Figures
- FIGURE 1
Activity of new agents against Gram-negative pathogens. Grey shading: variable activity; red shading: non-activity; green shading: activity. KPC: Klebsiella pneumoniae carbapenemases; OXA: OXA-β-lactamases; NDM: New Delhi metallo-β-lactamase.
Tables
- TABLE 1
Risk factors associated with community-acquired pneumonia (CAP) caused by Gram-negative bacteria (including multidrug-resistant (MDR) strains)
Risk factor for MDR strain Demographics Older age [102] No Underweight [103] Yes Residence in a nursing home or extended care facility [102] No Underlying conditions Chronic lung disease, mainly COPD and bronchiectasis [104–106] Yes Immunodepression [102] No Chronic dialysis [102] No Cardiovascular disease [103, 105] Yes Cerebrovascular disease [105] No Diabetes [107] No Others Smoking [107] No Antimicrobial (both oral and intravenous) in the preceding 90 days [104, 106] Yes Home wound care [102] No Prior infection or colonisation with an MDR Gram-negative pathogen (e.g. Pseudomonas aeruginosa) [104, 107] Yes Prior hospitalisation [103] Yes Enteral tube feeding [105] No Clinical presentation Severe disease (e.g. CAP requiring ICU admission) [103, 106] No PSI score III, IV [104] No ICU: intensive care unit; PSI: pneumonia severity index.
- TABLE 2
Dosage, pros and author's perspective of the new antibiotics currently approved for the treatment of pneumonia due to Gram-negative pathogens
Ceftobiprole Ceftolozane-tazobactam Ceftazidime-avibactam Cefiderocol Meropenem-vaborbactam Imipenem-relebactam Antimicrobial activity Moraxella catarrhalis, Haemophilus influenza, non-ESBL-, non-AmpC- and noncarbapenemases-producing Enterobacterales; Pseudomonas aeruginosa ESBL-producing Enterobacterales; MDR P. aeruginosa ESBL-, KPC-, AmpC- and OXA-48-producing Enterobacterales; MDR P. aeruginosa ESBL- and CRE (class A, B, and D enzymes)-producing Enterobacterales; MDR P. aeruginosa, S. maltophilia and A. baumannii ESBL-, KPC- and AmpC-producing Enterobacterales; non-MDR P. aeruginosa; non-MDR A. baumannii ESBL- and KPC-producing Enterobacterales; MDR P. aeruginosa Approved dosage for the treatment of pneumonia 2 h i.v. infusion 500 mg every 8 h 2 g of ceftolozane and 1 g of tazobactam every 8 h by i.v. infusion over 1 h 2 g of ceftazidime and 0.5 g of avibactam every 8 h by i.v. infusion over 2 h 2 g every 8 h by i.v. infusion over 3 h 2 g of meropenem and 2 g of vaborbactam every 8 h by i.v. infusion over 3 h 500 mg of imipenem and 250 mg of relebactam by i.v. infusion every 6 h over 30 min Pros Approved for CAP and HAP, but not for VAP Best β-lactam with activity against P. aeruginosa
Carbapenem-sparing agent
Lower mortality observed in patients with ventilated HAPGood clinical experience for treatment of KPC infection
Carbapenem-sparing agent
Good activity OXA-48-producing Enterobacterales
Can be combined with aztreonam for the treatment of MBL-producing EnterobacteralesWide spectrum of activity
Unique drug with activity against MBL-producing EnterobacteralesPotent activity against KPC
Low-propensity for developing in vivo resistancePotent activity against KPC
Potent activity against MDR P. aeruginosaAuthors’ perspective Ceftobiprole could be a viable single therapeutic option for the treatment of CAP and HAP caused by Gram-negatives, especially when concomitant MRSA is suspected. We believe that ceftolozane-tazobactam represents the first option as a backbone for the treatment of MDR P. aeruginosa as well as a carbapenem-sparing regimen for the treatment of pneumonia in clinical settings with a high rate of ESBL-producing strains. Ceftazidime–avibactam currently represents one of the drugs of choice for the treatment of CRE infections. When treating patients with MDR Gram-negative bacteria pneumonia, ceftazidime-avibactam can be used in association with a second drug such as gentamycin, fosfomycin or colistin (or, in the future, with plazomycin). Moreover, it may have a role as a potential alternative to carbapenems in patients with nosocomial pneumonia with high rates (>20–25%) of infections caused by ESBL-producing or OXA-48-producing Gram-negative bacteria. We believe that cefiderocol represents an interesting choice for empirical and definitive treatment of HAP and VAP when a carbapenem-resistant Gram-negative bacteria, including CRE, MDR P. aeruginosa, and MDR A. baumannii is suspected or confirmed. Whether or not it should be used as part of a combination treatment is still an unresolved issue. In our opinion, meropenem-vaborbactam should be considered the first treatment option for CRE pneumonia, especially in consideration of its lower mortality rates, as recently documented in the TANGO II trial. Imipenem-relebactam could offer an important new treatment option as part of an empirical or targeted therapy for HAP or VAP due to MDR Gram-negative bacteria. We believe that further studies coming from real-life experiences are needed. A.: Acinetobacter; CAP: community-acquired pneumonia; CRE: carbapenem-resistant Enterobacterales; ESBL: extended-spectrum β-lactamases; HAP: hospital-acquired pneumonia; KPC: Klebsiella pneumoniae carbapenemases; MBL: metallo-β-lactamases; MDR: multidrug resistant; MRSA: methicillin-resistant Staphylococcus aureus; OXA: OXA-β-lactamases; S.: Stenotrophomonas; VAP: ventilator-associated pneumonia.
