828
Penetration of Pefloxacin into Maxillary Sinus Cavity and Nasal Secretions G. Petrikkos 1., P. G o u m a s 2, E. Moschovakis 2, H. Giamarellou I
The ability of oral pefloxacin to penetrate into maxillary sinus cavity and nasal secretions was studied in 39 patients suffering from an exacerbation of chronic maxillary sinusitis. The mean levels of pefloxacin in sinus aspirate fluid 0, 3, 6, 9 and 12 h after the second oral dose of 400 mg were 2.30, 6.92, 3.74, 3.47 and 2.82 rag/! respectively. In sinus cystic fluid (macroscopically non-purulent) the mean pefloxacin levels were 2.30, 7.15, 4.20 and 4.15 rag/! respectively, and in nasal secretion 1.90, 9.05, 3.71, 3.20 and 2.85 mg/l respectively. The mean pefloxacin levels in serum obtained simultaneously were 1.50, 5.00, 3.10, 2.70 and 2.20 mg/I respectively. It is concluded that pefloxacin accumulates in inflamed sinus fluid at concentrations exceeding blood levels.
Chronic maxillary sinusitis (CMS) can lead to irreversible mucosal damage with replacement of the ciliate epithelium by stratified squamous epithelium and loss of effective clearance of bacteria (1). Since normal defence mechanisms are hampered, therapy of CMS should be based mainly on antimicrobial chemotherapy and, when indicated, surgical drainage. An appropriate antibiotic for treating CMS should not only be active in vitro against the potential pathogens but should possess advantageous pharmacokinetics in sinus secretions. In selecting antimicrobial agents, factors other than antimicrobial activity against the potential pathogens must be taken into account, in particular the ability of an antibiotic to penetrate in to the sinus cavity. This property is of major importance in CMS since the infection is localised in a bone enclosed cavity with impaired or completely 1First Department of Propedeutic Medicine, Athens University School of Medicine,Laiko General Hospital, Agiou Thoma 17, Athens 115 27, Greece. ZDepartment of Otolaryngology, University of Patras, Patras, Greece.
Eur. J. Clin. Microbiol. Infect. Dis.
occluded drainage plus a poorly vascularized mucosa. Pefloxacin is a new fluorinated quinolone which is reported to have potent antimicrobial activity against Enterobacteriaceae and Pseudomonas aeruginosa, including strains resistant to other classes of antibiotics, and is also active against Haemophilus spp. and methicillin-susceptible staphylococci (2-8). Its activity against methicillin-resistant staphylococci is disputed however, (9) while increasing resistance of Pseudomonas aeruginosa has been reported in some countries (10). Bacteroides fragilis and Bacteroides melaninogenicus oralis are generally resistant to pefloxacin (2). The absorption of pefloxacin following oral administration is excellent. The serum half-life is 12 hours, while less than 10 % of the administered dose is excreted in the urine in unchanged form and about 40 % as two major metabolites (11, 12). In view of these properties and the satisfactory tolerance of pefloxacin when administered orally (6), we evaluated its pharmacokinetics in maxillary sinus cavity and nasal secretions.
Patients and Methods. Thirty-nine patients (14 males and 25 females) whose ages ranged from 18 to 46 years (mean 33.1 -+ 12.5, median 32) were entered in the study. All patients were suffering from an exacerbation of CMS. The diagnosis was verified in every case by reviewing the clinical course of the disease which in all cases exceeded a duration of one year (13). All patients presented with protracted nasal congestion, purulent nasal discharge and facial pain or toothache. Air-fluid levels or completely opaque sinuses were observed on conventional x-ray examination in all patients. The infection was unilateral in 27 patients and bilateral in 12, while 5 patients had concomitant frontal sinus involvement. Before starting therapy, undiluted antral secretions were obtained by aspiration with a trocar inserted through the inferior nasal meatus. Quantitative aerobic and anaerobic cultures of all specimens were performed by conventional methods. Having obtained maxillary secretions by aspiration, a thin plastic catheter was inserted through the trocar into the maxillary sinus while the trocar was removed. The catheter remained in place throughout the period of collection of samples for pharmacokinetic studies. Purulent nasal secretions were also obtained by aspiration from the floor of the nose and from the area of the middle meatus where drains the anterior ethmoid complex.
