Table 1.
Select Characteristics of the 19 Publications Included in This Review
| Author (Publication Year) |
Study Design, Period, Region | Treatment Arms, No. of Patients | Dosing and Duration | Patient Demographics | Diagnosis and Source of Infection | Mortality | Clinical Outcomes | Microbiologic Outcomes |
|---|---|---|---|---|---|---|---|---|
| Clinical studies comparing TMP-SMX to fluoroquinolones | ||||||||
| Czosnowski (2011) [57] | Retrospective, single-center, 1997–2007, USA | 101 pts; 77 TMP-SMX, 14 CIP | TMP-SMX 11.2 mg/kg/d, 11 d | Adult trauma pts; age 40 y, 76% male, APACHE II 17; 0% IC | VAP | ACM 13%; VAP-related 7% | Clinical success 87%, clinical + microbiological success 82% | NR |
| Cho (2014) [58] | Retrospective, single-center, 2000–2012, Korea | 86 pts; 53 TMP-SMX, 35 LVX | NR | Adults; age 58 y; MV 16.3%; IC 18.6%; septic shock 23.3% | BSI | 30 d ACM; 27.5% TMP-SMX; 20% LVX (P = .43) | LOS: 25 d TMP-SMX, 27 d LVX (P = .82); recurrent bacteremia: 11.9% TMP-SMX, 5.7% LVX (P = .46) | 50% of pts with recurrence developed LVX-R isolates |
| Wang (2014) [59] | Retrospective, single-center, 2008–2011, USA | 98 pts; 35 TMP-SMX, 63 FQ (48 LVX, 15 CIP) | TMP-SMX 8 d (IQR, 2–28); FQ 9 d (IQR, 2–38 d) (P = .265) Median daily dose: TMP-SMX 7.8 mg/kg/d; LVX 500 mg/d; CIP 1000 mg/d (PO) |
Adults; age 73 y; 24% ICU; 39% cancer, 43% recent surgery | PNA 56% (TMP-SMX 49%; FQ 60%); 77% polymicrobial infection (TMP-SMX 63%, FQ 84%) | 30 d mortality: FQ 31%, TMP-SMX 22% (P = .42) In-hospital mortality: FQ 25%; TMP-SMX 20% (P = .55) In-hospital mortality: PNA, 31%; BSI 33% |
Overall, clinical success 55% (FQ 52%; TMP-SMX 61%) (P = .451) PNA: clinical success 50%; BSI: clinical success 40% |
Cure at EOT: TMP-SMX 65% (13/20); FQ 62% (23/37) (P = .832) PNA: cure, 50%; BSI: cure, 40% Resistance on repeat culture within 30 d: FQ 30%; TMP-SMX 20% (P = .426) Reduced % S: TMP-SMX 96%→ 71%; LVX 82%→ 29% |
| Watson (2018) [60] | Retrospective, single-center, 2004–2014, USA | 54 pts; 32 TMP-SMX, 22 FQ | NR | Adults; age 50–53 y; APACHE II 12–16; MV 27%–37%; IC 36%–50% | BSI | Inpatient mortality: 13.6% FQ; 31.3% TMP-SMX (P = .20) | LOS: 9 d FQ; 15 d TMP-SMX (P = .12) | Baseline: TMP-SMX 0%; FQ 9% |
| Samonis (2012) [61] | Retrospective, single-center, 2005–2010, Greece | 68 pts; 5 TMP-SMX, 23 CIP | NR | Adults; age 71 y, 21% ICU; 66% IC | PNA 54% BSI 16% |
ACM 14.7% IRM 4.4% |
78% clinical cure, LOS 17 d | NR |
| Nys (2019) [62] | Retrospective, single-center, 2012–2016, USA | 76 pts; 45 TMP-SMX, 31 LVX | TMP-SMX 10.3 mg/kg/d, LVX 500 mg/d 13 d |
Adults; age 63 y; APACHE II 16; MV 47%; ICU 55%, IC 17% | PNA 92% | 28 d ACM 14.5%; NR for treatment groups | Clinical cure: 82.2% TMP-SMX, 74.2% LVX (P = .40); ME: 84.4% TMP-SMX, 77.4% LVX (P = .55) | 19.3% developed R in LVX, 6.7% TMP-SMX AEs: 4% TMP-SMX, 0% LVX (P = .26) |
| Clinical studies comparing TMP-SMX to fluoroquinolones and/or tetracyclines | ||||||||
| Tekçe (2012) [63] | Retrospective, single-center, 2008–2010, Turkey | 45 pts; 26 TMP-SMX, 19 TGC | TMP-SMX, 800/160 mg Q8h; TGC, 50 mg Q12h 14–21d | Adults; age 65.4 y, 87% ICU, 62.2% APACHE II >20, 60% MV | PNA 51%, surgical site 29%, 11% BSI | 30 d ACM: 31% TMP-SMX, 21% TGC (P = .52) |