- TABLE 3
Efficacy data from large, randomised clinical trials investigating the use of novel agents with anti-Gram-negative activity in patients with community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP)
Reference, trial Drugs (dosage) Comparators (dosage) Primary end-point Disease and study population for the primary analysis Cured/total (rates, %) Percent difference (95% CI) Nicholson et al. [19] Ceftobiprole (500 mg every 8 h for 7–14 days) Ceftriaxone (2 g every 24 h for 7–14 days) ± linezolid (600 mg every 12 h if MRSA suspected) Clinical cure rate at the TOC visit CAP severe enough to require hospitalisation ITT population Ceftobiprole ITT 240/314 (76.4) – Ceftriaxone±linezolid ITT 257/324 (79.3) CE population Ceftobiprole CE 200/231 (86.6) – Ceftriaxone±linezolid CE 208/238 (87.4) Awad et al. [20] Ceftobiprole (500 mg every 8 h for 7–14 days) Ceftazidime (2 g every 8 h) plus linezolid (600 mg every 12 h) for 7–14 days Clinical cure rate at the TOC visit HAP including VAP ITT population Ceftobiprole ITT 195/391 (49.9) −2.9 (−10.0–4.1) Ceftriaxone plus linezolid ITT 206/390 (52.8) CE population Ceftobiprole CE 174/251 (69.3) −2.0 (−10.0–6.1) Ceftriaxone plus linezolid CE 174/244 (71.3) Kollef et al.[34], ASPECT-NP Ceftolozane-tazobactam (3 g every 8 h for 8–14 days) Meropenem (1 g every 8 h for 8–14 days) 28-day all-cause mortality Ventilated nosocomial pneumonia ITT population Ceftolozane-tazobactam 87/362 (24.0) 1.1 (−5.1–7.4) Meropenem 92/364 (25.3) Torres et al. [48], REPROVE Ceftazidime-avibactam (2 g/0.5 g every 8 h for 7–14 days) Meropenem (1 g every 8 h for 7–14 days) Clinical cure at TOC visit Nosocomial pneumonia including VAP cMITT population Ceftazidime-avibactam 245/356 (68.8) −4.2 (−10.76–2.46) Meropenem 270/370 (73.0) CE population Ceftazidime-avibactam 199/257 (77.4) −0.7 (−7.9–6.4) Meropenem 211/270 (77.1) Wunderink et al. [62], APEKS-NP Cefiderecol (2 g every 8 h for 7–14 days) Meropenem (2 g every 8 h for 7–4 days) All-cause 14-day mortality HAP, VAP or HCAP ITT population Cefiderocol 18/145 (12.4) 0.8 (−6.6–8.2) Meropenem 17/146 (11.6) Bassetti et al. [63], CREDIBLE-CR Cefiderecol (2 g every 8 h for 7–14 days) Best available therapy Clinical cure at TOC Nosocomial pneumonia CR-mITT population Cefiderocol 20/40 (50.0) – Best available therapy 10/19 (52.6) Wunderink et al.[73], TANGO II Meropenem-vaborbactam (2 g/2 g every 8 h for 7–14 days) Best available therapy Day 28 all-cause mortality Carbapenem-resistant Enterobacterales HABP/VABP mCRE-MITT population Meropenem-vaborbactam 4/20 (22.2) −22.2# Best available therapy 4/9 (44.4) Motsch et al. [85], STORE IMI-1 Imipenem-relebactam (500 mg/250 mg every 6 h for 5–21 days) Imipenem (500 mg every 6 h) plus colistin (loading dose 300 mg then 150 mg every 12 h) Favourable overall response HAP/VAP mMITT population Imipenem-relebactam 7/8 (87.5) – Imipenem plus colistin 2/3 (66.6) Titov et al. [86], RESTORE-IMI 2 Imipenem-relebactam (500 mg/250 mg every 6 h for 7–14 days) Piperacillin/tazobactam (4 g/0.5 g every 6 h for 7–14 days) Day 28 all-cause mortality HABP/VABP mITT population Imipenem-relebactam 42/264 (15.9) −5.3 (−11.9–1.2) Piperacillin/tazobactam 57/267 (21.3) McKinnel et al. [96], CARE Plazomicin (15 mg·kg−1 every 24 h for 7–14 days) plus meropenem or tigecycline Colistin 5 mg·kg−1 every 24 h plus meropenem or tigecycline Composite of death from any cause at 28 days or clinically significant disease-related complications HAP or VAP caused by suspected or confirmed CRE mMITT population Plazomicin-based regimen 2/3 (67) 27 (−48–82) Colistin-based regimen 2/5 (40) CE: clinically evaluable; cMITT: clinically modified intention-to-treat (population); CR: carbapenem resistant; CR-MITT: carbapenem-resistant microbiological ITT (population); HABP: hospital-acquired bacterial pneumonia; HCAP: healthcare-associated pneumonia; ITT: intent-to-treat (population); mCRE-MITT: microbiologic carbapenem resistant Enterobacterales-modified intent-to-treat (population); mITT: modified intent-to-treat (population); mMITT: modified microbiological intent to treat (population); MRSA: methicillin-resistant Staphylococcus aureus; TOC: test of cure; VABP: ventilator-associated bacterial pneumonia. #Data represent the difference in percentages for meropenem-vaborbactam and best available therapy.