Vol. 11, 1992
829
Pefloxacin was administered in two doses of 400 mg p.o. given 12 hours apart. Following the second oral dose of pefloxacin, sinus and nasal secretion specimens were obtained 0, 3, 6, 9 and 12 hours post-dose. Blood specimens were also obtained concomitantly. Pefloxacin levels were then measured by an agar-well diffusion bioassay with isotonic Sensitest agar (Oxoid 471, Oxoid, UK) using Escherichia coli (ICB 4004) as the indicator microorganism. Sinus or nasal samples containing visible blood were discarded.
Results and Discussion. The culture results are shown in Table 1. Overall, 48.7 % of the infections were characterised as pure aerobic, 15.4 % as pure anaerobic and 20.5 % as mixed aerobicanaerobic, while in 15.4 % sterile effusions were found, mainly in cystic sinus fluid. Staphylococcus spp. (35.4 %), Streptococcus spp. (22.5 %) and Haemophilus influenzae (22.5 %) were the most frequently isolated pathogens among the aerobes while Bacteroides spp. were the most frequently isolated pathogens among the anaerobes. Sinus fluid and nasal secretion samples obtained from six patients were not assayed because they contained blood. Mean peak pefloxacin levels (Table 2), which were observed 3 hours after the second dose in all types of specimens, were 5.0 -+ 1.3 mg/1, 6.9 +- 1.08 mg/l, 7.1 ± 1.34 mg/l and 9.1 :t 0.21 mg/1 in serum, sinus fluid, cystic fluid and nasal secretions respectively.
Table 1: Results of culture in 39 patients with an exacerbation of chronic maxillary sinusitis. Pathogen
Number
Aerobes Streptococcus pneumoniae Viridans streptococci Enterococcus f aecalis Group D streptococci Staphylococcus aureus Staphylococcus epidermidis Klebsiella oxytoca Escherichia coli Pseudomonas aeruginosa Haemophilus influenzae Branhamella catarrhalis
3 1 1 2 4 7 1 2 2 7 1
Anaerobes Bacteroides fragilis Other Bacteroides spp. Propionibacterium aches Peptostreptococcus spp. Mieroaerophilie cocci Fusobacterium spp.
2 3 3 2 2 1
In the treatment of sinusitis the choice of antibiotics should be based not only on the expected bacteriological findings and the antibiotic susceptibility patterns, but also on the pharmacokinetie behaviour of the agents in sinus secretions. The concentration of various older oral antibiotics (penicillin, ampicillin, cephradin, tetracycline, spiramycin and erythromycin) in the sinus cavity has been studied by several authors (14-17). Few investigators have, to the best of our knowledge, examined the ability of newer quinolones to penetrate into the sinus and nasal secretions and mucosa (18-20). The mean concentration of ciprofloxacin in maxillary sinus mucosa has been found to be 0.44 + 0.18 mg/l which is almost twice that of the simultaneous mean level of drug in serum (18). The concentrations of enoxacin in nasal secretions exceeded plasma levels whereas concentrations in saliva, tears and sweat were lower than those in plasma (19). However, enoxacin levels in sinus secretions were lower than serum levels (1.4 ± 0.4 mg/1) (20). From the results of the present study it is evident that pefloxacin penetrates well into purulent sinus fluid, levels varying around 6.9 mg/1.3 hours after the second 400 mg dose. Slightly higher mean levels (7.1 mg/l) were detected in cystic f u i d and even higher levels in nasal secretions (9.1 mg/1). The higher levels of pefloxacin in sinus secretions, which are higher than the simultaneous levels in the plasma, could reflect uptake of drug by phagocytic cells. Such accumulation within phagocytic cells would not necessarily mean a high level of antimicrobial activity (21). In bacteriological studies carried out in these patients after sinus puncture and aspiration the following pathogens were found: Haemophilus
influenzae, Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Enterobacteriaceae and Bacteroides spp. The choice of a newer quinolone such as pefloxacin for the therapy of CMS seems appropriate since HaemophiIus influenzae and Staphylococcus aureus are usually involved in sinusitis, while the rate of beta-lactamase producing strains of Haemophilus influenzae is increasing as well as the rate of Enterobacteriaceae resistant to oral antibiotics. However it should be pointed out that pefloxacin is not active against anaerobes which are frequently involved in sinusitis (2), and that methicillin-resistant Staphylococcus aureus strains are very often resistant to the newer fluoroquinolones (9).
