLE/CLARITH/AMOXICILLIN clarithromycin/amoxicillin SODIUM oxacillin OXACILLIN SODIUM/DEXTROSE,ISO oxacillin PAROMOMYCIN SULFATE paromomycin PEN G BENZ/PEN G PROCAINE G

5 PEN G POT/DEXTROSE-WATER penicillin G PENICILLIN G BENZATHINE penicillin G PENICILLIN G POTASSIUM penicillin G PENICILLIN G PROCAINE penicillin G PENICILLIN G SODIUM penicillin G PENICILLIN V POTASSIUM penicillin V SODIUM piperacillin PIPERACILLIN SODIUM/ piperacillin/tazobactam PIPERACILLIN-TAZO-DEXTROSE,ISO piperacillin/tazobactam POLYMYXIN B SULF/TRIMETHOPRIM polymyxin B/trimethoprim POLYMYXIN B SULFATE polymyxin B POLYMYXIN B SULFATE/TMP polymyxin B/trimethoprim PYRAZINAMIDE pyrazinamide QUINUPRISTIN/DALFOPRISTIN quinupristin/dalfopristin RETAPAMULIN retapamulin RIFABUTIN rifabutin RIFAMP/ISONIAZID/PYRAZINAMIDE rifampin/isoniazid/pyrazinamide RIFAMPIN rifampin RIFAMPIN/ISONIAZID rifampin/isoniazid RIFAMPIN/ISONIAZID/PYRAZINAMID rifampin/isoniazid/pyrazinamide RIFAPENTINE rifapentine RIFAXIMIN rifaximin STREPTOMYCIN SULFATE streptomycin SULFACETAMIDE SODIUM sulfacetamide SULFACETAMIDE/PREDNISOLONE SP sulfacetamide SULFACETM NA/PREDNISOL AC sulfacetamide SULFADIAZINE sulfadiazine SULFAMETHOXAZOLE/TRIMETHOPRIM trimethoprim/sulfamethoxazole TEDIZOLID PHOSPHATE tedizolid HCL telavancin TELITHROMYCIN telithromycin TETRACYCLINE HCL tetracycline /K CLAVULANATE ticarcillin/clavulanate TIGECYCLINE tigecycline TINIDAZOLE tinidazole TOBRAMYCIN tobramycin TOBRAMYCIN IN 0.225% NACL tobramycin TOBRAMYCIN SULF/DEXAMETHASONE tobramycin TOBRAMYCIN SULFATE tobramycin TOBRAMYCIN/DEXAMETHASONE tobramycin TOBRAMYCIN/LOTEPRED ETAB tobramycin TOBRAMYCIN/SODIUM CHLORIDE tobramycin TRIMETHOPRIM trimethoprim HCL vancomycin

6 Appendix Table 3. Trends in study population characteristics. Population characteristic Relative trend* (%) No. beneficiaries 41.3 (41.1, 41.6) Mean age –0.47 (–0.49, –0.46) Mean no. chronic conditions 0.55 (0.46, 0.64) % female –1.15 (–1.26, –1.04) % white 3.08 (3.00, 3.15) % dual –33.8 (–34.0, –33.6) % South –1.48 (–1.66, –1.30) % Midwest –2.85 (–3.10, –2.60) % West –1.42 (–1.72, –1.12) % Northeast 8.1 (7.8, 8.4) *: 2011-2015 change from Poisson regression (for first 3 characteristics) or log-binomial regression (for proportions) on population characteristic. Range shows 95% confidence interval. p < 0.001 (Wald χ2 test) for all trends.

