Table 6.
Summary of the Studies Investigating the Treatment of Metallo-Beta-Lactamase (MBL) Producing Enterobacterales Bloodstream Infections (BSIs), Complicated Intraabdominal (cIAIs) and Urinary Tract Infections (cUTIs) with Aztreonam-Avibactam, Cefiderocol and Combination Therapy with Meropenem and Fosfomycin
| Author, Year and Reference | Study Design | No. of Patients | Antibiotic and Dosing | Source of Infection | CPE-Producing Pathogens and Molecular Profile | Severity | Clinical Outcomes | Relapse Rate – Resistance Development | Comments |
|---|---|---|---|---|---|---|---|---|---|
| NDM+ pathogens | |||||||||
| Ceftazidime-avibactam + Aztreonam | |||||||||
| Falcone et al, 202093 | Prospective observational, multicenter with propensity score analysis | 102 (52 CAZ-AVI + Aztreonam vs 50 other active antibiotics) |
CAZ-AVI (2.5 g q8h – 50% of cases CI) + Aztreonam (2 g q8h) vs Colistin (LD 9 MU – MD 4.5 MU q12h); Tigecycline (LD 100 mg – MD 50 mg q12h); Fosfomycin (4–6 g q6h); Meropenem (2 g q8h); Gentamicin (3–5 mg/kg/day) |
All BSIs 33 cUTI 32 CR-BSI 12 SSTI 9 HAP/VAP 7 cIAI 14 unknown |
93 K. pneumoniae 5 Enterobacter spp 3 E. coli 1 M. morganii 82 NDM-producing 20 VIM-producing |
ICU admission 34.3% Solid organ transplantation 7.8% Septic shock 27.5% Mechanical ventilation 30.4% Median SOFA 4 |
30-day mortality rate: 19.2% vs 44% (p=0.007) |
NA | CAZ-AVI + ATM was associated with lower 30-day mortality (HR 0.37; P=0.01), lower clinical failure at day 14 (HR 0.30; P=0.002), and shorter length of stay (HR 0.49; P=0.007) |
| Shaw et al, 201794 | Case series | 10 | CAZ-AVI (0.94 g/day – 2.5 g q8h EI) + Aztreonam (1 g q8h – 2g q8h CI) |
4 cUTI 2 cIAI 2 HAP 1 CR-BSI 1 mediastinitis 50% bacteraemic |
10 K. pneumoniae 10 NDM-1/OXA-48/CTX-M-15 (outbreak) |
Mean SOFA: 3.7 Solid organ transplant recipient: 40% Immunocompromised: 50% |
Clinical cure rate at 30-day: 60% Mortality rate at 30-day: 30% |
Relapse 30% | |
| Benchetrit et al, 201995 | Case series | 2 | CAZ-AVI (0.94 g/day – 2.5 g/day EI) + Aztreonam 2 g q12-24 EI |
1 BSI 1 VAP |
2 K. pneumoniae 2 NDM-1 (MIC 0.032–0.064 mg/L) |
ICU admission: 100% Solid transplant recipient: 100% Immunocompromised: 100% |
Overall clinical cure rate: 100% Overall survival rate: 0% |
Relapse 100% | |
| Shah et al, 201996 | Case report | 1 | CAZ-AVI 0.94 g q12h + Aztreonam 1 g q8h |
bacteraemic cUTI |
K. pneumoniae No genotypification |
- | Clinical failure | - | |
| Hobson et al, 201997 | Case report | 1 | CAZ-AVI 150 mg/kg/day + Aztreonam (100 mg/kg/day) |
BSI |
Morganella morganii NDM-1 (MIC 0.016 mg/L) |
Haematological malignancy | Clinical and microbiological cure | No relapse at 6-month | |
| Sieswerda et al, 201998 | Case report | 1 | CAZ-AVI 2.5 g q8h CI + Aztreonam 1 g q8h EI |
cUTI |
K. pneumoniae NDM-1 (MIC 0.5 mg/L) |
Kidney transplant recipient | Clinical cure | Relapse at one month with the same strain. No difference in susceptibility |
|
| Yasmin et al, 202099 | Case report | 1 | CAZ-AVI 50 mg/kg q8h (EI 3h) + Aztreonam 50 mg/kg q8h |
BSI |
E. hormaechei NDM-1/KPC-4 (MIC 2/4 + 2 mg/L) |