830
Eur. J. Clin. M i c r o b i o l . Infect. D i s .
Table 2: Mean concentrations of pefloxacin in body fluids measured at different intervals after two oral doses of 400 mg given 12 hours apart in 33 patients with chronic maxillary sinusitis. Mean(±SD)eoneentration(m~l) ~me
Oh
3h
6h
9h
12h
Serum
1.5±0.I6 (n = 2)
5.0±1.3 (n = 6)
3.1±1.0 (n = ~
2.7±0.7 (n = 2)
2.2 (n = 1)
Sinus fluid
2.3 ± 0.99
6.9 + 1.8
3.7 + 0:67
3.5 ± 0.96
2.8 :t:1.41
(n = 2)
(n = 6)
(n = 6)
(n = 3)
(n = 4)
Cystic fluid Nasal secretions
2.3
7.1 ± 1.34
4.03 ± 0.81
4.2 ± 0.69
4.1 ± 1.6
(n = 1)
(n : 2)
(n : 3)
(n = 3)
(n = 2)
1.9 (n=l)
9.1 ± 0.21 (n=2)
3.7 + 0.66 (n=2)
3.0 (n=l)
2.8 (n=l)
In conclusion, this study shows that pefloxacin selectively a c c u m u l a t e s in the inflamed sinus cavity at c o n c e n t r a t i o n s exceeding b l o o d levels. T h e r e f o r e it m i g h t be suitable for the t h e r a p y o f C M S w h e n multiresistant a e r o b i c g r a m - n e g a t i v e bacteria o r methicillin-resistant s t a p h y l o c o c c i are implicated. I n view of the f r e q u e n t i n v o l v e m e n t o f a n a e r o b e s in C M S the c o m b i n a t i o n of pefloxacin with an antimicrobial agent possessing activity against a n a e r o b e s is indicated however. References
1. Lundberg C, Engquist S: Localization of bacteria and the cause of tissue destruction in maxillary sinusitis. Acta Otolaryngologica 1984, Supplement, 407: 30-32. 2. King A, Phillips I: The comparative in vitro activity of pefloxacin. Journal of Antimierobial Chemotherapy 1986, 17, Supplement B: 1-10. 3. Verhlst L: In vitro activity of pefloxacin against microorganisms multiply resistant to beta-taetam antibiotics and aminoglycosides. Journal of Antimicrobial Chemotherapy 1986, 17, Supplement B: 11-17, 4. Auekenthaler R, Michea-Hamzehpour M, Perhere JC: In vitro activity of newer quinolones against aerobic bacteria. Journal of Antimicrobial Chemotherapy 1986, 17, Supplement B: 29-39. 5. Fuss ILl, Helsel VL: In vitro antistaphyloeoccal activity of pefloxacin alone and in combination with other antistaphylococcal drugs. Antimierobial Agents and Chemotherapy 1987, 31: 1457-1460. 6. Giamarellou H, Perdikaris G, Galanakls N, Davoulos G, Mandragos K, Sfikakis P: Pefloxaein versus ceftazidime in the treatment of a variety of gram-negative bacterial infections. Antimierobial Agents and Chemotherapy 1989, 33: 1362--1367. 7. Neu HE" Quinolones in perspective. Journal of Antimicrobial Chemotherapy 1990, 26, Supplement B: 1-5. 8. Giamarellou H, Mandragos K, Bechrakls P, Rigas K, Bilalis D, Sfikakis P: Pefloxaein versus imipenem in the therapy of nosocomial lung infections of intensive care unit patients. Journal of Antimicrobial Chemotherapy 1990, 26, Supplement B: 117-127.
