Abstract
We conducted a systematic search to describe the current state of knowledge regarding the utility of saliva for clinical pharmacokinetic monitoring (CPM) of antibiotics. Although the majority of identified studies lacked sufficient pharmacokinetic data needed to assign an appropriate suitability classification, most aminoglycosides, fluoroquinolones, macrolides, penicillins/cephalosporins, and tetracyclines are likely not suitable for CPM in saliva. No clear pattern of correlation was observed between physiochemical properties that favor drug distribution into saliva and the likelihood of the antibiotic being classified as suitable for CPM in saliva (and vice versa). Insufficient data were available to determine if pathophysiological conditions affected salivary distribution of antibiotics. Additional confirmatory data are required for drugs (especially in patients) that are deemed likely suitable for CPM in saliva because only a few studies were available and many focused only on healthy subjects. All studies identified had relatively small sample sizes and exhibited large variability. Very few studies reported salivary collection parameters (e.g., salivary flow, pH) that could potentially have some impact on drug distribution into saliva. The available data are heavily weighted on healthy subjects, and insufficient data were available to determine if pathophysiology had effects on saliva drug distribution. Some studies also lacked assay sensitivity for detecting antibiotics in saliva. Overall, this review can be useful to clinicians who desire an overview on the suitability of saliva for conducting CPM of specific antibiotics, or for researchers who wish to fill the identified knowledge gaps to move the science of salivary CPM further.
Similar content being viewed by others
References
Koka S, Beebe TJ, Merry SP, et al. The preferences of adult outpatients in medical or dental care settings for giving saliva, urine or blood for clinical testing. J Am Dent Assoc. 2008;139:735–40.
Raju KS, Taneja I, Singh SP, et al. Utility of noninvasive biomatrices in pharmacokinetic studies. Biomed Chromatogr. 2013;27:1354–66.
Mullangi R, Agrawal S, Srinivas NR. Measurement of xenobiotics in saliva: is saliva an attractive alternative matrix? Case studies and analytical perspectives. Biomed Chromatogr. 2009;23:3–25.
Drobitch RK, Svensson CK. Therapeutic drug monitoring in saliva: an update. Clin Pharmacokinet. 1992;23:365–79.
Aps JK, Martens LC. Review: the physiology of saliva and transfer of drugs into saliva. Forensic Sci Int. 2005;150:119–31.
Najjar TA, Alkharfy KM, Saad SY. Mechanism and implication of cephalosporin penetration into oropharyngeal mucosa. J Infect Chemother. 2009;15:70–4.
Patsalos PN, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs by use of saliva. Ther Drug Monit. 2013;35:4–29.
Bosker WM, Huestis MA. Oral fluid testing for drugs of abuse. Clin Chem. 2009;55:1910–31.
ter Heine R, Bejinen JH, Huitema AD. Bioanalytical issues in patient-friendly sampling methods for therapeutic drug monitoring: focus on antiretroviral drugs. Bioanalysis. 2009;1:1329–38.
Kiang TK, Hafeli UO, Ensom MH. A comprehensive review on the pharmacokinetics of antibiotics in interstitial fluid spaces in humans: implications on dosing and clinical pharmacokinetic monitoring. Clin Pharmacokinet. 2014;53:695–730.
Kiang TK, Schmitt V, Ensom MH, et al. Therapeutic drug monitoring in interstitial fluid: a feasibility study using a comprehensive panel of drugs. J Pharm Sci. 2012;101:4642–52.
Berkovitch M, Bistritzer T, Aladjem M, et al. Clinical relevance of therapeutic drug monitoring of digoxin and gentamicin in the saliva of children. Ther Drug Monit. 1998;20:253–6.
Berkovitch M, Goldman M, Siliverman R, et al. Therapeutic drug monitoring of once daily gentamicin in serum and saliva of children. Eur J Pediatr. 2000;159:697–8.
Hendeles L, Hill M, Lafrate RP. Measurement of tobramycin concentrations in saliva. Drug Intell Clin Pharm. 1985;19:378–80.
Madsen V, Lind A, Rasmussen M, et al. Determination of tobramycin in saliva is not suitable for therapeutic drug monitoring of patients with cystic fibrosis. J Cyst Fibros. 2004;3:249–51.
Bender IB, Pressman RS, Tashman SG. Studies on excretion of antibiotics in human saliva. I. Penicillin and streptomycin. J Am Dent Assoc. 1953;46:164–70.
Spencer H, Kozlowska W, Davies JC, et al. Measurement of tobramycin and gentamicin in saliva is not suitable for therapeutic drug monitoring of patients with cystic fibrosis. J Cyst Fibros. 2005;4:209.
