IS THE AGE OF ANTIBIOTICS OVER? Review of current pipeline of antibacterial drugsagents aminothiazole moiety quaternary ammonium and amide linker moiety H2N- S O IZ 7 N N N 3 COO COOH oxime moiety 2 (A-2) O CI N OH N Me OH catechol moiety HON 11 S I N N COOH S N COO O N N H CI 3 (Cefiderocol, S-649266) .OH OH Figure 5: Chemical structure cCefiderocol17 The catechol moiety (siderophore), shown in Figure 5 in blue, is an iron chelating moiety which increases the penetration of cefiderocol through the outer membrane of Ggram- negative bacteria. It uses the iron transport system of bacteria to transport itself by the binding of the catechol moiety with extracellular iron18. The cyclic quaternary ammonium moiety on the C-3 side chain was shown to be important in inhibiting the activities of AmpC -lactamase and carbapenemase-producing strains17. The substitution of a halogen on the catechol moiety provides increased activities against OXA -lactamase producing A. baumannii17. These enzymes are all key resistance factors, that hydrolyse the -lactam ring
deactivating the antibacterial properties of -lactam antibiotics. Thus in vitro activity of cefiderocol against these bacteria is encouraging. n/N (%) Cefiderocol Imipenem-cilastatin Analysis population mITT population Microbiologically evaluable population 183/252 (73) 182/228 (80) 65/119 (55) 65/106 (61) Age, years <65 87/113 (77) 265 96/139 (69) 32/54 (60) 33/65 (51) Sex Men 84/119 (71) 99/133 (74) Women 25/48 (52) 40/71 (56) Clinical diagnosis CUTI with or without pyelonephritis Acute uncomplicated pyelonephritis 54/65 (83) 129/187(69) 41/84 (49) 24/35 (69) -40 -jo -20 -10 0 10 20 Favours imipenem-cilastatin 30 Favours cefiderocol 40 50 Treatment difference* (95% CI) 18.58 (8-23-28-92) 19.35 (8-87-29-82) 17.73 (2-50-32.96) 18-30 (3-92-32-67) 18-50 (2-17-34-84) 18-10 (4:38-31-81) 20-17 (7-60-32-75) 14-51 (-3-37-32-38) 60 Figure 6: Treatment difference between cefiderocol and imipenem-cilastatin in the primary efficacy outcome at test of cure by predefined subgroups 19 CUTI=complicated urinary tract infection. mITT=modified intention-to-treat. Dotted lines represent pre- specified non-inferiority margins at -ffi0% and -15%. *Treatment difference was adjusted for stratification factors at baseline (cUTI with or without pyelonephritis vs. acute uncomplicated pyelonephritis and region). *Primary efficacy outcome was composite of clinical response (defined as resolution or improvement of infection as determined by investigators) and the microbiological response (defined as a bacterial count of 1×105 CFU/ml or less) *At test of cure was 7 days after end of treatment 7 days Recently published results from a phase ffi clinical trial comparing cefiderocol-versus and imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Ggram-negative uropathogens were promising. Figure 6 shows that cefiderocol was slightly superior to imipenem-cilastatin across the several pre-defined subgroups. The confidence intervals of the treatment difference did non't cross the line of solid line of no difference,
except in the sub-group of acute uncomplicated pyelonephritis, showing that the results are statistically significant. Treatment differences in the range of 14.51 - ffi0.17-are good but support the superiority of cefiderocol. However, analysis showed that these differences were almost entirely driven by the microbiological component of the composite endpoint