Table 5.
Case-Control Analysesa
| Category | Analysis 1: Liver Injury | Analysis 2: Valid Cases of Liver Injury | ||||||
|---|---|---|---|---|---|---|---|---|
| Cases, n (%) | Controls, n (%) | OR | 95% CI | Cases, n (%) | Controls, n (%) | OR | 95% CI | |
| Total no. | 607 | 6070 | – | – | 312 | 3120 | – | – |
| Nonuse | 123 (20.3) | 1680 (27.7) | REF | REF | 56 (18) | 859 (28) | REF | REF |
| Current single use | ||||||||
| Amoxicillin | 23 (3.8) | 287 (4.7) | 1.52 | 0.88–2.62 | 15 (5) | 147 (5) | 2.27 | 1.10–4.66 |
| Amoxicillin-clavulanic acid | 30 (4.9) | 272 (4.5) | 1.54 | 0.91–2.59 | 19 (6) | 151 (5) | 2.53 | 1.29–4.97 |
| Cefuroxime | 14 (2.3) | 186 (3.1) | 1.04 | 0.53–2.04 | 5 (2) | 94 (3) | 0.85 | 0.28–2.58 |
| Clarithromycin | 16 (2.6) | 189 (3.1) | 1.34 | 0.70–2.53 | 8 (3) | 96 (3) | 1.79 | 0.74–4.34 |
| Doxycycline | 19 (3.1) | 278 (4.6) | 1.35 | 0.76–2.37 | 13 (4) | 139 (4) | 2.48 | 1.18–5.18 |
| Levofloxacin | 58 (9.6) | 328 (5.4) | 1.80 | 1.16–2.78 | 33 (11) | 162 (5) | 3.19 | 1.75–5.82 |
| Moxifloxacin | 30 (4.9) | 253 (4.2) | 1.31 | 0.76–2.23 | 17 (5) | 131 (4) | 2.29 | 1.11–4.69 |
| Telithromycin | 3 (0.5) | 70 (1.2) | 0.77 | 0.21–2.88 | 2 (1) | 35 (1) | 1.72 | 0.36–8.14 |
| Recent single use | ||||||||
| Amoxicillin | 27 (4.5) | 366 (6.0) | 1.26 | 0.75–2.11 | 10 (3) | 196 (6) | 1.24 | 0.57–2.70 |
| Amoxicillin-clavulanic acid | 26 (4.3) | 303 (5.0) | 1.03 | 0.59–1.79 | 13 (4) | 167 (5) | 0.98 | 0.44–2.16 |
| Cefuroxime | 12 (2.0) | 172 (2.8) | 0.74 | 0.36–1.53 | 6 (2) | 99 (3) | 0.90 | 0.33–2.43 |
| Clarithromycin | 12 (2.0) | 262 (4.3) | 0.86 | 0.44–1.67 | 6 (2) | 126 (4) | 1.18 | 0.46–3.04 |
| Doxycycline | 18 (3.0) | 266 (4.4) | 1.28 | 0.70–2.35 | 9 (3) | 135 (4) | 1.44 | 0.62–3.38 |
| Levofloxacin | 57 (9.4) | 357 (5.9) | 1.21 | 0.78–1.87 | 27 (9) | 158 (5) | 1.86 | 0.98–3.55 |
| Moxifloxacin | 25 (4.1) | 305 (5.0) | 0.94 | 0.55–1.59 | 12 (4) | 171 (5) | 0.99 | 0.47–2.06 |
| Telithromycin | 4 (0.7) | 88 (1.5) | 0.95 | 0.32–2.82 | 3 (1) | 43 (1) | 2.18 | 0.58–8.12 |
| Current multiple use | 37 (6.1) | 120 (2.0) | 2.46 | 1.45–4.18 | 20 (6) | 61 (2) | 3.23 | 1.56–6.72 |
| Recent multiple use | 36 (5.9) | 183 (3.0) | 1.28 | 0.76–2.16 | 15 (5) | 102 (3) | 1.37 | 0.66–2.86 |
| Mean age (yrs) | 56.5 | 56.1 | 1.02 | 0.99–1.06 | 55.0 | 54.7 | 1.01 | 0.96–1.07 |
| Prior liver disease | 81 (13.3) | 97 (1.6) | 2.60 | 1.59–4.24 | 32 (10) | 64 (2) | 1.47 | 0.74–2.93 |
