TABLE 2.
Activity of β-lactam monotherapy or combination therapy on MBL-bacterial burden in animal studiesa
| Reference | Animal infection model | Isolate (genotype) | Inoculum (CFU/ml) | BL MIC (mg/liter) | BL dose and frequency | MBL-I or BL-I dose and frequency | Dose initiation | Measured endpoint | Activity, BL alone | Activity, BL/MBL-I or BL/BL-I |
|---|---|---|---|---|---|---|---|---|---|---|
| Samuelsen et al., 2020 (32) | Murine neutropenic peritonitis model | K. pneumoniae 50752501 (NDM-1) | 5 × 106 | MEM: 64 | MEM 33 mg/kg single dose s.c. | ZN148 10 mg/kg single dose s.c. | MEM: 1.5 h postinoculation; ZN148: 1 h postinoculation | 5 h blood | ↓CFU | ↓CFU |
| 5 h peritoneal fluid | ↓CFU | ↓CFU | ||||||||
| MEM 33 mg/kg single dose s.c. | ZN148 33 mg/kg single dose s.c. | MEM: 1.5 h postinoculation; ZN148: 1 h postinoculation | 5 h blood | ↓CFU | ↓CFU | |||||
| 5 h peritoneal fluid | ↓CFU | ↓CFU | ||||||||
| MEM 33 mg/kg single dose s.c. | ZN148 100 mg/kg single dose s.c. | MEM: 1.5 h postinoculation; ZN148: 1 h postinoculation | 5 h blood | ↓CFU | ↓CFU | |||||
| 5 h peritoneal fluid | ↓CFU | ↓CFU | ||||||||
| Chen et al., 2020 (33) | Murine peritonitis model | E. coli EC10 (NDM-1) | 2 × 107 | MEM: 128 | MEM 10 mg/kg single dose i.p. | Cisplatin 5 mg/kg single dose i.p. | 0.5 h postinoculation | 48 h liver | No difference | ↓CFU |
| 48 h spleen | No difference | ↓CFU | ||||||||
| Liu et al., 2019 (34) | Murine neutropenic thigh model | E. coli B2 (NDM-5) | 1.5 × 106 | MEM: 32 | MEM 16 mg/kg single dose i.p. | PEP4 16 mg/kg single dose i.p. | 2 h postinoculation | 24 h thigh | No difference | ↓CFU |
| Liu et al., 2019 (35) | Murine thigh model | E. coli ZC-YN3 (NDM-1) | 5 × 106 | MEM: 16 | MEM 10 mg/kg s.c. | Pterostilbene 80 mg/kg s.c. | NA postinoculation, 3 doses at q8h for 24 hours | 72 h thigh | No difference | ↓CFU |
| Ma et al., 2019 (36) | Murine peritonitis model | E. coli XJ141026 (NDM-1) | 8 × 107 | MEM: 64 | MEM 10 mg/kg single dose i.p. | Thanatin 0.1 mg/kg single dose i.p. | 1 h postinoculation | 24 h spleen | ↓CFU | ↓CFU |
| 24 h liver | ↓CFU | ↓CFU | ||||||||
| Yarlagadda et al., 2018 (37) | Murine peritonitis model | K. pneumoniae R3934 (NDM-1) | ∼106 | MEM: >100 | MEM 10 mg/kg i.p. | Dipi-van 10 mg/kg i.p. | 2 and 24 h postinoculation | 48 h liver | ↓CFU | ↓CFU |
| 48 h kidney | ↓CFU | ↓CFU | ||||||||
| 48 h lungs | No difference | ↓CFU | ||||||||
| 48 h spleen | No difference | ↓CFU | ||||||||
| Monogue et al., 2018 (39) | Murine neutropenic cUTI model | 3 Isolates (NDM-1) | 105.5 | MEM: 64 to 256 | MEM 1 g q8h (HSR, s.c.) | NAC 1.5 g q8h (HSR, s.c.) | 3 h postinoculation | 48 h kidney | ↓CFU (3/3 isolates) | ↓CFU (3/3 isolates) |
| CAZ 25 mg/kg s.c. | AVI 6.25 mg/kg s.c. | 3, 7, 23, and 31 h postinoculation | 48 h kidney | No difference (3/3 isolates) | ||||||
| 7 Isolates (KPC, OXA-48) | 105.5 | MEM: 16 to 512 | MEM 1 g q8h (HSR, s.c.) | NAC 1.5 g q8h (HSR, s.c.) | 2 h postinoculation | 48 h kidney | No difference (5/7 isolates) | ↓CFU (7/7 isolates) | ||
| CAZ 25 mg/kg s.c. | AVI 6.25 mg/kg s.c. | 3, 7, 23, and 31 h postinoculation | 48 h kidney | ↓CFU (7/7 isolates) | ||||||
| Sully et al., 2017 (40) | Murine peritonitis model | E. coli CVB-1 (NDM-1) | 3 × 106 (5% mucin) | MEM: 16 | MEM 50 mg/kg s.c. | PPMO 5 mg/kg i.p. with inoculum | 0 h postinoculation | 6 h blood | No difference | ↓CFU |
| 0 and 6 h postinoculation | 10 h blood | ↓CFU | ↓CFU | |||||||
