Acta Otolaryngol 84: 292-295, 1977
PENETRATION OF ERYTHROMYCIN STEARATE INTO MAXILLARY SINUS MUCOSA AND SECRETION IN CHRONIC MAXILLARY SINUSITIS
M. Paavolainen, A. Kohonen, T. Palva and 0. V . Renkonen From the Otolaryngological Hospital and the Department of Serology und Bacteriology, University of Helsinki, Helsinki, Finland
(Received October 1, 1976)
Abstract. The penetration of oral erythromycin stearate
(Abboticin), administered in a dosage of 500 mg three times a day, into the maxillary sinus mucosa and secretion was studied in 15 patients (22 sinuses) operated on for chronic maxillary sinusitis. The average concentration in serum was 2.3 pg/ml, 1.2 pg/ml in secretion, and 1.8 pglml in mucosa. These concentrations are highly effective against diplococci and most aerobic and anaerobic streptococci (MIC value 0.06 pg/ml) but not against Haemophilus influenzue (MIC value for 80 % of 2 pg/ml).
The causative agents in acute paranasal sinus infections are mostly pneumococcus and Haemophilus strains, and in some cases phaemolytic streptococci and staphylococci (Axelsson & Brorson, 1973; Eneroth & Lundberg, 1976; Kalm et al., 1975; Rantanen & Arvilommi, 1973). In chronic sinusitis, however, anaerobic bacteria, especially anaerobic streptococci, are also more prominent. The prerequisite for successful treatment is the use of an antibiotic with the right antimicrobial spectrum and adequate capacity to penetrate into the infection site. In maxillary sinus infections the concomitant increase in blood flow also increases the deposition of the antibiotic agent in the mucosa. The amount of antibiotic which will subsequently reach the sinus lumen depends upon the extent of capillary leakage in the acute phase, and, in the chronic stage, upon the secretory capacity of the mucosa. Further-
more, the amount of active antibiotic in the sinus secretion is dependent on the magnitude of the insoluble protein complexes formed. The concentration of various antibiotics in the sinus mucosa and/or secretion has been studied by several authors (Axelsson & Brorson, 1973, 1974; Eneroth & Lundberg, 1976; Gnarpe & Lundberg, 1971; Jokinen & Raunio, 1975; Kalm et al., 1975; Kohonen et al., 1975; Lundberg et al., 1968, 1969; Lundberg & Malmborg, 1971). Only a few of these studies deal with erythromycin, however. Axelsson & Brorson (1974) and Kalm et al. (1975) studied erythromycin in serum and sinus secretion in acute cases, whereas no data seem to be available on erythromycin concentrations in chronic maxillary sinusitis, and on mucosal concentrations data are lacking for both acute and chronic stages. New studies are needed, because erythromycin has recently gained a more widespread use, as new effective drugs against staphylococci have been developed and there is no longer any need to hold erythromycin in reserve. In the present study we have measured erythromycin concentration in the serum, the maxillary sinus mucosa and the secretion of chronic maxillary sinusitis patients. By chronic maxillary sinusitis we mean a disease which in radiological examination shows evidence of
Penetration of erythromycin into maxillary sinus marked mucosal hyperplasia, often polypous changes, and which does not heal despite repeated antral irrigations. In histological examination such mucosa shows enormous thickening as compared with normal, inflammatory cell infiltration, increased fibrosis and frequently a marked increase in the secretory elements (Palva et al., 1962). MATERIAL AND METHODS The material consisted of 15 patients, in whom 22 maxillary sinuses were operated on for chronic maxillary sinusitis by the CaldwellLuc procedure. The ages of the patients ranged from 16 to 65 years (mean age, 42). All conservative methods for the treatment of maxillary sinusitis, such as repeated antral irrigations and antibiotics combined with antihistamines and nose drops, had failed in these patients. All the sinuses contained purulent or mucopurulent secretion when last irrigated 2 weeks prior to surgery. Detailed data on all the antibiotics that the patients had received from other physicians as treatment