The role of PK/PD–based strategies to preserve new molecules against multi-drug resistant gram-negative strains

Figures & data

Table 1. Pharmacokinetic (PK), Percentage of binding protein, PK/PD, Dosage, and market approval for Ceftolozane/Tazobactam (TOL/TAZ), Ceftazidime-Avibactam (CAZ/AVI), Meropenem-vaborbactam (MER/VAB) and Cefiderocol.

Drug	FDA/EMA Approval	% Protein Binding	Manufacturer’s Dosage	Betalactam activity*
TOL/TAZ	cIAIs cUTIs VAP	Low for both	1.5 g q 8 iv in 1h infusion 3 g q 8 (VAP) iv	> 3PBPs
CAZ/AVI	cIAIs cUTIs VAP	Low for both	2.5 g q8 iv in 2h infusion	< 2PBPs
MER/VAB	cIAI, cUTI, HAP, VAP, Bacteraemia	Low for Meropenem 33% Vaborbactam	4 g q8 iv in 3h infusion	> 3PBPs
IMI/REL	cUTIs (FDA)	20 %	1.25 g q 6 in 30 min infusion	> 3PBPs
CEFIDEROCOL	cUTIs (FDA)	40-60% (mostly albumin)	2 g q8 iv in 3h infusion	> 3PBPs

* Betalactams having a prevailing activity only on one penicillin binding protein (PBP) have low or almost absent bactericidal activity, suffer from a considerable inoculum effect with a massive bacterial biomass increase and a high endotoxin release. Carbapenems, as well as 4^th generation cephalosporins, due to their capability of inhibiting more than two main PBPs, generally show a minimal inoculum effect, no biomass increase and a negligible endotoxin release and therefore are associated always with a fast and high killing activity. Cephalosporins such as ceftazidime, being capable of inhibiting no more than 2 PBPs have intermediate results (8).

Legenda cIAIs = complicated intra-abdominal infections, cUTIs = complicated Urinary Tract Infections, VAP = ventilation associated pneumonia.

Table 2. Spectrum of activity and MIC breakpoints of Ceftolozane/Tazobactam (TOL/TAZ), Ceftazidime-Avibactam (CAZ/AVI), Meropenem-vaborbactam (MER/VAB) and Cefiderocol.and Imipenem/Relebactam (IMI/REL).

DRUGS	SENSITIVITY (S) MIC BREACKPOINTS (GENERIC)	PSEUDOMONAS AERUGINOSA XDR/PDR	ENTEROBACTERALES ESBL				ACINETOBACTER BAUMANNII
			E.COLI	KLEBSIELLA SPP	ENTEROBACTER	P. MIRABILIS
TOL/TAZ	S≤ 4 mg/mL	More active than CAZ/AVI	Active	Active	Active	Active	Low activity
			No activity on KPC, VIM, NDM, GES	No activity on KPC, VIM, NDM, GES	No activity on KPC, VIM, NDM, GES	No activity on KPC, VIM, NDM, GES
CAZ/AVI	S≤ 8 mg/mL	Less activity than TOL/TAZ	Active	Active	Active	Active	Low Activity
			No activity on Class B MBL	No activity on Class B MBL	No activity on Class B MBL	No activity on Class B MBL
MER/VAB	S≤ 8 mg/mL	Active	Active Activity on Class A/ C	Active Activity on Class A and C	Active Activity on Class A/C	Active Activity on Class A/ C	No further activity than meropenem alone
			No activity on Class B and D	No activity on Class B and D	No activity on Class B and D	No activity on Class B and D
IMI/REL	S ≤4 mg/L	Active	Active	Active	Active	Active	Not Active
			Activity on Class A and C β-lactamase	Activity on Class A and C β-lactamase	Activity on Class A and C β-lactamase	Activity on Class A and C β-lactamase
			No activity on Class B and OXA-48 class D β-lactamase	No activity on Class B and OXA-48 class D β-lactamase	No activity on Class B and OXA-48 class D β-lactamase	No activity on Class B and OXA-48 class D β-lactamase
Cefiderocol	S≤ 4 mg/mL	Active	Active Class A,B,C,D	Active Class A,B,C,D	Active Class A,B,C,D	Active Class A,B,C,D	Active

Legenda: ESBL Extended Spectrum Beta-Lactamase, KPC Klebsiella producing carbapenemase, MBL Metallo Beta- Lactamase, NDM New Delhi metallo-β-lactamase, VIM Verona integron-encoded metallo-β-lactamase, GES Guiana extended-spectrum beta-lactamases.

Table 3. Pharmacokinetic (PK)/Pharmocodynamic (PD) PK/PD, Dosage adjustment, Infusion needs for Ceftolozane/Tazobactam (TOL/TAZ), Ceftazidime-Avibactam (CAZ/AVI), Meropenem-vaborbactam (MER/VAB) and Cefiderocol.

Drug	PK/PD target	Prolonged Infusion	Dose Adjustment according to renal function	Suggestion for conservation in severe infections /difficult site of infections
TOL/TAZ	32% fT > MIC	Suggested	Yes if CrCl < 50	Measure CrCl daily with Chen formula Evaluate if dosing reduction is really needed in the first 48 h necessary TDM
CAZ/AVI	50% fT > MIC	Suggested	Yes if CrCl < 50	Consider infection site: if pulmonary: increased dose TDM if possibile Combination therapy con amikacin or colistin^9^,^10 Combination therapy with aztreonam^11^,^12
MER/VAB	40% fT > MIC	Suggested	Yes if CrCl < 50	Vaborbactam has a weak activity on OXA-48-like TDM
IMI/REL	69% fT > MIC (I) fAUC0–24 hours/MIC ≥ 51.9 (R)	Suggested	Yes if CrCl < 50	TDM
Cefiderocol	75% fT > MIC	Suggested	Yes if CrCl < 50	TDM

Legenda: MIC minimum inhibitory concentration, CrCl creatinine clearence, TDM Target Drug Monitoring.

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