Table 2.
Comparative Risk of Adverse Events by Antibiotic Agent
| Outcome | Follow-up, days | Antibiotic Agenta | No. of Events | Person-Time, days | Rate per 10 000 Person-Days | Crude HR (95% CI) | Weighted HR (95% CI) |
|---|---|---|---|---|---|---|---|
| Adverse drug events | |||||||
| Dermatologic | |||||||
| Skin rash | 14 | Nitrofurantoin | 335 | 3 605 771 | 0.93 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 919 | 4 166 723 | 2.21 | 2.38 (2.10–2.70) | 2.42 (2.13–2.75) | ||
| Fluoroquinolone | 453 | 6 637 803 | 0.68 | .73 (.64–.85) | .76 (.64–.89) | ||
| Broad-spectrum BL | 25 | 165 296 | 1.51 | 1.63 (1.08–2.45) | 1.70 (1.49–1.95) | ||
| Narrow-spectrum BL | 42 | 400 929 | 1.05 | 1.13 (.82–1.55) | 1.13 (.97–1.31) | ||
| AMX/AMP | 11 | 96 631 | 1.14 | 1.23 (.67–2.24) | .75 (.63–.88) | ||
| Urticaria | 14 | Nitrofurantoin | 353 | 3 625 362 | 0.97 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 598 | 4 191 050 | 1.43 | 1.47 (1.29–1.68) | 1.37 (1.19–1.57) | ||
| Fluoroquinolone | 226 | 6 676 869 | 0.34 | .35 (.29–.41) | .35 (.29–.43) | ||
| Broad-spectrum BL | 15 | 166 103 | 0.90 | .93 (.55–1.56) | .76 (.65–.89) | ||
| Narrow-spectrum BL | 18 | 403 783 | 0.45 | .46 (.29–.73) | .42 (.34–.50) | ||
| AMX/AMP | 4 | 97 041 | NE | NE | |||
| Stevens-Johnson syndrome | 14 | Nitrofurantoin | 1 | 3 649 427 | 0.00 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 7 | 4 217 227 | 0.02 | NE | NE | ||
| Fluoroquinolone | 3 | 6 717 509 | 0.00 | NE | NE | ||
| Broad-spectrum BL | 0 | 167 462 | 0.00 | NE | NE | ||
| Narrow-spectrum BL | 0 | 406 219 | 0.00 | NE | NE | ||
| AMX/AMP | 0 | 97 686 | 0.00 | NE | NE | ||
| Hypersensitivity | |||||||
| Anaphylaxis | 3 (index + 2) | Nitrofurantoin | 10 | 837 830 | 0.12 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 12 | 985 021 | 0.12 | 1.02 (.44–2.36) | .92 (.38–2.26) | ||
| Fluoroquinolone | 11 | 1 520 232 | 0.07 | .61 (.26–1.43) | .55 (.20–1.56) | ||
| Broad-spectrum BL | 2 | 38 549 | 0.52 | NE | NE | ||
| Narrow-spectrum BL | 2 | 93 249 | 0.21 | NE | NE | ||
| AMP/AMX | 1 | 23 099 | 0.43 | NE | NE | ||
| Angioedema/laryngeal edema | 3 (index + 2) | Nitrofurantoin | 20 | 837 229 | 0.24 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 19 | 984 329 | 0.19 | .81 (.43–1.51) | .69 (.35–1.37) | ||
| Fluoroquinolone | 37 | 1 519 165 | 0.24 | 1.02 (.59–1.76) | .93 (.50–1.75) | ||
| Broad-spectrum BL | 1 | 38 516 | 0.26 | NE | NE | ||
| Narrow-spectrum BL | 3 | 93 163 | 0.32 | NE | NE | ||
| AMP/AMX | 1 | 23 067 | 0.43 | NE | NE | ||
| Hypersensitivity reaction | 14 | Nitrofurantoin | 316 | 3 623 701 | .87 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 1012 | 4 187 077 | 2.42 | 2.78 (2.45–3.15) | 2.62 (2.30–2.98) | ||