LeBel M, Vallee F, Bergeron MG. Tissue penetration of ciprofloxacin after single and multiple doses. Antimicrob Agents Chemother. 1986;29:501–5.
LeBel M, Barbeau G, Bergeron MG, et al. Pharmacokinetics of ciprofloxacin in elderly subjects. Pharmacotherapy. 1986;6:87–91.
Darouiche R, Perkins B, Musher D, et al. Levels of rifampin and ciprofloxacin in nasal secretions: correlation with MIC90 and eradication of nasopharyngeal carriage of bacteria. J Infect Dis. 1990;162:1124–7.
Zhai S, Wei X, Parker BM, et al. Relation between plasma and saliva concentrations of enoxacin, ciprofloxacin, and theophylline. Ther Drug Monit. 1996;18:666–71.
Kozjek F, Suturkova LJ, Antolic G, et al. Kinetics of 4-fluoroquinolones permeation into saliva. Biopharm Drug Dispos. 1999;20:183–91.
Brunner M, Stabeta H, Moller JG, et al. Target site concentrations of ciprofloxacin after single intravenous and oral doses. Antimicrob Agents Chemother. 2002;46:3724–30.
Jaehde U, Sorgel F, Reiter A, et al. Effect of probenecid on the distribution and elimination of ciprofloxacin in humans. Clin Pharmacol Ther. 1995;58:532–41.
Gonzalez MA, Uribe F, Moisen SD, et al. Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother. 1984;26:741–4.
Smith A, Weber A, Pandher R, et al. Utilization of salivary concentrations of ciprofloxacin in subjects with cystic fibrosis. Infection. 1997;25:106–8.
Stass H, Dalhoff A, Kubitza D, et al. Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrob Agents Chemother. 1998;42:2060–5.
Muller M, Stass H, Brunner M, et al. Penetration of moxifloxacin into peripheral compartments in humans. Antimicrob Agents Chemother. 1999;43:2345–9.
Burkhardt O, Borner K, Stass H, et al. Single- and multiple-dose pharmacokinetics of oral moxifloxacin and clarithromycin, and concentrations in serum, saliva and faeces. Scand J Respir Dis. 2002;34:898–903.
Beyer G, Hiemer-Bau M, Ziege S, et al. Impact of moxifloxacin versus clarithromycin on normal oropharyngeal microflora. Eur J Clin Microbiol Infec Dis. 2000;19:548–50.
Burkhardt O, Derendorf H, Jager D, et al. Moxifloxacin distribution in the interstitial space of infected decubitus ulcer tissue of patients with spinal cord injury measured by in vivo microdialysis. Scand J Infect Dis. 2006;38:904–8.
Muller M, Stass H, Brunner M, et al. Penetration of moxifloxacin into peripheral compartments in humans. Antimicrob Agnets Chemother. 1999;43:2345–9.
Ohkubo T, Suno M, Kudo M, et al. Column-switching high-performance liquid chromatography of ofloxacin in human saliva and correlation of ofloxacin level in saliva and serum. Ther Drug Monit. 1996;18:598–603.
Immanuel C, Hemanthkumar AK, Gurumurthy P, et al. Dose related pharmacokinetics of ofloxacin in healthy volunteers. Int J Tuberc Lung Dis. 2002;6:1017–22.
Warlich R, Korting HC, Schafer-Korting M, et al. Multiple-dose pharmacokinetics of ofloxacin in serum, saliva, and skin blister fluid of healthy volunteers. Antimicrob Agents Chemother. 1990;34:78–81.
Kern W, Kurrle E, Vanek E. Ofloxacin for prevention of bacterial infections in granulocytopenic patients. Infection. 1987;15:427–33.
Takagi K, Hasegawa T, Yamaki K, et al. Secretion of ofloxacin into saliva in patients with respiratory tract infection. Int J Clin Pharmacol Ther Toxicol. 1992;30:46–50.
Koizumi F, Ohnishi A, Takemura H, et al. Effective monitoring of concentrations of ofloxacin in saliva of patients with chronic respiratory tract infections. Antimicrob Agents Chemother. 1994;38:1140–3.
Fujita K, Matsuoka N, Takenaka I, et al. Pharmacokinetics of ofloxacin: measurement of drug concentration in saliva of patients with impaired renal function. Drugs. 1995;49:312–3.
Miya T, Hamakubo S, Goya T, et al. Ofloxacin concentrations in serum, saliva and pleural effusion of patients with pulmonary tuberculosis and lung cancer. Jpn J Antibiot. 1995;48:960–4.
Fujita I, Sindhu RK, Kikkawa Y. Hepatic cytochrome P450 enzyme imprinting in adult rat by neonatal benzo[a]pyrene administration. Pediatr Res. 1995;37:646–51.
