Table 2 Summary of PK/PD studies carried out with cefditoren (CDN)

[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