Scot.
moo. J., 1976,21: 197
THE PENETRATION OF MINOCYCLINE INTO HUMAN SINUS SECRETIONS D. Worgan and R. J. E. Daniel Royal South Hants Hospital Southampton and Lederle Laboratories, Cyanamid of Great Britain Limited, Gosport, Hampshire
Summary. The mean minocycline content of sinus secretions aspirated during antral wash-out in 8 patients suffering from sinusitis was found to be 1.06 I!g. per mI. (SD.1.03). This exceeds the M.I.C. for most strains of bacteria likely to be found in sinusitis. The mean minocycline serum level in these 8 patients was 3.16 ug. per ml. (S.D. 1.64). The sinus secretion to serum level ratio was therefore 0.34:1. No correlation was found between serum level and sinus secretion level, nor could any of the factors looked at in this study be correlated with the degree to which minocycline penetrated the sinus secretion. is a semi-synthetic tetracycline which has a longer half-life, M is more rapidly and more reliably absorbed I N0
eye
LIN E
and is more lipid soluble than its parent compound (Macdonald et al., 1973). A recent report (MacCulloch et al, 1974) indicating that minocycline penetrates into sputum to a greater extent than some other tetracyclines, prompted us to look at this antibiotic's ability to penetrate into sinus secretions in patients presenting for sinus wash-out. This paper presents the preliminary findings of our study. Method Patients of either sex, over the age of 12 years, who were diagnosed clinically as suffering from sinusitis of sufficient severity or chronicity to warrant antral wash-out, were eligible for the trial. Pregnant women and patients who had taken antibiotics in the week prior to inclusion in the study were excluded. The diagnostic criteria were frontal headaches, nasal obstruction with a purulent nasal discharge, and the characteristic mucosal thickening or fluid levels on X-ray examination of the sinuses. On inclusion each patient was given antibiotic cover consisting of minocycline tablets 200 mg. statim followed by 100 mg. twice a day for 4 days, and asked to attend for antral wash-out 1 to 4 days later. Patients were advised that no medication, other than simple analgesics, should be taken during the trial.
Immediately prior to wash-out the patients were asked whether they had been taking the medication as instructed and a note was made of the time since the last dose. A 10 ml. venous blood sample was then obtained, the antrum was punctured and any free fluid aspirated prior to wash-out. This sinus secretion was collected and sent in toto for analysis. When no aspirate was obtained, the washings were collected and a measured aliquot sent for analysis. The minocycline content of the serum and sinus secretion samples was measured microbiologically using Bacillus cereus ATCC 11778 as the test organism. Results Eleven patients have so far completed the study. Age, sex, diagnosis and side effects are shown in Table I. Table II gives the minocycline sinus secretion and serum levels. An aspirate was obtained 8 times in 7 patients. In 4 cases this was purulent, in 1 mucopurulent and in 3 mucoid. Washings were collected in the 3 cases where no aspirate was obtained and as might be expected only very small amounts of the antibiotic were recovered in this fluid. In the aspirated fluid, however, the mean concentration of minocycline was 1.06 ug, per ml. (S.D. 1.03), compared with a mean serum level of 3.16 ug, per ml. (S.D. 1.64), giving a sinus secretion to serum ratio of 0.34: 1. The correlation coefficient for sinus secretion to serum levels in those cases where an
Wtirgan and Daniel
Table I. Sex, age diagnosis and minocycline side effects at time of antral washout.