| Prior disease ofbiliary tract or pancreas | 202 (33.3) | 220 (3.6) | 7.27 | 5.47–9.66 | 105 (34) | 122 (4) | 7.95 | 5.34–11.84 |
| Prior or concurrent use of other potentially hepatotoxic drugs | 407 (67.1) | 3046 (50.2) | 1.13 | 0.88–1.44 | 205 (66) | 1534 (49) | 1.14 | 0.81–1.59 |
| Individual comorbidities of the Deyo-Charlson Comorbidity Index | ||||||||
| Myocardial infarction | 73 (12.0) | 194 (3.2) | 1.29 | 0.85–1.96 | 25 (8) | 88 (3) | 0.92 | 0.47–1.82 |
| Congestive heart failure | 154 (25.4) | 367 (6.1) | 2.37 | 1.61–3.50 | 66 (21) | 164 (5) | 2.47 | 1.41–4.33 |
| Peripheral vascular disease | 71 (11.7) | 257 (4.2) | 0.98 | 0.64–1.50 | 29 (9) | 118 (4) | 0.98 | 0.52–1.86 |
| Cerebrovascular disease | 114 (18.8) | 529 (8.7) | 0.78 | 0.54–1.11 | 56 (18) | 255 (8) | 0.84 | 0.50–1.40 |
| Dementia | 15 (2.5) | 69 (1.1) | 1.89 | 0.86–4.17 | 7 (2) | 36 (1) | 1.48 | 0.47–4.71 |
| Chronic pulmonary disease | 233 (38.4) | 1298 (21.4) | 1.02 | 0.76–1.37 | 121 (39) | 659 (21) | 1.20 | 0.79–1.82 |
| Rheumatologic disease | 41 (6.8) | 141 (2.3) | 1.76 | 1.06–2.93 | 17 (5) | 67 (2) | 1.61 | 0.74–3.54 |
| Peptic ulcer disease | 42 (6.9) | 112 (1.9) | 1.57 | 0.93–2.65 | 24 (8) | 56 (2) | 2.06 | 1.01–4.21 |
| Mild liver disease | 28 (4.6) | 11 (0.2) | 2.39 | 0.84–6.80 | 8 (3) | 7 (0) | 0.70 | 0.12–4.00 |
| Mild-to-moderate diabetes mellitus | 153 (25.2) | 775 (12.8) | 0.77 | 0.55–1.08 | 66 (21) | 372 (12) | 0.77 | 0.47–1.25 |
| Hemiplegia or paraplegia | 9 (1.5) | 29 (0.5) | 0.53 | 0.17–1.66 | 5 (2) | 17 (1) | 0.78 | 0.14–4.26 |
| Moderate-to-severe renal disease | 86 (14.2) | 152 (2.5) | 2.12 | 1.36–3.29 | 30 (10) | 68 (2) | 1.50 | 0.75–2.98 |
| Diabetes with complications | 47 (7.7) | 166 (2.7) | 0.88 | 0.51–1.49 | 18 (6) | 86 (3) | 0.78 | 0.35–1.77 |
| Malignancy | 164 (27.0) | 565 (9.3) | 1.27 | 0.87–1.86 | 85 (27) | 294 (9) | 1.15 | 0.66–1.99 |
| Moderate-to-severe liver disease | 17 (2.8) | 1 (0.0) | 19.91 | 1.45–274.02 | 9 (3) | 0 (0) | NE | NE |
| Metastatic solid tumor | 62 (10.2) | 111 (1.8) | 1.40 | 0.83–2.38 | 39 (13) | 62 (2) | 2.11 | 1.05–4.24 |
| Acquired immunodeficiency syndrome | 0 (0.0) | 0 (0.0) | NE | NE | 0 (0) | 0 (0) | NE | NE |
| Deyo-Charlson Comorbidity Index score | ||||||||
| 0 | 176 (29.0) | 3544 (58.4) | REF | REF | 100 (32) | 1850 (59) | REF | REF |
| 1–2 | 159 (26.2) | 1724 (28.4) | 1.24 | 0.88–1.75 | 84 (27) | 874 (28) | 1.07 | 0.66-1.72 |