14 d clinical improvement: 69.2% TMP-SMX, 68.4 TGC (P = .954) |
NR |
| Hand (2016) [64] | Retrospective, single-center, 2006–2012, USA | 45 pts; 22 TMP-SMX, 23 MIN | Mean daily dose (PO/IV): TMP-SMX, 8.5 mg/kg/d; MIN, 200 mg Median (range): TMP-SMX, 7 d (3–15); MIN, 13 d (4–32) |
Adults, age: TMP-SMX 49 y, MIN 54 y MV: MIN 57% (13/23); TMP-SMX 45% (10/22) Chronic lung disease: MIN 52% (12/23); TMP-SMX 9% (2/22) |
PNA: MIN 69% (16/23); TMP-SMX 59% (13/22); polymicrobial 65%–82% | TMP-SMX 9% (2/22); MIN 8.7% (2/23) | Clinical failure: TMP-SMX 41% (9/22); MIN 30% (7/23) (P = .67) | Positive repeat cultures: MIN 21.7% (5/23); TMP-SMX 31.8% (7/22) No resistance in follow-up cultures within 30 d posttherapy |
| Ebara (2017) [65] | Retrospective, 2 centers, 2007–2013, Japan | 44 adults; 3 TMP-SMX, 15 FQ, 10 MIN, 16 other | NR | Adults; age 48.9 y; 52.3% ICU, 54.5% MV, 36.5% malignancy, 31.5% neutropenia | BSI | 30 d mortality 37.5%; 90 d mortality 62.5%; no difference between treated (42%) and untreated (70%) | NR | NR |
| Junco (2021) [66] | Retrospective, single-center, 2010–2016, USA | 284 pts; 217 TMP-SMX, 39 MIN, 28 FQ | TMP-SMX 9.7 mg/kg/d, MIN 200 mg/d, CIP 800 mg/d LVX 750 mg/d, MOX 400 mg/d Median, 12 d (all) (P = .22) |
Adults; age 59.6 y; APACHE II 19; MV 55.6%; HAI 63.4% | PNA 68.3%; BSI 10.2%; UTI 8.5%; skin 11.3%; other 1.8% | ACM (30 d): TMP-SMX 14.7%; MIN 5.1%; FQ, 7.1% (P = .16) |
Clinical failure: TMP-SMX 35.5%; MIN 30.8%; FQ 28.6% (P = .69) |
Emergence of resistance: TMP-SMX 3.7%; MIN 7.7%; FQ 3.6% (P = .45) |
| Zha (2021) [67] | Retrospective, multicenter (3 centers), 2017–2020, China | 82 pts; 46 TGC, 36 FQ | TGC 50 mg Q12h, LVX 500 mg Q12h, MOX 400 mg/d 9 d |
Adults; age 76 y, APACHE II 21, MV 100% | VAP | 28 d ACM: 47.8% TGC, 27.8% FQ (P = .105) | Clinical cure: 32.6% TGC, 63.9% FQ (P = .009) | Microbiological cure: 28.6% TGC, 59.1% FQ (P = .045) |
| Meta-analysis comparing TMP-SMX to fluoroquinolones | ||||||||
| Ko (2019) [74] | 14 publications; 7 retrospective cohort studies, 7 case-control through Mar 2018 | 663 pts; 332 TMP-SMX, 331 FQ (187 LVX, 114 CIP, 15 other) | NR | All | Any | Overall mortality: 29.6% (30 d ACM or in-hospital mortality) Mortality: FQ 25.7% (85/331); TMP-SMX 33.4% (111/332) Mortality in FQ cohort: OR, 0.62 (95% CI, .39–.99) but LVX, CIP separately showed no mortality benefit vs TMP-SMX (CIP: OR, 0.44 [95% CI, .17–1.12]; LVX: OR, 0.78 [95% CI, .48–1.26]) |
NR | NR |
| Systematic reviews evaluating monotherapy vs combination therapy | ||||||||
| Falagas (2008) [20] | 34 publications through Feb 2008 | 49 pts (29 case reports, 5 case series with 18 pts) | NR | Avg age, 52 y (0–80y) | Any | IRM 5/49 (10.2%) | Cure/improvement: CIP MT or CT, 90%; CRO or CAZ MT or CT, 75%; T/C MT or CT, 66.7% | NR |
| Clinical studies comparing monotherapy to combination therapy | ||||||||
| Jacobson (2016) [68] | Retrospective, single-center; 2010–2014, USA | 93 adults; 45 MIN, 48 MIN combination | MIN 200 mg/d | Adults, 53% ICU; APACHE II 15 ± 6.6 | PNA (63%), BSI (15%) | 30 d mortality: MIN 16.0% (15/94) | Clinical failure: MIN MT and CT, 18% (17/94). MIN MT, 9% (4/45) Failure related to APACHE II, or MIC = 4 mg/L (29.4%) vs MIC <4 mg/L (2.6%) (P = .004) |
NR |