Haematological malignancy | Clinical and microbiological cure | No relapse | |
| Bocanegra-Ibarias et al, 2020100 | Case report | 1 | CAZ-AVI 2.5 g q8h + Aztreonam 2 g q8h |
BSI |
K. pneumoniae NDM-1 (MIC 4/4 mg/L) |
Haematological malignancy | Clinical and microbiological cure | No relapse | |
| Cefiderocol | |||||||||
| Contreras et al, 201987 | Case report | 1 | Cefiderocol 1.5 g q12h |
bacteraemic cIAI |
K. pneumoniae NDM-1-OXA-48 |
ICU admission CRRT/ECMO Kidney transplant recipient |
Clinical and microbiological cure, but death due to ischaemic colitis | No relapse | |
| Dobias et al, 201788 | In vitro study | 134 NDM-VIM-IMP+ isolates | 67 E. coli, 38 K. pneumoniae, 29 Enterobacter spp. Cefiderocol MIC range: 0.03–64 (MIC50 1 mg/L; MIC90: 4 mg/L) | ||||||
| Mushtaq et al, 2020102 | In vitro study | 61 NDM isolates | 21 E. coli, 20 Klebsiella spp, 10 Enterobacter spp, 3 Citrobacter spp, 3 Providencia spp, 2 Morganella spp, 1 Serratia spp, 1 Proteus spp. Cefiderocol MIC range: 0.25–32 (MIC 2 S 41%; MIC 4 S 72.1%) | ||||||
| Kazmierczak et al, 201989 | In vitro study | 12 NDM isolates | 11 K. pneumoniae, 1 E. cloacae. Cefiderocol MIC range: 1–8 (MIC50 4 mg/L; MIC90: 8 mg/L) | ||||||
| Meropenem + fosfomycin | |||||||||
| Seija et al, 2015103 | Case report | 1 | Meropenem 2 g q8h EI + Fosfomycin 4 g q8h |
bacteraemic cUTI |
Morganella morganii NDM-1 |
Kidney transplant recipient | Clinical and microbiological cure | No relapse | |
| Sengel et al, 2020104 | In vitro study | 10 NDM isolates (5 NDM + 5 OXA-48/NDM) |
10 K. pneumoniae. Synergic activity in 100% of isolates | ||||||
| IMP/VIM+ pathogens | |||||||||
| Ceftazidime-avibactam + Aztreonam | |||||||||
| Cairns et al, 2020101 | Case series | 4 | CAZ-AVI 0.94 q12h - 2.5 g q8h + Aztreonam 1.5–2 g q8h |
2 bacteraemic cUTI 1 sternal osteomyelitis 1 CR-BSI |
4 E. cloacae IMP-4 (MIC 0.125–0.25 mg/L) |
ICU admission 50% 3 Solid organ transplant recipients 1 Haematological malignancy |
Clinical and microbiological cure: 100% |
Relapse 25% | |
| Cefiderocol | |||||||||
| Mushtaq et al, 2020102 | In vitro study | 62 VIM/IMP+ isolates | 22 Klebsiella spp, 20 E. coli, 12 Enterobacter spp, 8 Citrobacter spp. Cefiderocol MIC range: 0.03–8 (MIC 2 S 80.9%; MIC 4 S 95.7%) | ||||||
| Kazmierczak et al, 201989 | In vitro study | 27 VIM+ isolates | 8 K. pneumoniae, 7 E. cloacae, 7 C. freundii, 3 S. marcescens, 1 K. Oxytoca, 1 C. amanolaticus. Cefiderocol MIC range: 0.12–4 (MIC50 1 mg/L; MIC90: 4 mg/L) | ||||||
Abbreviations: BSIs, bloodstream infections; CAZ-AVI, ceftazidime-avibactam; CI, continuous infusion; cIAI, complicated intra abdominal infections; CR-BSI, catheter-related bloodstream infections; CRRT, continuous renal replacement therapy; cUTI, complicated urinary tract infection; ECMO, extracorporeal membrane oxygenation; EI, extended infusion; HR, hazard ratio; ICU, intensive care unit; LD, loading dose; MD, maintenance dose; MIC, minimum inhibitory concentration; NA, not available; NDM, New-Delhi metallo-beta-lactamase; SSTI, skin and soft tissue infections; VAP, ventilator-associated pneumonia; VIM, Verona-integrase metallo-beta-lactamase