for the sinusitis were not available, but in most cases Penicillin V or tetracycline derivatives had been administered. The patients were premedicated with a combination of atropine and pethidine or with a combination of morphine and scopolamine. Six patients had their operation under general and 9 under local anaesthesia. The patients were given oral erythromycin stearate (Abboticin) in a dosage of 500 mg three times a day for 4 days before operation. No other medication was given during 2 weeks before surgery. The operation was performed 24 h (kih) after the last dose of erythromycin. When there was secretion which was uncontaminated with blood, a sample was aspirated through a cannula into a syringe from the opened maxillary sinus. Simultaneously a sample of venous blood was drawn from the cubital vein, and a large piece of the thick sinus mucosa including the mucoperiosteum was obtained. All three samples were sent to
293
the laboratory for estimation of erythromycin concentration. A second sample of mucosa was removed for histopathological examination. The concentration of erythromycin was determined with the punched holes technique according to Bennet et al. (1966). Samples for bacteriological analysis were taken from the nose before starting erythromycin therapy, from the secretion at operation, and from the returning fluid at irrigation, if there was still some secretion at the postoperative visit. All the patients had a check-up 2-6 months after the operation and the operated sinuses were irrigated with saline. RESULTS The bacteriological findings in 12 nasal swab specimens obtained preoparatively were pneumococci (2 patients), Haemophilus strains (2 patients) and P-hemolytic streptococci (one patient). Staphylococci were identified in three and other bacteria, also considered saprophytic, in four specimens. One specimen yielded no growth. The samples from the maxillary sinus secretion, taken after 4 days of erythromycin treatment, showed that 12 sinuses were sterile. Haemophilus injluenzae was cultured from three and para-injluenzae from two sinuses. None showed diplococci. P-hemolytic streptococci were found in one sinus, anaerobic streptococci in one and staphylococcus in two sinuses. Postoperatively, all but three sinuses were free from secretion. One had yellow staphylococci in culture and in one patient both sinuses showed continuous infection with Haemophilus injluenzae. Primarily the sinus system of this patient was extensively diseased with severely damaged mucosa in the nasal passages too and it has not been possible to bring the infection under complete control after surgery with any drug. An adequate sample of blood-free secretion was obtained from 18 sinuses for the determination of erythromycin concentration. The
294
M . Paavolainen et al.
Table I. Concentration of erythromycin in serum, secretion and rnucosa Concentration, p g / d Secretion Patient no.
Serum
Left
Mucosa Right
1 0.94 0.56 2 2.3 0.27 3 0.21 0.13 4 0.49 0.18 5 1.5 0.88 6 0.66 0.20 7 3.6 8 2.8 0.70 9 No sample 2.5 10 5.0 2.1 1.6 I1 3.6 1.1 2.3 12 2.6 1.5 3 .O 13 3.1 1.2 1.4 14 4.4 1.1 15 0.4 0.13 No. of 14 I8 samples Mean 2.3 1.2 Range 0.21-5.0 0.13-3.0 Secretion/serum 0.5 Mucosa/serum
Left
Right
0.66 1.3 0.24
PENETRATION OF ERYTHROMYCIN STEARATE INTO MAXILLARY SINUS MUCOSA AND SECRETION IN CHRONIC MAXILLARY SINUSITIS
M. Paavolainen, A. Kohonen, T. Palva and 0. V . Renkonen From the Otolaryngological Hospital and the Department of Serology und Bacteriology, University of Helsinki, Helsinki, Finland
(Received October 1, 1976)
Abstract. The penetration of oral erythromycin stearate
(Abboticin), administered in a dosage of 500 mg three times a day, into the maxillary sinus mucosa and secretion was studied in 15 patients (22 sinuses) operated on for chronic maxillary sinusitis. The average concentration in serum was 2.3 pg/ml, 1.2 pg/ml in secretion, and 1.8 pglml in mucosa. These concentrations are highly effective against diplococci and most aerobic and anaerobic streptococci (MIC value 0.06 pg/ml) but not against Haemophilus influenzue (MIC value for 80 % of 2 pg/ml).