| Araoka (2017) [51] | Retrospective, single-center, 2012–2014, Japan | 20 pts; 14 TMP-SMX + FQ, 6 TMP-SMX or FQ | NR | Adults; ages, 60.5–65 y; Pitt scores 1–2.5; neutropenia 43%–50% | BSI | 30 d mortality: TMP-SMX + FQ, 50% (7/14); TMP-SMX alone, 33% (2/6) | NR | NR |
| Shah (2019) [69] | Retrospective, single-center, 2011–2017, USA | 252 adult pts; 218 monotherapy, 38 combination (various) | NR | Age 62 y; MV 69.4%; ICU 76.2%; 54.4% polymicrobial pneumonia; median APACHE II score 16 | PNA | 30 d ACM: CT 39.5% (15/38); MT 22.9% (49/214); (P = .03) 30 d IRM: CT 15.8% (6/38); MT 8.9% (19/214); (P = .19) |
7 d clinical response: CT 47.4%; MT 39.7% (P = .38) controlling for immune status, APACHE II score, and polymicrobial pneumonia | Emergence of resistance during or after treatment (n = 33 pts): CT 15.8% (6/38); MT 12.6% (27/214) 30 d infection recurrence: CT 10.5%; MT 7.9% Emergence of resistance during therapy (n = 54): CT 37.5% (3/8); MT 32.6% (15/46) Emergence of resistance after therapy (n = 21): CT 75% (3/4); MT 70.6% (12/17) |
| Tokatly Latzer (2019) [70] | Retrospective, multicenter (4 sites), 2012–2017, Israel | 61 pts; 22 TMP-SMX, 13 CIP, 6 CAZ, 11 TMP-SMX + CIP, 9 TMP-SMX + CIP + MIN, 7 none | TMP-SMX 20 mg/kg/d, MIN 8 mg/kg/d, CIP 30 mg/kg/d, CAZ 150 mg/kg/d (IV) |
Pediatric; age 2.1 y; prior MV 72%; recent chemotherapy 27% | BSI | 42% ACM; attributable mortality within 30 d, 25%; CIP + TMP-SMX + MIN (n = 9) resulted in longest survival (mean, 54 d [range, 44–65 d]) |
NR | NR |
| Guerci (2019) [71] | Retrospective, multicenter (25 ICUs), 2012–2017, France | 282 pts; 82 TMP-SMX, 71 CIP, 68 T/C | NR Median duration of effective therapy, 11 d (7–15) |
Adults; age 65 y, 81% VAP, 84% intubated; 100% ICU, IC <15% | 100% nosocomial PNA; 81% VAP | In-hospital mortality 49.7%; attributable mortality 24.3% | Treatment failure 23.1%; combination therapy and DOT >7 d did not impact mortality | NR |
| Sierra-Hoffman (2020) [72] | Retrospective, multicenter registry (6 sites), 2015–2018; USA | 29 pts; 9 MIN, 20 MIN combination | 25 MIN 100 mg BID, 4 MIN 200 mg BID Median 9 d (IQR, 5–15) |
Adults; age 57.6 y; MV 53.5% | PNA 71.4%; BSI 14.3%; skin 8.6%; UTI 5.7% | 30.0% (in-hospital) | Clinical response: PNA + BSI, 79.3% (23/29) | 27.6% (PNA + BSI); 1 emergence of R in MIN |
Abbreviations: ACM, all-cause mortality; AE, adverse event; APACHE, Acute Physiology and Chronic Health Evaluation; BID, twice-daily dose; BSI, bloodstream infection/bacteremia; CAZ, ceftazidime; CI, confidence interval; CIP, ciprofloxacin; CRO, ceftriaxone; CT, combination therapy; DOT, days of therapy; EOT, end of therapy; FQ, fluoroquinolone; HAI, hospital-acquired infection; IC, inhibitory concentration; ICU, intensive care unit; IQR, interquartile range; IRM, infection-related mortality; IV, intravenous; LOS, length of stay; LVX, levofloxacin; ME, microbiological eradication; MIC, minimum inhibitory concentration; MIN, minocycline; MOX, moxifloxacin; MT, monotherapy; MV, mechanical ventilation; NR, not reported; OR, odds ratio; PNA, pneumonia; PO, oral; pts, patients; Q8h, every 8 hours; Q12h, every 12 hours; R, resistant; S, susceptible; T/C, ticarcillin-clavulanate; TGC, tigecycline; TMP-SMX, trimethoprim-sulfamethoxazole; UTI, urinary tract infection; VAP, ventilator-associated pneumonia.