| ≥ 3 | 272 (44.8) | 802 (13.2) | 1.89 | 1.06–3.37 | 128 (41) | 396 (13) | 1.80 | 0.77-4.20 |
| No. of hospitalization days | ||||||||
| 0 | 344 (56.7) | 5386 (88.7) | REF | REF | 197 (63) | 2796 (90) | REF | REF |
| 1–3 | 48 (7.9) | 237 (3.9) | 1.25 | 0.81–1.92 | 20 (6) | 101 (3) | 0.92 | 0.46–1.84 |
| ≥ 4 | 215 (35.4) | 447 (7.4) | 2.10 | 1.56–2.83 | 95 (30) | 223 (7) | 1.72 | 1.12-2.63 |
| No. of outpatient visits | ||||||||
| 0 | 45 (7.4) | 1793 (29.5) | REF | REF | 23 (7) | 938 (30) | REF | REF |
| 1–5 | 246 (40.5) | 3018 (49.7) | 2.20 | 1.54–3.14 | 142 (46) | 1538 (49) | 2.75 | 1.68–4.51 |
| ≥ 6 | 316 (52.1) | 1259 (20.7) | 3.04 | 2.03–4.54 | 147 (47) | 644 (21) | 2.77 | 1.56–4.91 |
| No. of unique prescription drugs | ||||||||
| 0–2 | 36 (5.9) | 1222 (20.1) | REF | REF | 23 (7) | 1538 (49) | REF | REF |
| 3–5 | 95 (15.7) | 1987 (32.7) | 1.30 | 0.85–1.99 | 142 (46) | 644 (21) | 1.46 | 0.80–2.67 |
| 6–10 | 175 (28.8) | 1871 (30.8) | 2.12 | 1.37–3.30 | 147 (47) | 312 (11) | 2.36 | 1.27–4.40 |
| ≥ 11 | 301 (49.6) | 990 (16.3) | 3.33 | 2.04–5.43 | 938 (30) | 312 (11) | 3.58 | 1.77–7.21 |
| Category | Analysis 3: Restricted Liver Injury | Analysis 4: Severe Liver Injury | ||||||
|---|---|---|---|---|---|---|---|---|
| Cases, n (%) | Controls, n (%) | OR | 95% CI | Cases, n (%) | Controls, n (%) | OR | 95% CI | |
| Total no. | 63 | 630 | – | – | 82 | 820 | – | – |
| Nonuse | 13 (21) | 162 (26) | REF | REF | 9 (11.0) | 230 (28.1) | REF | REF |
| Current use | ||||||||
| Amoxicillin | 6 (10) | 34 (5) | 3.71 | 1.09–12.70 | 7 (8.5) | 40 (4.9) | 6.94 | 1.88–25.63 |
| Amoxicillin-clavulanic acid | 7 (11) | 31 (5) | 4.03 | 1.24–13.07 | 5 (6.1) | 41 (5.0) | 6.04 | 1.42–25.72 |
| Cefuroxime | 1 (2) | 23 (4) | 0.40 | 0.04–4.25 | 3 (3.7) | 23 (2.8) | 2.12 | 0.32–14.09 |
| Clarithromycin | 1 (2) | 26 (4) | 0.88 | 0.10–7.85 | 2 (2.4) | 25 (3.1) | 2.77 | 0.39–19.69 |
| Doxycycline | 0 (0) | 32 (5) | 0.00 | 0.00–NE | 3 (3.7) | 34 (4.2) | 2.54 | 0.48–13.46 |
| Levofloxacin | 8 (13) | 41 (7) | 3.45 | 1.13–10.57 | 13 (15.9) | 38 (4.6) | 7.19 | 2.05–25.22 |
| Moxifloxacin | 5 (8) | 32 (5) | 2.92 | 0.82–10.44 | 3 (3.7) | 37 (4.5) | 3.10 | 0.55–17.33 |
| Telithromycin | 1 (2) | 4 (1) | 5.70 | 0.44–73.74 | 1 (1.2) | 9 (1.1) | 5.67 | 0.41–78.34 |
| Recent single use | ||||||||
| Amoxicillin | 0 (0) | 42 (7) | 0.00 | 0.00–NE | 3 (3.7) | 47 (5.7) | 2.26 | 0.47–10.93 |