9. Barry AL, Fuchs PC: Antistaphylocoeeal activity of the fluoroquinolones CI-960, DP 131628, sparfloxacin, ofloxacin and ciprofloxacin. European Journal of Clinical Microbiology and Infectious Diseases 1991, 10: 168-171. 10. Hooper DE, Wolfson JS: Bacterial resistance to the quinolone antimicrobial agents. American Journal of Medicine 1989, 87, Supplement 6C: 17-23. 11. Barre M, Houin G, Tillement JP: Dose dependent pharmacokinetic study of pefloxacin a new antibacterial agent in humans. Journal of Pharmaceutical Sciences 1984, 73: 1379-1382. 12. Frydman AM, LeRoux Y, Lefervre MA, Djebbar F, Fourtillan JB, Gaillot J: Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg bid) in young healthy volunteers. Journal of Antimierobial Chemotherapy 1986, 17, Supplement B: 65-79. 13. Charles L, Daley A, Merle S: The runny nose: infection of the paranasal sinuses. Infectious Diseases Clinics of North America 1988, 2: 131-147. 14. Axelsson A, Brorson JE: Concentration of antibiotics in sinus secretion. Doxyeyline and spiramycin. Annals of Otology, Rhinology and Laryngology 1973, 82: 4448. 15. Axelsson A, Brorson JE: The concentration of antibiotics in sinus secretions. Ampieillin eephradine and erythromyein estolate. Annals of Otology, Rhinology and Laryngology 1974, 83: 323-330. 16. Lundberg C, Gullets K, Malbborg AS: Antibiotics in sinus secretions. Lancet 1968, ii: 107. 17. Paavolainen M, Kohonen A, Palva T, Rendkonen VO: Penetration of erythromycin stearate into maxillary sinus mucosa and secretion in chronic maxillary sinusitis. Aeta Otolaryngologica 1977, 84: 292-295. 18. Dan M, Englander M, Corea A, Havel M, Berger AS: Concentrations of eiprofloxacin in external ear granulation tissue and maxillary sinus mucosa. Reviews of Infectious Diseases 1989, 11, Supplement 5: 1080. 19. Zucher J, Jaehde U, S0rger F, Naberk K, Schumacher H, Kraus C, Schunaek W: Distribution of enoxacin and its main metabolite oxo-enoxacin into saliva, nasal secretions, tears and sweat of healthy volunteers. Reviews Infectious Diseases 1989, 11, Supplement 5: 1136.
Voi. 11, t992
20. Malmborg AS, Kumlien J, Samueison A, Svennerus K" Concentration of enoxaein in sinus secretions. Reviews Infectious Diseases 1989, 11, Supplement 5: 1205-1206. 21. Desnotles JF, Jacotot F, Bruel J, Bassoullet MT, Niel G' Effects of pefloxacin on phagoeytosis function of rat macrophages and polymorphonuelear leucocytes. Journal of Antimicrobial Chemotherapy, 1986,17,Supplement B: 53-57.
L
Infective Endocarditis with Involvement of the Tricuspid Valve due to Capnocytophaga canimorsus H.K. A n d e r s e n 1., M. P e d e r s e n 2
A case of endocarditis with vegetations on the tricuspid valve caused by Capnocytophaga canimorsus is described. Extensive diagnostic investigations preceded the diagnosis, including blood cultures, 34 of which were sterile. A possible role of the pulmonary circulation in the negative blood cultures is discussed.
Capnocytophaga canimorsus, formerly designated dysgonic fermenter 2 (DF2), was first described in 1976 (1) and has been associated with septicaemia, meningitis, wound infection and endocarditis (1). It has been found in immunocompromised patients, especially asplenic patients, and alcoholics, but also in previously healthy persons (1). We report a case of infective endocarditis with vegetations on the tricuspid valve caused by Capnocytophaga canimorsus in a previously healthy male.
Case Report. A 56-year-old previously healthy man with no history of drug abuse was admitted to hospital on 19 August 1990 with a history of intermittent high fever for two months and a weight loss of 22 pounds, a slight cough, functional dyspnoea and malaise. On admission his temperature was 39 °C. There was a stasis of the veins of the collum. The haemoglobin level was 6.1 mmolll and the total leucocyte count 48.8 x 106/ml, with an increased proportion of immature 1Department of Clinical Microbiology, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark. 2Department of Medicine and Haematology, Gentofte Hospital, Universityof Copenhagen, Gentofte, Denmark.