The causative agents in acute paranasal sinus infections are mostly pneumococcus and Haemophilus strains, and in some cases phaemolytic streptococci and staphylococci (Axelsson & Brorson, 1973; Eneroth & Lundberg, 1976; Kalm et al., 1975; Rantanen & Arvilommi, 1973). In chronic sinusitis, however, anaerobic bacteria, especially anaerobic streptococci, are also more prominent. The prerequisite for successful treatment is the use of an antibiotic with the right antimicrobial spectrum and adequate capacity to penetrate into the infection site. In maxillary sinus infections the concomitant increase in blood flow also increases the deposition of the antibiotic agent in the mucosa. The amount of antibiotic which will subsequently reach the sinus lumen depends upon the extent of capillary leakage in the acute phase, and, in the chronic stage, upon the secretory capacity of the mucosa. Further-
more, the amount of active antibiotic in the sinus secretion is dependent on the magnitude of the insoluble protein complexes formed. The concentration of various antibiotics in the sinus mucosa and/or secretion has been studied by several authors (Axelsson & Brorson, 1973, 1974; Eneroth & Lundberg, 1976; Gnarpe & Lundberg, 1971; Jokinen & Raunio, 1975; Kalm et al., 1975; Kohonen et al., 1975; Lundberg et al., 1968, 1969; Lundberg & Malmborg, 1971). Only a few of these studies deal with erythromycin, however. Axelsson & Brorson (1974) and Kalm et al. (1975) studied erythromycin in serum and sinus secretion in acute cases, whereas no data seem to be available on erythromycin concentrations in chronic maxillary sinusitis, and on mucosal concentrations data are lacking for both acute and chronic stages. New studies are needed, because erythromycin has recently gained a more widespread use, as new effective drugs against staphylococci have been developed and there is no longer any need to hold erythromycin in reserve. In the present study we have measured erythromycin concentration in the serum, the maxillary sinus mucosa and the secretion of chronic maxillary sinusitis patients. By chronic maxillary sinusitis we mean a disease which in radiological examination shows evidence of
Penetration of erythromycin into maxillary sinus marked mucosal hyperplasia, often polypous changes, and which does not heal despite repeated antral irrigations. In histological examination such mucosa shows enormous thickening as compared with normal, inflammatory cell infiltration, increased fibrosis and frequently a marked increase in the secretory elements (Palva et al., 1962). MATERIAL AND METHODS The material consisted of 15 patients, in whom 22 maxillary sinuses were operated on for chronic maxillary sinusitis by the CaldwellLuc procedure. The ages of the patients ranged from 16 to 65 years (mean age, 42). All conservative methods for the treatment of maxillary sinusitis, such as repeated antral irrigations and antibiotics combined with antihistamines and nose drops, had failed in these patients. All the sinuses contained purulent or mucopurulent secretion when last irrigated 2 weeks prior to surgery. Detailed data on all the antibiotics that the patients had received from other physicians as treatment for the sinusitis were not available, but in most cases Penicillin V or tetracycline derivatives had been administered. The patients were premedicated with a combination of atropine and pethidine or with a combination of morphine and scopolamine. Six patients had their operation under general and 9 under local anaesthesia. The patients were given oral erythromycin stearate (Abboticin) in a dosage of 500 mg three times a day for 4 days before operation. No other medication was given during 2 weeks before surgery. The operation was performed 24 h (kih) after the last dose of erythromycin. When there was secretion which was uncontaminated with blood, a sample was aspirated through a cannula into a syringe from the opened maxillary sinus. Simultaneously a sample of venous blood was drawn from the cubital vein, and a large piece of the thick sinus mucosa including the mucoperiosteum was obtained. All three samples were sent to
293
the laboratory for estimation of erythromycin concentration. A second sample of mucosa was removed for histopathological examination. The concentration of erythromycin was determined with the punched holes technique according to Bennet et al. (1966). Samples for bacteriological analysis were taken from the nose before starting erythromycin therapy, from the secretion at operation, and from the returning fluid at irrigation, if there was still some secretion at the postoperative visit. All the patients had a check-up 2-6 months after the operation and the operated sinuses were irrigated with saline. RESULTS The bacteriological findings in 12 nasal swab specimens obtained preoparatively were pneumococci (2 patients), Haemophilus strains (2 patients) and P-hemolytic streptococci (one patient). Staphylococci were identified in three and other bacteria, also considered saprophytic, in four specimens. One specimen yielded no growth. The samples from the maxillary sinus secretion, taken after 4 days of erythromycin treatment, showed that 12 sinuses were sterile. Haemophilus injluenzae was cultured from three and para-injluenzae from two sinuses. None showed diplococci. P-hemolytic streptococci were found in one sinus, anaerobic streptococci in one and staphylococcus in two sinuses. Postoperatively, all but three sinuses were free from secretion. One had yellow staphylococci in culture and in one patient both sinuses showed continuous infection with Haemophilus injluenzae. Primarily the sinus system of this patient was extensively diseased with severely damaged mucosa in the nasal passages too and it has not been possible to bring the infection under complete control after surgery with any drug. An adequate sample of blood-free secretion was obtained from 18 sinuses for the determination of erythromycin concentration. The
294
M . Paavolainen et al.
Table I. Concentration of erythromycin in serum, secretion and rnucosa Concentration, p g / d Secretion Patient no.
Serum
Left
Mucosa Right
1 0.94 0.56 2 2.3 0.27 3 0.21 0.13 4 0.49 0.18 5 1.5 0.88 6 0.66 0.20 7 3.6 8 2.8 0.70 9 No sample 2.5 10 5.0 2.1 1.6 I1 3.6 1.1 2.3 12 2.6 1.5 3 .O 13 3.1 1.2 1.4 14 4.4 1.1 15 0.4 0.13 No. of 14 I8 samples Mean 2.3 1.2 Range 0.21-5.0 0.13-3.0 Secretion/serum 0.5 Mucosa/serum
Left
Right
0.66 1.3 0.24