minocycline passes from blood to secretion. The character of the secretion is one possible Patfactor which may account for the variable ient Sex Age Diagnosis sinusitis Side extent to which minocycline penetrates into No. (yr.) effects the secretion. Like Axelsson and Brorson 1 Female 43 Bilateral Chronic Dizziness (1973), however, we were unable to show any maxillary nausea 2 Male 51 Right acute maxillary Nil significant correlation between the purulence 3 Male 24 Bilateral chronic maxillary Light-heof the secretion and the degree of antibiotic adedness 4 Female 26 Right chronic maxillary Not stated penetration. Similarly age, sex, time elapsed 5 Male 39 Bilateral acute maxillary Nil since last dose, duration of therapy before 6 Female 14 Right chronic maxillary Nil aspiration and outcome of therapy showed 7 Male· 30 Right chronic maxillary Nil no correlation with antibiotic sinus secretion. 8 Male 26 Right chronic maxillary Nil 9 Male 65 Right chronic maxillary Nil It may in fact be that none of these factors 10 Male 50 Bilateral chronic maxillary Nil is important in determining the degree to 11 Male 17 Left chronic maxillary Nil which this antibiotic penetrates into sinus aspirate was obtained was r=0.096, indicating secretions, but on the other hand it has to be an absence of correlation between blood level admitted that there are great difficulties in of the antibiotic and sinus secretion level. obtaining samples of secretion and the chances The mean sinus secretion level in the purul- of error are considerable. A much larger ent samples was higher (1.34 ~g./ml., S.D.1.25) series of patients would be needed to validate than when the sample was mucoid (0.51 ~g./ the present findings. mI., S.D. 0.21), (but this difference is not statNevertheless, it is clear from this study that istically significant). Therefore, when consid- minocycline can achieve significant levels in ering the data derived from this small series sinus secretions. A level of 1 ug. per ml. can of patients, it would appear that the concen- reasonably be expected to inhibit most strains tration of the antibiotic in the sinus secretion of bacteria responsible for sinusitis (Steigis unrelated to the appearance of the secretion. bigel et al., 1968) and if the suggestion by All 11 patients were seen at follow-up a May (1968)that relapses of chronic bronchitis week or so after wash-out. Six were symptom may be caused by organisms trapped in free, 2 were improving but still had symptoms, the secretions of the upper and lower 1 had improved for a few days but had respiratory tract is correct, then minocycline relapsed, 1 was still suffering symptoms and may be expected to be of use not only in the eventually needed a Caldwell-Luc procedure, treatment of sinusitis, but also in the prevenand 1 was found to be suffering from Wege- tion of exacerbations of chronic bronchitis. ner's granuloma with secondary sinusitis. A C K NOW LED GEM E N T S . The minocycline There was no obvious correlation between assays were carried out by the Product Research and clinical cure or failure and antibiotic serum or Development Laboratories Europe Mid-East Africa Division of Cyanamid International. sinus secretion levels. Side effects occurred in 2 patients. One REFERENCES Axelsson, A., Brorson, J. E. (1973). Concentration female became dizzy and nauseated shortly 1. ofantibiotics in sinus secretions. Ann. Otol, 82,1973 after taking the initial dose of minocycline; 2. MacCulloch, D., Richardson, R. A., Allwood, G. K. the other was a male who became light(1974). The penetration of doxycycline, oxytetraheaded on retiring to bed. cycline and minocycline into sputum. New Zealand Discussion
The present study confirms that minocycline, a new lipid soluble derivative of tetracycline, is able to penetrate into sinus secretion. The fact that there appears to be little correlation between antibiotic serum level and sinus secretion level in this study, suggests that factors other than the concentration in the serum are responsible for the extent to which 198
Medical Journal, 80, (525) 300 3. Macdonald, H., Kelly, R. G., Allen, E. S., ~obl~, J. F., Kanegis, L. A. (1973). Pharmacokinetic studies on minocycline in man. Clinical PharmaPharmacology and Therapeutics, 14, 852 4. May, J. R. (1968). Chemotherapy of chronic bronchitis and allied disorders, p43. London: English University Press Limited 5. Steigbigel, N. H., Reed, C. W., Finland, M. (1~68). Susceptibility of common pathogenic bactena to seven tetracycline antibodies in vitro. American Journal of Medical Science, 255, 179
'C 'C
-
1 1 1 1 1 1
6 7 8 9 10 11
2 2 2 2 3 7
16 2 2 2 5
Since last dose (hr.)
Volume of aspirate (ml.)
Nature of aspirate
Correlation coefficient for sinus/serum levels r=0.096
1 4 3 1 1
1 2 3 4 5
Patient From start of number minocycline to washout (days)
Time
Table II. Sinus secretion and serum minocycline levels.
Antral washout Cone. Volume of minocycline washout if in aspirate no aspirate (ug./ml.) (ml.)
- - - - - - - - - - - - - _... -
0.02
0.02
0.02
Cone. minocycline in washout (ug./ml.)
n = 11 mean=2.50 S.D.=1.5
5.10 5.10 2.23 1.98 2.13 0.53
1.30 1.15 2.35 1.65 4.00
Serum level (ug./ml.)