| Fluoroquinolone | 377 | 6 670 039 | .57 | .65 (.56–.75) | .68 (.57–.80) | ||
| Broad-spectrum BL | 11 | 165 933 | .66 | .76 (.42–1.39) | .53 (.44–.64) | ||
| Narrow-spectrum BL | 32 | 403 004 | .79 | .91 (.63–1.31) | .64 (.53–.76) | ||
| AMP/AMX | 5 | 96 897 | .52 | .59 (.24–1.43) | .60 (.50–.72) | ||
| Gastrointestinal | |||||||
| Abdominal pain | 14 | Nitrofurantoin | 4199 | 3 244 168 | 12.94 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 5589 | 3 698 287 | 15.11 | 1.16 (1.12–1.21) | 1.14 (1.09–1.19) | ||
| Fluoroquinolone | 10 532 | 5 728 628 | 18.38 | 1.42 (1.37–1.48) | 1.36 (1.31–1.42) | ||
| Broad-spectrum BL | 269 | 137 346 | 19.59 | 1.51 (1.34–1.71) | 1.52 (1.46–1.58) | ||
| Narrow-spectrum BL | 547 | 321 443 | 17.02 | 1.32 (1.20–1.44) | 1.30 (1.25–1.35) | ||
| AMX/AMP | 157 | 83 715 | 18.75 | 1.44 (1.23–1.69) | 1.45 (1.39–1.50) | ||
| Nausea/vomiting | 14 | Nitrofurantoin | 1299 | 3 510 085 | 3.70 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 1817 | 4 042 451 | 4.49 | 1.21 (1.13–1.30) | 1.18 (1.10–1.28) | ||
| Fluoroquinolone | 2781 | 6 409 201 | 4.34 | 1.18 (1.10–1.26) | 1.17 (1.08–1.26) | ||
| Broad-spectrum BL | 97 | 157 715 | 6.15 | 1.66 (1.35–2.04) | 1.52 (1.42–1.63) | ||
| Narrow-spectrum BL | 200 | 374 650 | 5.34 | 1.44 (1.24–1.67) | 1.11 (1.03–1.20) | ||
| AMX/AMP | 34 | 93 028 | 3.65 | .98 (.70–1.38) | .95 (.88–1.03) | ||
| Cardiovascular | |||||||
| Aortic aneurysm and dissection | 90 | Nitrofurantoin | 16 | 18 585 791 | 0.01 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 16 | 21 688 918 | 0.01 | .86 (.43–1.72) | 1.10 (.56–2.17) | ||
| Fluoroquinolone | 32 | 35 015 856 | 0.01 | 1.06 (.58–1.94) | 1.02 (.51–2.02) | ||
| Broad-spectrum BL | 4 | 835 791 | 0.05 | NE | NE | ||
| Narrow-spectrum BL | 0 | 2 066 881 | 0.00 | NE | NE | ||
| AMX/AMP | 0 | 483 202 | 0.00 | NE | NE | ||
| Renal | |||||||
| Acute renal failure | 14 | Nitrofurantoin | 21 | 3 649 482 | 0.06 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 57 | 4 217 219 | 0.14 | 2.33 (1.41–3.84) | 2.56 (1.55–4.25) | ||
| Fluoroquinolone | 93 | 6 717 353 | 0.14 | 2.42 (1.51–3.89) | 2.39 (1.43–3.97) | ||
| Broad-spectrum BL | 1 | 167 468 | 0.06 | NE | NE | ||
| Narrow-spectrum BL | 5 | 406 236 | 0.12 | 2.14 (.81–5.68) | 1.20 (.67–2.14) | ||
| AMX/AMP | 1 | 97 675 | 0.10 | NE | NE | ||
| Neuromuscular and skeletal | |||||||
| Tendinopathy (including tendon rupture) |
90 | Nitrofurantoin | 433 | 18 475 398 | 0.23 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 454 | 21 566 921 | 0.21 | .90 (.79–1.02) | .92 (.80–1.06) | ||
| Fluoroquinolone | 1019 | 34 787 372 | 0.29 | 1.25 (1.12–1.40) | 1.19 (1.04–1.35) | ||
| Broad-spectrum BL | 24 | 830 851 | 0.29 | 1.23 (.82–1.86) | 1.48 (1.31–1.67) | ||