7 Appendix Table 4. Patterns and trends in overall antibiotic use by demography and geography. Claims per 1,000 beneficiaries per year 2011 2015 Relative change* (%) Overall 1362 1362 –0.20 (–0.32, –0.07) Age 65-75 1302 1287 –0.85 (–1.02, –0.68) 76-85 1403 1431 1.2 (1.0, 1.5) 86-95 1522 1534 –0.78 (–0.12, –0.43) 96 and up 1640 1613 –4.2 (–5.4, –2.9) Sex female 1465 1471 0.80 (0.64, 0.95) male 1187 1178 –2.4 (–2.6, –2.2) Race white 1406 1416 0.48 (0.43, 0.62) Hispanic 1272 1217 –2.8 (–3.3, –2.3) other 1222 1102 –5.6 (–6.2, –5.0) black 1075 1025 –3.2 (–3.6, –2.7) Region South 1486 1518 0.91 (0.71, 1.10) Midwest 1350 1335 –1.5 (–1.7, –1.2) West 1264 1199 –4.4 (–4.7, –4.1) Northeast 1217 1245 2.9 (2.6, 3.2) *: Adjusted value for 2011-2015 change from Poisson regression on claims per beneficiary per year adjusted for dual eligibility, number of chronic conditions, and (depending on subpopulation) age, sex, race, and Census region. Range shows 95% confidence interval. p < 0.001 (Wald χ2 test) for all trends except for the overall population (p = 0.002).

8 Appendix Table 5. Trends in use of ciprofloxacin, metronidazole, and levofloxacin for gastrointestinal conditions. Claims per 1,000 beneficiaries per yeara Ciprofloxacin Metronidazole Levofloxacin Antibiotics Relative Relative Relative Diagnosis 2011 2015c 2011 2015c 2011 2015c appropriate?b changed (%) changed (%) changed (%) Infectione Potentially 36.5 32.9 –8.1 ± 0.8 29.7 28.5 –5.3 ± 0.9 17.1 19.5 14.8 ± 1.3 Other No 43.0 40.0 –5.1 ± 0.8 29.4 29.5 –0.4 ± 1.0 (n.s.) 23.9 29.5 23.0 ± 1.2 conditionsf a: Includes claims for each antibiotic linked to the given diagnosis. A single claim may be linked to multiple diagnoses, so the sum of the “2011” and “2015” columns exceeds the number of claims associated with any listed diagnosis (see eMethods). b: As determined by CDC working group (see main text Methods) c: Claims in the fourth quarter of 2015 were not linked to diagnoses. These values are projected from the first three quarters to a full-year period (see main text Methods). d: Adjusted value for 2011-2015 change from Poisson regression on claims per beneficiary per year adjusted for age, sex, race, census region, dual eligibility, and number of chronic conditions. Plus-minus contains 95% confidence interval. p < 0.001 (Wald χ2 test) for all trends except metronidazole for other conditions (p = 0.38). e: Includes intestinal infectious diseases, symptoms involving the abdomen or digestive system f: Includes other conditions of the digestive system n.s.: not significant (p > 0.05)

9 Appendix Table 6. Trends in use of ciprofloxacin, trimethoprim/sulfamethoxazole, and nitrofurantoin for genitourinary conditions. Claims per 1,000 beneficiaries per yeara Ciprofloxacin TMP/SMX Nitrofurantoin Antibiotics Relative Relative Relative Diagnosis 2011 2015c 2011 2015c 2011 2015c appropriate?b changed (%) changed (%) changed (%) Infectione Yes 92.7 82.2 –9.9 ± 0.5 40.5 36.0 –7.6 ± 0.8 44.7 43.8 2.9 ± 0.8 Other No 76.7 73.4 –4.5 ± 0.6 30.1 29.9 2.1 ± 1.0 24.0 25.1 9.9 ± 1.2 conditionsf a: Includes claims for each antibiotic linked to the given diagnosis. A single claim may be linked to multiple diagnoses, so the sum of the “2011” and “2015” columns exceeds the number of claims associated with any listed diagnosis (see eMethods). b: As determined by CDC working group (see main text Methods) c: Claims in the fourth quarter of 2015 were not linked to diagnoses. These values are projected from the first three quarters to a full-year period (see main text Methods). d: Adjusted value for 2011-2015 change from Poisson regression on claims per beneficiary per year adjusted for age, sex, race, census region, dual eligibility, and number of chronic conditions. Plus-minus contains 95% confidence interval. p < 0.001 (Wald χ2 test) for all trends. e: Includes acute pyelonephritis, renal abscess, other pyelonephritis/pyelonephrosis, unspecified kidney infection, acute cystitis, unspecified cystitis, and unspecified UTI f: Includes other symptoms involving urinary system, including dysuria