0.38
0.53 0.05 0.01 0.18
0.75
-
0.52
Ratio sinus secretion serum level
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moo. J., 1976,21: 197
THE PENETRATION OF MINOCYCLINE INTO HUMAN SINUS SECRETIONS D. Worgan and R. J. E. Daniel Royal South Hants Hospital Southampton and Lederle Laboratories, Cyanamid of Great Britain Limited, Gosport, Hampshire
Summary. The mean minocycline content of sinus secretions aspirated during antral wash-out in 8 patients suffering from sinusitis was found to be 1.06 I!g. per mI. (SD.1.03). This exceeds the M.I.C. for most strains of bacteria likely to be found in sinusitis. The mean minocycline serum level in these 8 patients was 3.16 ug. per ml. (S.D. 1.64). The sinus secretion to serum level ratio was therefore 0.34:1. No correlation was found between serum level and sinus secretion level, nor could any of the factors looked at in this study be correlated with the degree to which minocycline penetrated the sinus secretion. is a semi-synthetic tetracycline which has a longer half-life, M is more rapidly and more reliably absorbed I N0
eye
LIN E
and is more lipid soluble than its parent compound (Macdonald et al., 1973). A recent report (MacCulloch et al, 1974) indicating that minocycline penetrates into sputum to a greater extent than some other tetracyclines, prompted us to look at this antibiotic's ability to penetrate into sinus secretions in patients presenting for sinus wash-out. This paper presents the preliminary findings of our study. Method Patients of either sex, over the age of 12 years, who were diagnosed clinically as suffering from sinusitis of sufficient severity or chronicity to warrant antral wash-out, were eligible for the trial. Pregnant women and patients who had taken antibiotics in the week prior to inclusion in the study were excluded. The diagnostic criteria were frontal headaches, nasal obstruction with a purulent nasal discharge, and the characteristic mucosal thickening or fluid levels on X-ray examination of the sinuses. On inclusion each patient was given antibiotic cover consisting of minocycline tablets 200 mg. statim followed by 100 mg. twice a day for 4 days, and asked to attend for antral wash-out 1 to 4 days later. Patients were advised that no medication, other than simple analgesics, should be taken during the trial.
Immediately prior to wash-out the patients were asked whether they had been taking the medication as instructed and a note was made of the time since the last dose. A 10 ml. venous blood sample was then obtained, the antrum was punctured and any free fluid aspirated prior to wash-out. This sinus secretion was collected and sent in toto for analysis. When no aspirate was obtained, the washings were collected and a measured aliquot sent for analysis. The minocycline content of the serum and sinus secretion samples was measured microbiologically using Bacillus cereus ATCC 11778 as the test organism. Results Eleven patients have so far completed the study. Age, sex, diagnosis and side effects are shown in Table I. Table II gives the minocycline sinus secretion and serum levels. An aspirate was obtained 8 times in 7 patients. In 4 cases this was purulent, in 1 mucopurulent and in 3 mucoid. Washings were collected in the 3 cases where no aspirate was obtained and as might be expected only very small amounts of the antibiotic were recovered in this fluid. In the aspirated fluid, however, the mean concentration of minocycline was 1.06 ug, per ml. (S.D. 1.03), compared with a mean serum level of 3.16 ug, per ml. (S.D. 1.64), giving a sinus secretion to serum ratio of 0.34: 1. The correlation coefficient for sinus secretion to serum levels in those cases where an
Wtirgan and Daniel
Table I. Sex, age diagnosis and minocycline side effects at time of antral washout.