| Amoxicillin-clavulanic acid | 2 (3) | 35 (6) | 1.00 | 0.17–5.90 | 2 (2.4) | 41 (5.0) | 0.68 | 0.07–7.13 |
| Cefuroxime | 1 (2) | 26 (4) | 0.87 | 0.10–7.40 | 1 (1.2) | 30 (3.7) | 0.31 | 0.02–4.59 |
| Clarithromycin | 3 (5) | 30 (5) | 2.18 | 0.50–9.43 | 1 (1.2) | 28 (3.4) | 1.62 | 0.16–16.26 |
| Doxycycline | 3 (5) | 18 (3) | 2.35 | 0.48–11.44 | 1 (1.2) | 42 (5.1) | 0.80 | 0.08–7.93 |
| Levofloxacin | 2 (3) | 28 (4) | 0.80 | 0.13–5.06 | 8 (9.8) | 39 (4.8) | 4.92 | 1.25–19.44 |
| Moxifloxacin | 3 (5) | 33 (5) | 1.07 | 0.23–4.91 | 5 (6.1) | 56 (6.8) | 1.25 | 0.27–5.71 |
| Telithromycin | 2 (3) | 6 (1) | 15.44 | 2.27–105.13 | 0 (0.0) | 16 (2.0) | 0.00 | 0.00–NE |
| Current multiple use | 3 (5) | 7 (1) | 10.87 | 1.95–60.53 | 7 (8.5) | 13 (1.6) | 12.27 | 2.84–53.04 |
| Recent multiple use | 2 (3) | 20 (3) | 1.55 | 0.28–8.59 | 8 (9.8) | 31 (3.8) | 3.86 | 1.07–13.98 |
| Mean age (yrs) | 50.4 | 49.8 | 1.07 | 0.95–1.20 | 55.7 | 55.3 | 1.05 | 0.94–1.17 |
| Prior liver disease | 2 (3) | 11 (2) | 0.50 | 0.07–3.67 | 9 (11.0) | 10 (1.2) | 1.52 | 0.39–5.92 |
| Prior disease of biliary tract or pancreas | 16 (25) | 26 (4) | 6.09 | 2.39–15.50 | 29 (35.4) | 32 (3.9) | 9.05 | 3.74–21.90 |
| Prior or concurrent use of other potentially hepatotoxic drugs | 37 (59) | 285 (45) | 1.10 | 0.53–2.29 | 55 (67.1) | 380 (46.3) | 1.22 | 0.59–2.51 |
| Individual comorbidities of the Deyo-Charlson Comorbidity Index | ||||||||
| Myocardial infarction | 4 (6) | 11 (2) | NAb | NAb | 5 (6.1) | 21 (2.6) | NAb | NAb |
| Congestive heart failure | 6 (10) | 18 (3) | NAb | NAb | 16 (19.5) | 36 (4.4) | NAb | NAb |
| Peripheral vascular disease | 2 (3) | 12 (2) | NAb | NAb | 13 (15.9) | 30 (3.7) | NAb | NAb |
| Cerebrovascular disease | 9 (14) | 32 (5) | NAb | NAb | 13 (15.9) | 60 (7.3) | NAb | NAb |
| Dementia | 0 (0) | 1 (0) | NAb | NAb | 1 (1.2) | 7 (0.9) | NAb | NAb |
| Chronic pulmonary disease | 18 (29) | 114 (18) | NAb | NAb | 34 (41.5) | 165 (20.1) | NAb | NAb |
| Rheumatologic disease | 2 (3) | 10 (2) | NAb | NAb | 6 (7.3) | 22 (2.7) | NAb | NAb |
| Peptic ulcer disease | 2 (3) | 12 (2) | NAb | NAb | 7 (8.5) | 15 (1.8) | NAb | NAb |
| Mild liver disease | 0 (0) | 0 (0) | NAb | NAb | 2 (2.4) | 2 (0.2) | NAb | NAb |
| Mild-to-moderate diabetes mellitus | 10 (16) | 60 (10) | NAb | NAb | 17 (20.7) | 102 (12.4) | NAb | NAb |
| Hemiplegia or paraplegia | 0 (0) | 2 (0) | NAb | NAb | 1 (1.2) | 5 (0.6) | NAb | NAb |
