Model-Informed Precision Dosing of Antibiotics in Osteoarticular Infections

Figures & data

Table 1 Overview Characteristics of Included Studies

Drug	First Author (Year)	Number of Patients (Male/Female)	Age (y)^a	Weight (kg)^a	Total Number of Samples	Pathogens	Model	Modeling Approach	Number of Compartments	Retained Covariates in Final Model
										Covariates ~CL	Covariates ~Vc
Cloxacillin	Johan Courjon (2020)^Citation36	11 (8/3)	53 (21–65)	CI/II: 83 (52–95) II/CI: 70 (60–97)	84	MSSA	PPK	NPAG	Two	None	BSA
Cephalexin	Amanda Gwee (2020)^Citation41	12 (7/5)	7.6 (1.2–16.7)	25 (10.0–78.8)	53	MSSA	PPK	NONMEM	One	Weight	Weight
Clindamycin	Naïm Bouazza (2012)^Citation44	50 (30/20)	56.7 ± 3.0	69.9 ± 2.7	122	MSSA	PPK	NONMEM	One	Weight,	None
Ciprofloxacin	Cornelia B. (2020)^Citation49	37 (12/25)	66 ± 9	74 ± 20	/	MSSA	PBPK	NONMEM	Five^b	/	/
	Noël Zahr (2021)^Citation50	92 (57/35)	59.8 ± 32.9	79.6 ± 23.9	397	G^+ (7.6%) G^− (92.4%)	PPK	NONMEM	Two	Fat-free mass, eGFR, rifampicin co-administration	Fat-free mass,
Levofloxacin	Gauthier Eloy (2020)^Citation55	59 (28/31)	57.5 ± 20.1	72.1 ± 15.9	197	S. aureus	PPK	NONMEM	One	Age, eGFR	None
Rifampicin	Amélie Marsot (2017)^Citation57	62 (46/16)	57.4 (20–89)	72.3 (46–119)	103	Staphylococci	PPK	NONMEM	One	Fusidic acid co-administration	Fusidic acid co-administration
Rifampicin	Amélie Marsot (2020)^Citation58	83	51.9 (19–82)	81.4 (57–100)	129	Staphylococci	PPK	NONMEM	One	Fusidic acid co-administration	Fusidic acid co-administration
Dalbavancin	Michael W. (2015)^Citation63	18 (9/9)	38.1 (21–55)	/^c	/	S. aureus	PPK	NONMEM	Three	CLCR	BSA
	Michael W. (2015)^Citation63	31 (14/17)	66.7 (47–82)	/^d	/	S. aureus	PPK	NONMEM	Four	/	/
	Pier Giorgio (2021)^Citation64	15 (8/7)	60 (51–72)	71 (66.5–82.5)	120	S. aureus	PPK	NONMEM	Two	None	None
Daptomycin	Sylvain Goutelle (2016)^Citation68	23 (14/9)	68 (19–84)	72 (47–140)	203	S. aureus	PPK	NONMEM	Two	Sex	Sex
	Romain Bricca (2019)^Citation69	81 (47/34)	60 ± 18	79 ± 20	577	S. aureus	PPK	NONMEM	Two	CLCR, sex	Weight, CGC
	Romain Garreau (2021)^Citation70	183 (106/77)	60.5 ± 16.0	79.2 ± 20.2	1303	S. aureus	PPK	NONMEM	Two	CLCR, sex	Weight, age, sex, rifampicin co-administration.
Ertapenem	Jonathan Chambers (2019)^Citation72	10 (8/2)	64 [57–74]	112.3 (79–188)	69	Enterobacteriaceae	PPK	NONMEM	Two	CLCR	CLCR
	Sylvain Goutelle (2018)^Citation73	31 (21/10)	58 (19–87)	75 (50–136)	133	Enterobacteriaceae	PPK	NPAG	Two	/	/
Fosfomycin	Matteo Rinaldi (2021)^Citation80	48 (34/14)	56.4 [42.9–66.7]	80 [68–90]	116	G^+ and G^−	PPK	NPAG	Two	CLCR	Weight

Notes: ^amean ± SD or median (range) or median[IQR]; ^bThe PB/PK model of ciprofloxacin included a central (blood) compartment, two peripheral tissue compartments, and compartments for the organic and inorganic (hydroxyapatite) matrix in cortical and cancellous bone; ^cno data of weight, but BMI of subjects is 27 (22–32) kg/m^{2; d}no data of weight, but the BMI of subjects is 32.1 (22.4–43.4) kg/m²; /: not stated;

Abbreviations: PB/PK, physiological-based pharmacokinetic model; PPK, population pharmacokinetic model; NONMEM, non-linear mixed-effects model; NPAG, the non-parametric adaptive grid algorithm; BSA, body surface area; CL_CR, creatinine clearance; eGFR, estimated glomerular filtration rate.

