Table 1.

Examples of the application of pharmacometrics analyses for anti-infectives.

Drug	Organism	Disease	Target Site	Objective for performing pharmacometrics analysis	Outcome	Population	Ref.
Biapenem	Gram positive and gram negative anaerobes	Continuous venovenous hemodiafiltration (CVVHDF)	Plasma and filtrate-dialysate	Determine appropriate dosage recommendation for patients on CVVHDF	300 mg BID, intravenous (2 h infusion)	Adult Japanese (mean 65.1 yr), N=7	[29]
Cefditoren	Streptococcus pneumoniae	Lower respiratory tract infections	Plasma and BAL	PD profiling & determining PTA (Dose: 400 mg QD, oral)	PTA is <80% (at T>MIC of 33%, MIC = 0.06mg/L)	Adult Caucasian (35–78 yr) N=24	[35]
Cefepime	Streptococcus pneumoniae	Extracerebral infections	Serum and CSF	PD profiling & determining PTA (2g BID, 0.5h IV infusion)	PTA in CSF is 91.8% (at T>MIC of 50%) and 82% (at T>MIC of 100%)	Adult females (mean 58.9 yr) N=7	[53]
Ceftobiprole	Staphylococcus aureus	Staphylococcal pneumonia	ELF, serum, BAL	PD profiling & determining PTA (500 mg, TID, 2h IV infusion)	PTA with T>MIC is 15% for 1-log10 CFU/g reduction; 25% for 2-log10 CFU/g reduction	Adults (>18 yr) N=25	[54]
	Staphylococcus aureus, Streptococcus pneumoniae	Nosocomial pneumonia	Skin, Plasma	PD profiling & determining PTA & renal dose adjustments (500 mg BID, 1h infusion; 500 mg TID, 2h infusion)	With 500 mg, BID: PTA of 30% and 50% T>MIC exceeded 90%. With 500 mg, TID: PTA of 40% and 60% T>MIC exceeded 90%. 500mg, BID is optimal dose for CLCr ≤ 50mL/min	Adults, N=150	[55]
Ceftriaxone	Streptococcus pneumoniae	Extracerebral infections	CSF	PD profiling & determining PTA (2g BID, 0.5h infusion)	PTA is 76% for 50% T>MIC in CSF; PTA is 65% for 100% T>MIC in CSF	Adult females (mean age 58.9 yr) N=7	[53]
Garenoxacin	Streptococcus pneumoniae	Community-acquired pneumonia (CAP)	Serum, ELF	Evaluate exposure-response relationship by population PK/PD	fAUC0-24/MIC90 > 200 400 mg QD, Oral dosing is safe and adequate for efficacy	Adults (≥18 yr) N=580	[56,57 ]
	Streptococcus pneumonia, Staphylococcus aureus, Klebsiella pneumonia, Moraxella catarrhalis, Haemophilus influenzae	Pneumonia, secondary infection of chronic respiratory diseases, bronchitis, sinusitis, otis media, laryngopharyngitis, tonsillitis		Determine PTA in serum and ELF	PTA > 95% for fAUC0-24/MIC90 is 100 (serum) and 120 (ELF)	Adult Japanese (≥18 yr) N=136	[27]
Gatifloxacin	Streptococcus pneumoniae	Community-acquired pneumonia (CAP)	N/A	PD profiling & determining PTA at 400 mg QD, oral (young) and 200 mg QD, oral (elderly)	PTA for AUC0-24/MICall ≥ 30 is 92.3% in young; 91.4% in elderly	Adults Young (<65 yr) Elderly (>65 yr) N=183	[58]
Gemifloxacin	Streptococcus pneumoniae	Community-acquired pneumonia (CAP)	Serum, ELF	PD profiling & PTA in serum and ELF (320 mg QD, oral)	PTA (>95%, or >99% [59]) for fAUC0-24/MIC90 is 100 (ELF) and 78.3–88 (Serum)	N/A	[57,59 ]
Levofloxacin	Eschirichia coli, Chlamydia	Prostatitis	Prostatic tissue	Determine penetration at site of action (500 mg QD)	AUCprostrate/AUCplasma is 2.96	Adult (47–94 yr) N=22	[60]
