Table 2.
Summary of pharmacological characteristics of candidate antimicrobials
| Characteristic | Amikacin | Tobramycin | Fosfomycin | Flomoxef | Cefepime |
|---|---|---|---|---|---|
| Molecular target | 16S ribosomal subunit | 16S eibosomal subunit | MurA | PBP | PBP |
| Spectrum of activity | GN bacteria (including pseudomonads); some activity in staphylococci | GN bacteria (including pseudomonads); some activity in staphylococci | Enterobacterales, pseudomonads, streptococci, and staphylococci | Enterobacterales, streptococci, enterococci, and staphylococci | Enterobacterales, pseudomonads, streptococci, and staphylococci |
| Important efficacy gaps | Streptococci | Streptococci; gentamicin-resistant GN bacteria with cross-reactive AMEs | Acinetobacter, listeria; GN bacteria with chromosomal FosA | AmpC-like ESBL-producing GN bacteria; enterococci; Pseudomonas species; Acinetobacter species | Enterococci; anaerobes; potentially non-class C ESBL-producing GN bacteria |
| Relevant resistance mechanisms | (1) AMEs; (2) methylation of 16S; (3) enhanced efflux | (1) AMEs; (2) methylation of 16S; (3) enhanced efflux | (1) fosfomycin-modifying enzymes; (2) MurA modification; (3) disruption to GlpT or UhpT uptake mechanisms | (1) AmpC-like ESBL; (2) modification of porins; (3) enhanced efflux (presumed) | (1) Non-AmpC ESBLs?; (2) modification of PBPs; (3) modification of porins; (4) enhanced efflux |
| Characterisation of neonatal pharmacokinetics | ++ | ++ | ++ | ++ | + |
| Significant toxicities | Dose-dependent renal impairment; non-dose-dependent ototoxicity (rare); neuro-muscular blockade (very rare) | Dose-dependent renal impairment; non-dose-dependent ototoxicity (rare); neuro-muscular blockade (very rare) | Sodium overload; hypokalaemia | Pneumonitis (very rare) | Neurotoxicity (rare) |
| CSF:plasma partition | 0.103 | Undefined | 0.32 | 0.05 | 0.05–0.34 |
| Presumed pharmacodynamic index (bacterial killing) | Cmax/MIC ratio | Cmax/MIC ratio | AUC/MIC ratio or %Time > MIC | %Time>MIC | %Time>MIC |
| Characterisation of exposure response (bacterial killing) | + | + | + | + | – |
| Characterisation of exposure response (emergence of resistance) | – | – | + | – | – |
AME aminoglycoside-modifying enzymes, AUC area under the concentration–time curve, Cmax peak plasma concentration, CSF cerebrospinal fluid, ESBL extended-spectrum β-lactamase, GN Gram negative, MIC minimum inhibitory concentration, PBP penicillin-binding protein, ++ indicates substantial data available, + indicates some data available but, ideally, more required, – indicates no data available