Ciprofloxacin Integrated Plasma, Saliva and Sweat Population Pharmacokinetics and Emergence of Resistance in Human Commensal Bacteria
Radojka Savic (1,6,9), Bruno Fantin (1,2,3), Andremont Antoine (1,2,8), Laurent Massias (7), Xavier Duval (1,4,5,6), France Mentre (1,4,6)
(1) Université Paris Diderot, (2) EA3964, “Emergence de la résistance bactérienne in vivo,” Université Paris Diderot, (3) AP-HP Hôpital Beaujon, (4) AP-HP Hôpital Bichat, (5) INSERM CIC 007, (6) INSERM UMR 738, (7) Laboratoire de Toxicologie et Pharmacocinétique, Service de Pharmacie, (8) CNR “Résistance dans les flores commensales,” AP-HP Hôpital Bichat, Paris, France (9) Stanford University, Division of Clinical Pharmacology, Stanford, USA
Objectives: Emergence of resistance to fluoroquinolones is an increasing therapeutic problem (1). One of the routes for resistance development is from selection in commensal bacteria. The ciprofloxacin pharmacodynamic AUC/MIC ratio linked to efficacious outcome in bacterial infection is well established; however its impact on the emergence of resistance in commensal bacteria is unknown. Our aim is to determine the PKPD link associated with the emergence of resistance in healthy volunteers receiving different dosages of ciprofloxacin for 14 days.
Methods: A prospective study was conducted in 48 subjects randomly assigned to six different therapeutic dosages of oral ciprofloxacin . Blood, sweat and saliva samples were collected at days 1, 7 and 14. Population PK analysis was performed using non-linear mixed effects. Drug exposure ratios in saliva:plasma and sweat:plasma samples were estimated. Model-based individual drug exposures in saliva/plasma in combination with ciprofloxacin MIC and/or mutant prevention concentration against viridians group streptococci in the pharyngeal flora and Escherichia coli in the fecal flora were used to assess potential relationship with emergence of resistance patterns using logistic regression analysis.
Results: Ciprofloxacin PK was best described by a two compartment model linked to the transit compartment absorption model. Data from all fluids were fitted simultaneously. Apparent clearance (CL) and volume of distribution (Vd) were 38.5 L/hr and 165 L (2). The saliva:plasma concentration ratio was determined to vary over time with a baseline of 0.33 exponentially decreasing to an asymptote of 0.07. The sweat:plasma concentration ratio was stable over time, indicating no accumulation of drug in sweat. Resistance emerged in the fecal (25%) and pharyngeal flora (33%) and it largely coincided with local concentrations less than the MIC. However, no variable that integrated PK data and PD parameters was found to differ significantly between the subjects in whom resistance emerged and those in whom it did not. Furthermore, probabilities of the emergence of resistance were not significantly different across the different antibiotic dosages (3).
Conclusions: Ciprofloxacin population PK in plasma, saliva and sweat was simultaneously described for the first time. Selection of resistant commensal bacteria during ciprofloxacin therapy is a frequent ecological side-effect that is not preventable simply by dosage optimization.
 Chen, D. K.,McGeer, A.,de Azavedo, J. C., Low, D. E., Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network, N Engl J Med. 1999; 341(4):233-9.
 Payen S, Serreau R, Munck A, Aujard Y, Aigrain Y, Bressolle F, Jacqz-Aigrain E., Population Pharmacokinetics of Ciprofloxacin in Pediatric and Adolescent Patients with Acute Infections, Antimicrob Agents Chemother. 2003 Oct; 47(10):3170-8.
 Fantin B, Duval X, Massias L, Alavoine L, Chau F, Retout S, Andremont A, Mentré F, Ciprofloxacin Dosage and Emergence of Resistance in Human Commensal Bacteria, J Infect Dis. 2009 Aug 1;200(3):390-8.,