	Organisms causing Pneumonia	Nocosomial pneumonia	Plasma, ELF	Determine penetration ratio in ELF (500 mg QD; 750 mg QD)	AUCELF/AUCplasma is 1.16	Adult (> 18 yr) N=24	[32]
Metronidazole	Bacteroides fragilis	N/A	Plasma and urine	PD profiling & determining PTA at 500 mg, TID; 1000 mg QD; 1500 mg QD	PTA for AUC/MIC ≥70 is 99%	Adults males, N=18 (10 healthy, 8 patients)	[61]
Moxifloxacin	Streptococcus pneumoniae	Community-acquired pneumonia (CAP) Gram-positive	Serum, ELF	PD profiling & determining PTA (400 mg QD, 1h infusion) PD profiling & prediction of	PTA (>95%) for fAUC0-24/MIC90 is 120 (ELF) and 78.3–88 (Serum); Cmax/MIC90 >10, AUC/MIC90 ~ 100	Adults (18–80 yr) N=16	[57,62]
Norvancomycin	Staphylococcus aureus	bacterial infections	Serum	CL estimates in population (400mg QD, intravenous)	95% cured clinical outcome with AUC0-24/MIC of 579.9 CL=2.54(CLCr/50) in patients with renal dysfunction CL=6.0(Body Weight/60)0.52 in healthy subjects	Adult, N=166	[38]
Oseltamivir and Oseltamivir carboxylate (OC)	Influenza A (H1N1 virus)	Influenza A and B	Serum	To determine dosing in neonates and infants	3mg/kg, BID, Oral in infants 1.7mg/kg, BID, Oral in neonates	Adult males N=6; Infants (<2 yr) N=43; Neonates (1.5–17.5 weeks)	[47,63]
Piperacillin/T azobactam (combination)	Escherichia coli, S. aureus, Klebsiella pneumonia, Pseudomonas aeruginosa, Bacteroides fragilis, Acinetobacter baumannii	Gram-negative bacterial infections	Serum	To determine PK/PD parameters & in vivo effectiveness with doses 3.375g, Q4h, Q6h; 4.5g, Q6h, Q8h (intravenous,0.5 h infusion)	T>MIC is >60% for all doses	N=20 Adult males N=12	[64,65]
Rifampin	Mycobacterium tuberculosis	Tuberculosis	Plasma, ELF, BAL, Alveolar Cells (ACs)	Determine pulmonary PK/PD in lungs & evaluate recommended dose (600 mg, QD, oral)	Cmax/MIC ≥ 175 are 95% (ACs), 48.8% (plasma), 35.9% (ELF) AUC0-24/MIC ≥ 271 is 100% (plasma); AUC0-24/MIC ≥ 665 is 54.5%(ELF); Higher doses (1200 mg) were needed as pulmonary concentration is too low with recommended dosing	Adults, N=40	[39]
Telavancin	Staphylococcus aureus	Health care associated pneumonia	Plasma and ELF	To determine penetration in ELF with 10 mg/kg QD (intravenous, 1h infusion)	AUCELF/AUCplasma is 0.73	Adult Caucasians, N=20	[36]
Vancomycin	Staphylococcus aureus	Ventilator-associated pneumonia	Plasma, Bronchoalveolar lavage fluid, ELF	To determine penetration in ELF with 1000 mg BID (intravenous)	AUCELF/AUCplasma is 0.675 AUC/MIC ≥ 400	Adults (>18 yr) N=10	[34]
Voriconazole	Candida strains	N/A	Plasma	To investigate the effect of concomitant fluconazole on Voriconazole PK	Coadministration is not recommended, Monitor for adverse events if voriconazole is sequentially administered after fluconazole	Adult males (21–55 yr) N=10	[40]

BAL bronchoalveolar lavage fluid; BID twice daily; CL clearance; CL_CR creatinine clearance; CSF cerebrospinal fluid; ELF epithelial lining fluid; N/A not available; PD pharmacodynamic; PTA pharmacodynamic target attainment; QD once daily; Q6h every six hours; Q8h every 8 hours