minocycline passes from blood to secretion. The character of the secretion is one possible Patfactor which may account for the variable ient Sex Age Diagnosis sinusitis Side extent to which minocycline penetrates into No. (yr.) effects the secretion. Like Axelsson and Brorson 1 Female 43 Bilateral Chronic Dizziness (1973), however, we were unable to show any maxillary nausea 2 Male 51 Right acute maxillary Nil significant correlation between the purulence 3 Male 24 Bilateral chronic maxillary Light-heof the secretion and the degree of antibiotic adedness 4 Female 26 Right chronic maxillary Not stated penetration. Similarly age, sex, time elapsed 5 Male 39 Bilateral acute maxillary Nil since last dose, duration of therapy before 6 Female 14 Right chronic maxillary Nil aspiration and outcome of therapy showed 7 Male· 30 Right chronic maxillary Nil no correlation with antibiotic sinus secretion. 8 Male 26 Right chronic maxillary Nil 9 Male 65 Right chronic maxillary Nil It may in fact be that none of these factors 10 Male 50 Bilateral chronic maxillary Nil is important in determining the degree to 11 Male 17 Left chronic maxillary Nil which this antibiotic penetrates into sinus aspirate was obtained was r=0.096, indicating secretions, but on the other hand it has to be an absence of correlation between blood level admitted that there are great difficulties in of the antibiotic and sinus secretion level. obtaining samples of secretion and the chances The mean sinus secretion level in the purul- of error are considerable. A much larger ent samples was higher (1.34 ~g./ml., S.D.1.25) series of patients would be needed to validate than when the sample was mucoid (0.51 ~g./ the present findings. mI., S.D. 0.21), (but this difference is not statNevertheless, it is clear from this study that istically significant). Therefore, when consid- minocycline can achieve significant levels in ering the data derived from this small series sinus secretions. A level of 1 ug. per ml. can of patients, it would appear that the concen- reasonably be expected to inhibit most strains tration of the antibiotic in the sinus secretion of bacteria responsible for sinusitis (Steigis unrelated to the appearance of the secretion. bigel et al., 1968) and if the suggestion by All 11 patients were seen at follow-up a May (1968)that relapses of chronic bronchitis week or so after wash-out. Six were symptom may be caused by organisms trapped in free, 2 were improving but still had symptoms, the secretions of the upper and lower 1 had improved for a few days but had respiratory tract is correct, then minocycline relapsed, 1 was still suffering symptoms and may be expected to be of use not only in the eventually needed a Caldwell-Luc procedure, treatment of sinusitis, but also in the prevenand 1 was found to be suffering from Wege- tion of exacerbations of chronic bronchitis. ner's granuloma with secondary sinusitis. A C K NOW LED GEM E N T S . The minocycline There was no obvious correlation between assays were carried out by the Product Research and clinical cure or failure and antibiotic serum or Development Laboratories Europe Mid-East Africa Division of Cyanamid International. sinus secretion levels. Side effects occurred in 2 patients. One REFERENCES Axelsson, A., Brorson, J. E. (1973). Concentration female became dizzy and nauseated shortly 1. ofantibiotics in sinus secretions. Ann. Otol, 82,1973 after taking the initial dose of minocycline; 2. MacCulloch, D., Richardson, R. A., Allwood, G. K. the other was a male who became light(1974). The penetration of doxycycline, oxytetraheaded on retiring to bed. cycline and minocycline into sputum. New Zealand Discussion
The present study confirms that minocycline, a new lipid soluble derivative of tetracycline, is able to penetrate into sinus secretion. The fact that there appears to be little correlation between antibiotic serum level and sinus secretion level in this study, suggests that factors other than the concentration in the serum are responsible for the extent to which 198
Medical Journal, 80, (525) 300 3. Macdonald, H., Kelly, R. G., Allen, E. S., ~obl~, J. F., Kanegis, L. A. (1973). Pharmacokinetic studies on minocycline in man. Clinical PharmaPharmacology and Therapeutics, 14, 852 4. May, J. R. (1968). Chemotherapy of chronic bronchitis and allied disorders, p43. London: English University Press Limited 5. Steigbigel, N. H., Reed, C. W., Finland, M. (1~68). Susceptibility of common pathogenic bactena to seven tetracycline antibodies in vitro. American Journal of Medical Science, 255, 179
'C 'C
-
1 1 1 1 1 1
6 7 8 9 10 11
2 2 2 2 3 7
16 2 2 2 5
Since last dose (hr.)
Volume of aspirate (ml.)
Nature of aspirate
Correlation coefficient for sinus/serum levels r=0.096
1 4 3 1 1
1 2 3 4 5
Patient From start of number minocycline to washout (days)
Time
Table II. Sinus secretion and serum minocycline levels.
Antral washout Cone. Volume of minocycline washout if in aspirate no aspirate (ug./ml.) (ml.)
- - - - - - - - - - - - - _... -
0.02
0.02
0.02
Cone. minocycline in washout (ug./ml.)
n = 11 mean=2.50 S.D.=1.5
5.10 5.10 2.23 1.98 2.13 0.53
1.30 1.15 2.35 1.65 4.00
Serum level (ug./ml.)
0.38
0.53 0.05 0.01 0.18
0.75
-
0.52
Ratio sinus secretion serum level
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rLJ
.., =
~
g;
= 51
::t:
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:
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