10 Appendix Table 7. Trends in use of cephalexin, trimethoprim/sulfamethoxazole, and ciprofloxacin for skin, cutaneous and mucosal conditions. Claims per 1,000 beneficiaries per yeara Cephalexin TMP/SMX Ciprofloxacin Antibiotics Relative Relative Relative Diagnosis 2011 2015c 2011 2015c 2011 2015c appropriate?b changed (%) changed (%) changed (%) Infectione Potentially 31.6 32.9 5.2 ± 1.0 22.4 21.3 –1.2 ± 1.1 12.5 9.6 –20.8 ± 1.2 Other No 44.0 48.6 10.1 ± 0.8 27.4 27.2 3.4 ± 1.0 34.4 31.2 –7.5 ± 0.8 conditionsf a: Includes claims for each antibiotic linked to the given diagnosis. A single claim may be linked to multiple diagnoses, so the sum of the “2011” and “2015” columns exceeds the number of claims associated with any listed diagnosis (see eMethods). b: As determined by CDC working group (see main text Methods) c: Claims in the fourth quarter of 2015 were not linked to diagnoses. These values are projected from the first three quarters to a full-year period (see main text Methods). d: Adjusted value for 2011-2015 change from Poisson regression on claims per beneficiary per year adjusted for age, sex, race, census region, dual eligibility, and number of chronic conditions. Plus-minus contains 95% confidence interval. p < 0.001 (Wald χ2 test) for all trends except TMP/SMX for infections (p = 0.02). e: Includes cellulitis, carbuncle/furuncle, impetigo, lymphadenitis, erysipelas, dermatophytosis, folliculitis, myositis, mastitis, necrotizing fasciitis, and infective otitis externa f: Includes inflammatory and other skin conditions, open wounds, superficial injuries, burns, diseases of the eye/adnexa, ear diseases other than otitis media and mastoiditis, symptoms of skin/integumentary tissues excluding acne, gangrene, and enlargement of lymph nodes

11 Appendix Methods.

Demographic and clinical variables We flagged beneficiaries as dual-eligible in a year if they were also enrolled in Medicaid at any time that year. Of the 27 chronic conditions defined by the Chronic Condition Warehouse, we selected the 20 conditions that have one-year reference periods to prevent a bias toward more chronic conditions among individuals who have been Medicare beneficiaries for more years.

Outcomes We considered the 13 diagnosis categories that had at least one drug with more than 20 claims per 1,000 beneficiaries per year in 2011. This filter excluded the 8 diagnosis categories with the smallest number of associated antibiotic claims: miscellaneous bacterial infections (Tiers 1 and 3), otitis media (Tiers 2 and 3), pharyngitis, flu, viral flu, and acne.

We organized the 13 diagnostic categories into four infection sites: respiratory, gastrointestinal, genitourinary, and skin/cutaneous/mucosal.

For each infection site, we considered the three antibiotics with the greatest number of contributing claims in 2011: azithromycin, levofloxacin, and amoxicillin/clavulanate for respiratory; ciprofloxacin, metronidazole, and levofloxacin for gastrointestinal; and ciprofloxacin, nitrofurantoin, and trimethoprim/sulfamethoxazole for genitourinary; and cephalexin, trimethoprim/sulfamethoxazole, and ciprofloxacin for skin/cutaneous/mucosal.

We allowed antibiotic claims to be linked to multiple diagnoses. For example, if an azithromycin claim was preceded by a pneumonia diagnosis and a sinusitis diagnosis, we counted that claim when considering azithromycin prescribing for pneumonia and when considering azithromycin prescribing for sinusitis, but we counted the claim only once when determining the trend in overall azithromycin use.

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