Mignot A, Guillaume M, Brault M, et al. Multiple-dose pharmacokinetics and excretion balance of gatifloxacin, a new fluoroquinolone antibiotic, following oral administration to healthy Caucasian volunteers. Chemotherapy. 2002;48:116–21.
Edlund C, Bergan T, Josefsson K, et al. Effect of norfloxacin on human oropharyngeal and colonic microflora and multiple-dose pharmacokinetics. Scand J Infec Dis. 1987;19:113–21.
Janin N, Meugnier H, Desnottes JF, et al. Recovery of pefloxacin in saliva and feces and its action on oral and fecal floras of healthy volunteers. Antimicrob Agents Chemother. 1987;31:1665–8.
Malizia T, Tejada MR, Ghelardi E, et al. Periodontal tissue disposition of azithromycin. J Periodontol. 1997;68:1206–9.
Blandizzi C, Malizia T, Lupetti A, et al. Periodontal tissue disposition of azithromycin in patients affected by chronic inflammatory periodontal diseases. J Periodontol. 1999;70:960–6.
Malizia T, Batoni G, Ghelardi E, et al. Interaction between piroxicam and azithromycin during distribution to human periodontal tissues. J Periodontol. 2001;72:1151–6.
Idkaidek N, Arafat T. Saliva versus plasma pharmacokinetics: theory and application of a salivary excretion classification system. Mol Pharm. 2012;9:2358–63.
Wust J, Hardegger U. Penetration of clarithromycin into human saliva. Chemotherapy. 1993;39:293–6.
Kees F, Wellenhofer M, Grobecker H. Serum and cellular pharmacokinetics of clarithromycin 500 mg q.d. and 250 mg b.i.d. in volunteers. Infection. 1995;23:168–72.
Goddard AF, Jessa MJ, Barrett DA, et al. Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice. Gastroenterology. 1996;111:358–67.
Bolhuis MS, van Altena R, van Hateren K, et al. Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2013;57:3676–80.
Berend N, Rutland J, Marlin GE. Plasma and saliva concentrations for a new formulation of erythromycin stearate. Curr Med Res Opin. 1979;6:118–23.
Henry J, Turner P, Garland M, et al. Plasma and salivary concentrations of erythromycin after administration of three different formulations. Postgrad Med J. 1980;56:707–10.
Ducci M, Scalori V, Del Tacca M, et al. The pharmacokinetics of two erythromycin esters in plasma and in saliva following oral administration in humans. Int J Clin Pharmacol Ther Toxicol. 1981;19:494–7.
Stephen KW, McCrossan J, Mackenzie D, et al. Factors determining the passage of drugs from blood into saliva. Br J Clin Pharmacol. 1980;9:51–5.
Geerdes-Fenge HF, Goetschi B, Rau M, et al. Comparative pharmacokinetics of dirithromycin and erythromycin in normal volunteers with special regard to accumulation in polymorphonuclear leukocytes and in saliva. Eur J Clin Pharmacol. 1997;53:127–33.
Stjernquist-Desatnik A, Samuelsson P, Walder M. Penetration of penicillin V to tonsillar surface fluid in healthy individuals and in patients with acute tonsillitis. J Laryngol Otol. 1993;107:309–12.
Del Tacca M, Danesi R, Bernardini N, et al. Roxithromycin penetration into gingiva and alveolar bone of odontoiatric patients. Chemotherapy. 1990;36:332–6.
Baglie S, Del Ruenis AP, Motta RH, et al. Plasma and salivary amoxicillin concentrations and effect against oral microorganisms. Int J Clin Pharmacol Ther. 2007;45:556–62.
Ortiz RA, Calafatti SA, Corazzi A, et al. Amoxicillin and ampicillin are not transferred to gastric juice irrespective of Helicobacter pylori status or acid blockade by omeprazole. Ailment Pharmacol Ther. 2002;16:1163–70.
Akimoto Y, Mochizuki Y, Uda A, et al. Concentrations of ampicillin in human serum and mixed saliva following a single oral administration of lenampicillin, and relationship between serum and mixed saliva concentrations. J Nihon Univ Sch Dent. 1990;32:14–8.
Speirs CF, Stenhouse D, Stephen KW, et al. Comparison of human serum, parotid and mixed saliva levels of phenoxymethylpenicillin, ampicillin, cloxacillin and cephalexin. Br J Clin Pharmacol. 1971;43:242–7.
May JR, Delves DM. Treatment of chronic bronchitis with ampicillin: some pharmacological observation. Lancet. 1965;1:233.
Stewart SM, Fisher M, Young JE, et al. Ampicillin levels in sputum, serum, and saliva. Thorax. 1970;25:304–11.