Table 2 Summary of Drug PK Parameters and Dosing Recommendations for OAI Patients

Drug	Mean of PK Parameters		Dosing Recommendations for OAI Patients		Target
	CL (L/h)	Vd (L)	From Label or Guideline	Proposed by the Model
Cloxacillin^Citation36	16.2	V1:16.0 V2:2.7	4–6 g/d, iv	6–12 g/d, 3 h infusions or CI against S. aureus at MIC ≤ 0.5 mg/L	50% fT>MIC
Cephalexin^Citation41	CL/F:8.21	V/F:15.9	25 mg/kg, qid, po	22–45 mg/kg, bid, po or 15–25 mg/kg, tid, po against MSSA at MIC of 1–2 mg/L; 80 mg/kg, bid, po or 45 mg/kg, tid, po against MSSA at MIC of 4 mg/L	40% fT > MIC
Clindamycin^Citation44	15.2	66.2	600–900 mg, q8 h, iv	600 mg, tid, iv/po for patients ≤ 75 kg against S. aureus at MIC ≤ 0.125 mg/L; 900 mg, tid, iv/po for patients >75 kg against S. aureus at MIC ≤ 0.125 mg/L	Cmin (plasma) ≥ 2 mg/L
Ciprofloxacin^Citation49	20.7	V1:5.85	400 mg, q8 h/q12 h, iv	400 mg, q8 h, iv against S. aureus at MIC ≤ 0.75 mg/L; 400 mg, q12 h, iv against S. aureus at MIC ≤ 0.5 mg/L	fAUC/MIC ≥ 40
Ciprofloxacin^Citation50	CL/F:44	V1/F:56.5	1583±430 mg/d, po	1375 mg/d, poor 500 mg, q8 h, po, for a patient with 70 kg, eGFR = 100 mL/min/1.73 m^2 and no rifampicin against P. aeruginosa with a MIC of 0.25 mg/L. 2200 mg/d, po for same patient but co-administration of rifampicin	fAUC/MIC≥125,110,35^c
Levofloxacin^Citation55	CL/F:6.10	V/F:90.6	500–750 mg, qd, iv/po	750 mg, qd, iv/po against S. aureus at MIC<1 mg/L	AUC/MIC ≥ 100
Rifampicin^Citation58	CL/F:5.1^a CL/F:12.8^b	V1/F:39.8^a V1/F:74.0^b	300 mg, tid, po	900–1200 mg/d, po with fusidic acid against Staphylococci at MIC ≤ 0.064 mg/L	AUC0-24h/MIC ≥ 952
Dalbavancin^Citation63	/	/	1500 mg, single, iv; 1000 mg followed one week later by 500 mg, iv	Two 1500mg dosing regimen one week apart, iv against S. aureus at MIC ≤ 0.12 mg/L	fAUC0-24h /MIC: 265±143
Dalbavancin^Citation64	0.106	V1:17.40 V2:15.10	1500 mg, single, iv; 1000 mg followed one week later by 500 mg, iv	Two 1500mg dosing regimen one week apart, iv against MSSA and MASA at MIC ≤ 0.125 mg/L	fAUC0-24h/MIC > 27.1, 53.3 and 111.1
Daptomycin^Citation69	0.585	V1:10.1 V2:3.39	6 mg/kg, qd, iv	10 mg/kg, qd, iv against S. aureus at MIC ≤ 1mg/L	fAUC0-24h/MIC > 66
Daptomycin^Citation70	0.365	V1:3.59 V2:4.71	6 mg/kg, qd, iv	10 mg/kg, qd, iv for male against S. aureus at MIC ≤ 1 mg/L; 8 mg/kg, qd, iv for female against S. aureus at MIC ≤ 1 mg/L	fAUC0-24h/MIC > 66
Ertapenem^Citation72	1.34	V1:5.72 V2:4.77	1 g, qd, iv	1 g, qd, iv against Enterobacteriaceae at MIC ≤ 0.064 mg/L	50%fT > MIC
Ertapenem^Citation73	0.055	V1:6.091	1 g, qd, iv	1 g, bid, iv/sc against Enterobacteriaceae at MIC ≤ 1 mg/L	40%fT > MIC
Fosfomycin^Citation80	1.31	V1:6.4	4–12 g/d, iv	2g, q6 h, iv against S. aureus, E. coli, ESBL-producing E. Coli and MRSA; 8g/d, CI against CoNS, K.pneumoniae, ESBL-producing K.pneumoniae; 12g/d, CI against P. aeruginosa; 16g/d, CI against KPC-producing K. pneumoniae	70%T> MIC

Notes: ^aWith fusidic acid; ^bWithout fusidic acid; ^cThe PK/PD target for ciprofloxacin is AUC/MIC≥125 for Gram-negative aerobic bacteria,≥110 for staphylococcus infections and ≥35 for Gram-positive bacteria, respectively. /: not stated;

Abbreviations: CL, clearance; V1, apparent volume of distribution of the central compartment; V2, apparent volume of distribution of the peripheral compartment; qd, once a day; bid, twice a day; tid, three times a day; qid, four times a day; q6 h, every 6 h; q8 h, every 8 h; q12 h, every 12 h; CI, continuous infusion; iv, intravenous injection; po, oral administration; sc, subcutaneous injection; (f)AUC_0-24h/MIC, (free) drug area under the concentration-time curve over 24 h divided by the MIC; %(f)T>MIC, time that the (free) drug concentration exceeds the MIC for at least % of the dosing interval.

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