| 0 and 6 h postinoculation | 10 h spleen | ↓CFU | ↓CFU | |||||||
| Falconer et al., 2015 (41) | Murine peritonitis model | K. pneumoniae (NDM-1) | 2 × 106 | MEM: >2 µM | MEM 10 mg/kg single dose s.c. | SIT-Z5 10 mg/kg single dose s.c. | 0.5 h postinoculation | 48 h liver | No difference | ↓CFU |
| 48 h spleen | No difference | ↓CFU | ||||||||
| King et al., 2014 (42) | Murine peritonitis model | K. pneumoniae N11-2218 (NDM-1) | 2 × 106 | MEM: 32 | MEM 10 mg/kg single dose s.c. | AMA 10 mg/kg single dose s.c. | 0.5 h postinoculation | 48 h spleen | No difference | ↓CFU |
| 48 h liver | No difference | ↓CFU | ||||||||
| Wiskirchen et al., 2014 (43) | Murine thigh model | 10 Isolates (wild-type, isogenic-derived and clinical NDM) | 108 | DOR MIC range: 0.03 to >64 | DOR 2 g q8h (HSR, s.c.)b | 2 h postinoculation | 24 h thigh | ↓CFU (10/10 isolates) | ||
| ETP MIC range: 0.012 to 128 | ETP 1 g q24h (HSR, s.c.)b | 2 h postinoculation | 24 h thigh | ↓CFU (8/10 isolates) | ||||||
| CAZ MIC range: 0.25 to >128 | CAZ 2 g q8h (HSR, s.c.)b | 2 h postinoculation | 24 h thigh | ↓CFU (3/10 isolates) | ||||||
| ATM MIC range: ≤0.25 to >256 | ATM 2 g q6h (HSR, s.c.)b | 2 h postinoculation | 24 h thigh | ↓CFU (4/10 isolates) | ||||||
| Wiskirchen et al., 2013 (30) | Murine thigh model | 6 Isolates (wild-type, isogenic-derived and clinical NDM) | 108 | ETP MIC range: 0.012 to >32 | ETP 1 g q24h (HSR, s.c.)b | 2 h postinoculation | 24 h thigh | ↓CFU (5/6 isolates) | ||
| DOR MIC range: 0.03 to >32 | DOR 2 g q8h (HSR, s.c.)b | ↓CFU (6/6 isolates) | ||||||||
| Isogenic-derived KPC-2 | 108 | ETP: 0.012 to 4 | ETP 1 g q24h (HSR, s.c.)b | 2 h postinoculation | 24 h thigh | No difference | ||||
| DOR: 0.03 to 1 | DOR 2 g q8h (HSR, s.c.)b | No difference | ||||||||
| Murine thigh model | E. coli 389 (NDM-1, TEM-1, CTX-M-15) | 108 | ETP: >32 | ETP 1 g q24h (HSR, s.c.)b | 2 h postinoculation | 72 h thigh | ↓CFU | |||
| DOR: 8 | DOR 2 g q8h (HSR, s.c.)b | ↓CFU | ||||||||
| Yoshizumi et al., 2012 (44) | Murine peritonitis model | E. coli TUM10702 (NDM-1) | 2.7 × 107 | IMI: 512 | IMI/cilastatin 25 mg/kg single dose s.c. | Ca-EDTA 200 mg/kg single dose s.c. | 2 h postinoculation | 4 h liver | No difference | ↓CFU |
| 4 h blood | ↓CFU | |||||||||
| Murine neutropenic peritonitis model | E. coli TUM10702 (NDM-1) | 6 × 107 | IMI: 512 | IMI/cilastatin 10 mg/kg single dose s.c. | Ca-EDTA 100 mg/kg single dose s.c. | 2 h postinoculation | 4 h liver | No difference | ↓CFU | |
| 4 h blood | No difference | ↓CFU | ||||||||
| Souli et al., 2011 (45) | Rabbit intra-abdominal abscess model | E. coli (VIM-1) | 108 | IMI: 1 | IMI 70 mg/kg q12h, 30 min i.v. infusion | 4 h postinoculation | 96 h bacterial abscess | ↓CFU | ||
| MEM: ≤0.25 | MEM 125 mg/kg q12h, 10 min i.v. infusion | 4 h postinoculation | 96 h bacterial abscess | ↓CFU | ||||||
| ERT: 1.5 | ERT 60 mg/kg q12h, i.v. bolus | 4 h postinoculation | 96 h bacterial abscess | ↓CFU | ||||||
| ATM: ≤0.25 | ATM 70 mg/kg q12h, i.v. bolus | 4 h postinoculation | 96 h bacterial abscess | ↓CFU |
a
BL, β-lactam; MBL-I, metallo-β-lactamase inhibitor; MEM, meropenem; IMI, imipenem; DOR, doripenem; ETP or ERT, ertapenem; FEP, cefepime; CAZ, ceftazidime; AZT, aztreonam; AVI, avibactam; ZID, zidebactam; NAC, nacubactam; HSR, human simulated regimen; cUTI, complicated urinary tract infection; s.c., subcutaneous; i.p., intraperitoneal; i.v., intravenous; NA, not available; q12h, every 12 hours.
b
Pretreatment with uranyl nitrate.