Stromberg A, Friberg U, Cars O. Concentrations of phenoxymethylpenicillin and cefadroxil in tonsillar tissue and tonsillar surface fluid. Eur J Clin Microbiol. 1987;6:525–9.
Grahn E, Holm SE. Penicillin concentration in saliva and its influence on bacterial interference. Scand J Infect Dis. 1987;19:235–41.
Quiding H, Arwidsson HG, Grahn E, et al. Saliva-resistant coating of tablets prevents oral release of penicillin: plasma but not saliva equivalence. Eur J Clin Pharmacol. 1998;54:749–52.
Zerfowski M, Schlegel P, Maier H. Pharmacokinetics of cefotiam in plasma, parotid saliva and mixed saliva in healthy adults. Arzneimittelforschung. 1991;41:257–9.
Venetis G, Chatzika K, Pitsiou G, et al. Saliva and blood concentration of cefuroxime in patients undergoing maxillofacial surgery. J Oral Maxillofac Surg. 2012;70:1398–403.
Havard CW, Bax RP, Samanta TC, et al. Sputum and blood concentrations of cefuroxime in lower respiratory tract infection. Thorax. 1980;35:379–83.
Hoeprich PD, Warshauer DM. Entry of four tetracyclines into saliva and tears. Antimicrob Agents Chemother. 1974;5:330–6.
Stoller NH, Johnson LR, Trapnell S, et al. The pharmacokinetic profile of a biodegradable controlled-release delivery system containing doxycycline compared to systemically delivered doxycycline in gingival crevicular fluid, saliva, and serum. J Periodontol. 1998;69:1085–91.
Sakellari D, Goodson JM, Kolokotronis A, et al. Concentration of 3 tetracyclines in plasma, gingival crevice fluid and saliva. J Clin Periodontol. 2000;27:53–60.
Burian B, Zeitlinger M, Donath O, et al. Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers. Antimicrob Agnets Chemother. 2012;56:532–5.
Hara S, Uchiyama M, Toshinari M, et al. A simple high-performance liquid chromatography for the determination of linezolid in human plasma and saliva. Biomed Chromatogr. 2015:3441–2 (Epub ahead of print).
Van Oosten MA, Notten FJ, Mikx FH. Metronidazole concentrations in human plasma, saliva, and gingival crevice fluid after a single dose. J Dent Res. 1986;65:1420–3.
Rotzetter PA, Le Liboux A, Pichard E, et al. Kinetics of spiramycin/metronidazole (Rodogyl) in human gingival crevicular fluid, saliva and blood. J Clin Periodontol. 1994;21:595–600.
Pahkla ER, Koppel T, Saaq M, et al. Metronidazole concentrations in plasma, saliva and periodontal pockets in patients with periodontitis. J Clin Periodontol. 2005;32:163–6.
Devine LF, Johnson DP, Hagerman CR, et al. Rifampin. Levels in serum and saliva and effect on the meningococcal carrier state. JAMA. 1970;214:1055–9.
Devine LF, Johnson DP, Rhode SL, et al. Rifampin: effect of two-day treatment on the meningococcal carrier state and the relationship to the levels of drug in sera and saliva. Am J Med Sci. 1971;261:79–83.
McCracken GH, Ginsburg CM, Zweighaft RC, et al. Pharmacokinetics of rifampin in infants and children: relevance to prophylaxis against Haemophilus influenzae type b disease. Pediatrics. 1980;66:17–21.
Orisakwe OE, Akunyili DN, Agbasi PU, et al. Some plasma and saliva pharmacokinetics parameters of rifampicin in the presence of pefloxacin. Am J Ther. 2004;11:283–7.
Ezejiofor NA, Brown S, Barikpoar E, et al. Effect of ofloxacin and norfloxacin on rifampicin pharmacokinetics in man. Am J Ther. 2015;22:29–36.
Catena E, Perez G, Sadaba B, et al. A fast reverse-phase high performance liquid chromatographic tandem mass spectrometry assay for the quantification of clindamycin in plasma and saliva using a rapid resolution package. J Pharm Biomed Anal. 2009;50:649–54.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Neither authors (Tony K.L. Kiang and Mary H.H. Ensom) received any funding for the preparation of this manuscript. Tony K.L. Kiang and Mary H.H. Ensom have no real or perceived conflicts of interests to declare.
Rights and permissions
About this article
Cite this article
Kiang, T.K.L., Ensom, M.H.H. A Qualitative Review on the Pharmacokinetics of Antibiotics in Saliva: Implications on Clinical Pharmacokinetic Monitoring in Humans. Clin Pharmacokinet 55, 313–358 (2016). https://doi.org/10.1007/s40262-015-0321-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-015-0321-z