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Entry of four tetracyclines into saliva and tears
Abstract:
Although meningococci are susceptible to the tetracyclines by testing in vitro, oxytetracycline (OC) and doxycycline (DC) have failed to eliminate carriage, whereas minocycline (MC) has been effective. Because these congeners differ in lipophilicity, they and tetracycline (TC) were studied in volunteers by assay of serum, saliva, and tears obtained after 5 days of treatment. OC and TC were undetectable or attained concentrations subinhibitory for meningococci in saliva and tears. The concentrations of MC in saliva and tears were equal to or greater than the average minimal inhibitory concentration as long as 12 h post-dose. Near inhibitory concentrations resulted with DC at 100 mg/day; yet, doubling the dose to 100 mg/12 h did not yield concentrations that exceeded the average minimal inhibitory concentration for meningococci. The previous reports of failure or meager entry of DC and MC into saliva probably reflected extraction of these drugs in the paraffin chewed by subjects to stimulate salivary flow. The efficiency of entry of the tetracyclines into the secretions of the noninflamed upper respiratory tract correlates with lipophilicity at physiological pH, enabling prediction of meningococcal chemoprophylactic efficacy.
Insights
Minocycline effectively eliminates meningococcal carriage by achieving high concentrations in saliva and tears. Other tetracyclines like doxycycline show limited efficacy due to poor entry into these secretions.
Area of Science:
- Pharmacology
- Microbiology
- Infectious Diseases
Background:
- Meningococci carriage is a target for chemoprophylaxis.
- Tetracyclines exhibit in vitro activity against meningococci.
- Clinical efficacy varies, with minocycline (MC) successful and oxytetracycline (OC)/doxycycline (DC) failing to eliminate carriage.
Purpose of the Study:
- To investigate the pharmacokinetic differences of tetracyclines in human secretions.
- To correlate drug lipophilicity with entry into saliva and tears.
- To predict meningococcal chemoprophylactic efficacy based on drug penetration.
Main Methods:
- Volunteers received tetracycline (TC), OC, DC, or MC for 5 days.
- Serum, saliva, and tears were collected and assayed for drug concentrations.
- Minimal inhibitory concentrations (MIC) for meningococci were used as a benchmark.
Main Results:
- OC and TC concentrations were subinhibitory in saliva and tears.
- MC achieved concentrations exceeding meningococcal MIC in saliva and tears for 12 hours.
- DC at 100 mg/day showed near-inhibitory concentrations, but higher doses did not improve penetration significantly.
Conclusions:
- Drug lipophilicity at physiological pH dictates entry into upper respiratory tract secretions.
- Minocycline's superior penetration explains its efficacy in eliminating meningococcal carriage.
- This correlation allows prediction of chemoprophylactic effectiveness for other tetracyclines.