| Narrow-spectrum BL | 52 | 2 054 294 | 0.25 | 1.08 (.81–1.44) | 1.09 (.96–1.25) | ||
| AMX/AMP | 10 | 481 107 | 0.21 | .89 (.47–1.66) | .86 (.75–.99) | ||
| Potential microbiome-related adverse events | |||||||
| Gastrointestinal | |||||||
| Non–Clostridium difficile diarrhea | 30 | Nitrofurantoin | 1046 | 7 146 911 | 1.46 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 1268 | 8 259 018 | 1.54 | 1.05 (.97–1.14) | 1.02 (.93–1.11) | ||
| Fluoroquinolone | 2255 | 13 193 422 | 1.71 | 1.17 (1.09–1.26) | 1.14 (1.05–1.24) | ||
| Broad-spectrum BL | 86 | 323 185 | 2.66 | 1.82 (1.46–2.26) | 1.78 (1.65–1.92) | ||
| Narrow-spectrum BL | 189 | 783 229 | 2.41 | 1.65 (1.41–1.92) | 1.50 (1.38–1.62) | ||
| AMX/AMP | 45 | 187 533 | 2.40 | 1.63 (1.21–2.20) | 1.54 (1.43–1.67) | ||
| C. difficile infection | 90 | Nitrofurantoin | 8 | 18 585 361 | 0.00 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 5 | 21 689 566 | 0.00 | .54 (.18–1.64) | .50 (.15–1.67) | ||
| Fluoroquinolone | 61 | 35 018 524 | 0.02 | 4.07 (1.95–8.50) | 4.22 (1.96–9.10) | ||
| Broad-spectrum BL | 3 | 835 944 | 0.04 | NE | NE | ||
| Narrow-spectrum BL | 3 | 2 066 940 | 0.01 | NE | NE | ||
| AMX/AMP | 1 | 483 186 | 0.02 | NE | NE | ||
| Genitourinary | |||||||
| Vaginitis/vulvovaginal candidiasis | 30 | Nitrofurantoin | 3978 | 6 639 901 | 5.99 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 4335 | 7 711 026 | 5.62 | .94 (.90–.98) | .98 (.94–1.03) | ||
| Fluoroquinolone | 6839 | 12 265 099 | 5.58 | .93 (.90–.97) | .98 (.94–1.03) | ||
| Broad-spectrum BL | 224 | 300 178 | 7.46 | 1.24 (1.09–1.42) | 1.32 (1.26–1.37) | ||
| Narrow-spectrum BL | 550 | 743 141 | 7.40 | 1.24 (1.13–1.35) | 1.30 (1.25–1.35) | ||
| AMX/AMP | 144 | 172 293 | 8.36 | 1.39 (1.18–1.64) | 1.59 (1.53–1.65) | ||
| Respiratory/pulmonary | |||||||
| Pneumonia | 90 | Nitrofurantoin | 353 | 18 540 894 | 0.19 | 1 [Reference] | 1 [Reference] |
| TMP/SMX | 431 | 21 628 868 | 0.20 | 1.05 (.91–1.21) | 1.04 (.90–1.21) | ||
| Fluoroquinolone | 774 | 34 917 175 | 0.22 | 1.17 (1.03–1.33) | 1.12 (.97–1.29) | ||
| Broad-spectrum BL | 35 | 832 813 | 0.42 | 2.20 (1.56–3.11) | 2.21 (1.94–2.50) | ||
| Narrow-spectrum BL | 50 | 2 062 231 | 0.24 | 1.27 (.95–1.71) | 1.49 (1.30–1.71) | ||
| AMX/AMP | 11 | 481 486 | 0.23 | 1.19 (.66–2.18) | 1.02 (.88–1.18) |
Abbreviations: AMX/AMP, amoxicillin or ampicillin; BL, β-lactam; CI, confidence interval; HR, hazard ratio; NE, not estimable due to small case counts; TMP/SMX, trimethoprim-sulfamethoxazole.
aFor HR estimation, we required ≥5 adverse event cases in both the reference antibiotic treatment group (ie, nitrofurantoin) and the comparator treatment group to ensure stability of the effect estimate.