| Moderate-to-severe renal disease | 0 (0) | 9 (1) | NAb | NAb | 7 (8.5) | 21 (2.6) | NAb | NAb |
| Diabetes with complications | 1 (2) | 10 (2) | NAb | NAb | 6 (7.3) | 32 (3.9) | NAb | NAb |
| Malignancy | 6 (10) | 38 (6) | NAb | NAb | 31 (37.8) | 74 (9.0) | NAb | NAb |
| Moderate-to-severe liver disease | 1 (2) | 0 (0) | NAb | NAb | 2 (2.4) | 0 (0.0) | NAb | NAb |
| Metastatic solid tumor | 3 (5) | 8 (1) | NAb | NAb | 7 (8.5) | 12 (1.5) | NAb | NAb |
| Acquired immunodeficiency syndrome | 0 (0) | 0 (0) | NAb | NAb | 0 (0.0) | 0 (0.0) | NAb | NAb |
| Deyo-Charlson Comorbidity Index score | ||||||||
| 0 | 31 (49) | 411 (65) | REF | REF | 23 (28.1) | 487 (59.4) | REF | REF |
| 1–2 | 21 (33) | 170 (27) | 1.37 | 0.66–2.84 | 25 (30.5) | 234 (28.5) | 1.86 | 0.84–4.11 |
| ≥ 3 | 11 (17) | 49 (8) | 1.84 | 0.59–5.77 | 34 (41.5) | 99 (12.1) | 5.20 | 1.84–14.69 |
| No. of hospitalization days | ||||||||
| 0 | 46 (73) | 583 (93) | REF | REF | 46 (56.1) | 746 (91.0) | REF | REF |
| 1–3 | 2 (3) | 14 (2) | 1.14 | 0.19–7.06 | 7 (8.5) | 26 (3.2) | 2.95 | 0.82–10.59 |
| ≥ 4 | 15 (24) | 33 (5) | 3.23 | 1.32–7.90 | 29 (35.4) | 48 (5.9) | 3.34 | 1.41–7.88 |
| No. of outpatient visits | ||||||||
| 0 | 10 (16) | 209 (33) | REF | REF | 4 (4.9) | 262 (32.0) | REF | REF |
| 1–5 | 38 (60) | 308 (49) | 1.74 | 0.72–4.18 | 45 (54.9) | 402 (49.0) | 5.07 | 1.57–16.42 |
| ≥ 6 | 15 (24) | 113 (18) | 0.87 | 0.26–2.95 | 33 (40.2) | 156 (19.0) | 3.49 | 0.89–13.65 |
| No. of unique prescription drugs | ||||||||
| 0–2 | 6 (10) | 153 (24) | REF | REF | 3 (3.7) | 163 (19.9) | REF | REF |
| 3–5 | 14 (22) | 223 (35) | 1.27 | 0.41–3.92 | 15 (18.3) | 302 (36.8) | 1.46 | 0.33–6.45 |
| 6-10 | 24 (38) | 177 (28) | 2.61 | 0.83–8.20 | 27 (32.9) | 244 (29.8) | 3.21 | 0.72–14.34 |
| ≥ 11 | 19 (30) | 77 (12) | 2.84 | 0.75–10.71 | 37 (45.1) | 111 (13.5) | 4.53 | 0.92–22.18 |
CI = confidence interval; NA = not available; NE = not estimable; OR = odds ratio; REF = reference category.
a
In addition to the variables shown, Analyses 1 and 2 included variables for current single use with recent use of another antimicrobial (data not shown), whereas in Analyses 3 and 4, current single use of a given study antimicrobial with concurrent recent use of another study antimicrobial was combined with current single use of the antimicrobial to which the patient was currently exposed.
b
Model was estimated without this variable.