Table 2.

Summary of PK/PD studies carried out with cefditoren (CDN)

Ref.	Type of study	Strains	Comparators	Main conclusion
[73]	Killing curves in the presence/absence of human albumin (Cmax: 4.1 mg/l)	S. pneumoniae (CDN MICs: 0.12–0.5 mg/l)	_	The activity of cefditoren should not be linked exclusively with the theoretical unbound fraction extrapolated from the plasma concentration.
[74]	Killing curves in the presence/absence of human albumin or human serum (Cmax: 4.1 mg/l)	S. pneumoniae (CDN MICs: 0.12–0.5 mg/l)	_	The presence of 90% human serum did not limit bactericidal activity as did the use of concentrations similar to free-drug.
[75]	In vitro computerized pharmacodynamic simulation in the presence of 75% human serum	S. pneumoniae (CDN MICs: 0.25–0.5 mg/l)	_	Cefditoren physiological concentrations exerted antibacterial activity against strains exhibiting MICs of 0.25 and 0.5 m/l under protein binding conditions similar to those in humans (experimentally measured)
[76]	In vitro computerized pharmacodynamic simulation (total vs. free concentrations)	H. influenzae (including BLNAR and BLPACR)	Co-amoxiclav	The experimental bactericidal activity of cefditoren (both total and free concentrations) was maintained over the dosing interval regardless of the presence of mutation in the ftsI gene or β-lactamase production, in contrast to co-amoxiclav.
[77]	In vitro computerized pharmacodynamic simulation	S. pneumoniae (amoxicillin MIC > penicillin MIC) (CDN MICs: 0.12–1 mg/l)	Cefuroxime Co-amoxiclav	Bactericidal activity at 12 and 24 h was obtained against all strains with cefditoren, but not with comparators.
[78]	In vitro computerized pharmacodynamic simulation	S. pneumoniae (mixed inocula) (CDN MICs: 0.015, 0.5, 1 mg/l)	Cefuroxime Cefixime Cefaclor Amoxicillin	Against penicillin resistant strains, cefditoren (but not comparators) decreased the initial bacterial load all along the simulation, without regrowth and with lower selection of resistant subpopulations
[79]	In vitro computerized pharmacodynamic simulation	H. influenzae (including BLNAR and BLPACR)	Cefuroxime Co-amoxiclav	Cefditoren exhibited the highest bactericidal activity maintained over time against ampicillin-resistant H. influenzae, regardless of beta-lactamase production and/or BLNAR phenotype.
[80]	In vitro computerized pharmacodynamic simulation	H. influenzae β− H. influenzae β+ BLNAR BLPACR (mixed inocula)	Cefuroxime Co-amoxiclav	Cefditoren offered higher antibacterial effect than comparators due to its higher activity against beta-lactamase-producing strains and those carrying ftsI gene mutations. BLNAR and BLPACR strains were selected by cefuroxime and co-amoxiclav, respectively.
[81]	In vitro computerized pharmacodynamic simulation	S. pyogenes S. pneumoniae H. influenzae β+ BLPACR (mixed inocula)	Amoxicillin Co-amoxclav	Cefditoren (but not comparators) completely countered indirect pathogenicity and eradicated S. pyogenes and both H. influenzae strains.
[82]	In vitro computerized pharmacodynamic simulation in media containing ftsI DNA	H. influenzae β− H. influenzae β+	Co-amoxiclav	Cefditoren (but not co-amoxiclav) was bactericidal and countered intrastrain ftsI gene diffusion
[83]	In vitro study assessing by flow cytometry the deposition/binding of components of the complement system to bacterial cells	S. pneumoniae	Ceftriaxone	Increased recognition of S. pneumoniae by the complement system in the presence of sub-inhibitory concentrations of cefditoren
[84]	Mice sepsis model (pre-immunized vs. non pre-immunized mice)	S. pneumoniae (CDN MICs: 1, 2, 4 mg/l)	_	In non pre-immunized animals, t > MIC values for CDN of approximately 35% (total) and approximately 19% (free) were associated with 100% survival, with lower values in pre-immunized animals
[85]	Monte Carlo simulation	_	_	Coverage with total concentrations: a. criterion of 40% t > MIC: MICs ≤0.5 mg/l b. criterion of 33% t > MIC: MICs ≤0.5 mg/l Coverage with extrapolated free concentrations: a. criterion of 40% t > MIC: MICs ≤0.12 mg/l b. criterion of 33% t > MIC: MICs ≤0.25 mg/l