831
cells. The erythrocyte sedimentation rate was 80 mm/h. Auscultation of the heart and lungs was normal but the ECG showed elevation of the S-T segment. On the basis of these findings exudative pericarditis was suspected. However, the echocardiogram suggested endocarditis with changes in the lateral portion of the tricuspid valve. Blood cultures performed on Colorbact medium (Statens Seruminstitute, Denmark) were negative. Cefuroxime plus gentamicin were administered; penicillin was not given because of a history of exanthema during previous penicillin treatment. The following day the echocardiographic findings were discounted as a sign of endocarditis and the antibiotics were discontinued. Infiltrative changes were seen on chest roentgenogram, and perfusion/ventilation scintigraphy was performed which indicated the presence of a pulmonary embolism. Anticoagulant treatment was initiated. In the following five months the patient received no antibiotics, and blood cultures of a total of 34 samples were all negative. Two and a half months after admission endotoxinaemia was observed with petechial haemorrhages on the legs. Intensive diagnostic investigations excluded carcinoma of the lung, periarteritis nodosa, hypernephroma, malignant lymphoma, Good Pastures syndrome or Wegeners granulomatosis. During these five months the patient continued to have intermittent episodes of chills and raised temperature. On 23 January 1991 a repeat echocardiogram showed dilatation of the right side of the heart, especially the right atrium, and the lateral portion of the tricuspid valve was seen to have three excrescences. Furthermore, an atrial septum secundum defect was seen. Blood cultures were repeated, and penicillin plus gentamicin were administered with no adverse reactions. Four days later two of four blood cultures were positive with a slender fusiform gram negative rod forming yellowish, fringe-like colonies. The organism showed gliding motility, was oxidase, catalase and ONPG positive, and melbiose negative. It was facultatively anaerobic but grew slowly in an anaerobic atmosphere, preferring an atmosphere with 5 % carbon dioxide. The microorganism was identified as Capnocytophaga canimorsus (DF2) this identification being confirmed by the Statens Seruminstitute, Copenhagen. After six weeks of penicillin treatment the patient showed no elevation of temperature, leucocyte
Penetration of Pefloxacin into Maxillary Sinus Cavity and Nasal Secretions G. Petrikkos 1., P. G o u m a s 2, E. Moschovakis 2, H. Giamarellou I
The ability of oral pefloxacin to penetrate into maxillary sinus cavity and nasal secretions was studied in 39 patients suffering from an exacerbation of chronic maxillary sinusitis. The mean levels of pefloxacin in sinus aspirate fluid 0, 3, 6, 9 and 12 h after the second oral dose of 400 mg were 2.30, 6.92, 3.74, 3.47 and 2.82 rag/! respectively. In sinus cystic fluid (macroscopically non-purulent) the mean pefloxacin levels were 2.30, 7.15, 4.20 and 4.15 rag/! respectively, and in nasal secretion 1.90, 9.05, 3.71, 3.20 and 2.85 mg/l respectively. The mean pefloxacin levels in serum obtained simultaneously were 1.50, 5.00, 3.10, 2.70 and 2.20 mg/I respectively. It is concluded that pefloxacin accumulates in inflamed sinus fluid at concentrations exceeding blood levels.
Chronic maxillary sinusitis (CMS) can lead to irreversible mucosal damage with replacement of the ciliate epithelium by stratified squamous epithelium and loss of effective clearance of bacteria (1). Since normal defence mechanisms are hampered, therapy of CMS should be based mainly on antimicrobial chemotherapy and, when indicated, surgical drainage. An appropriate antibiotic for treating CMS should not only be active in vitro against the potential pathogens but should possess advantageous pharmacokinetics in sinus secretions. In selecting antimicrobial agents, factors other than antimicrobial activity against the potential pathogens must be taken into account, in particular the ability of an antibiotic to penetrate in to the sinus cavity. This property is of major importance in CMS since the infection is localised in a bone enclosed cavity with impaired or completely 1First Department of Propedeutic Medicine, Athens University School of Medicine,Laiko General Hospital, Agiou Thoma 17, Athens 115 27, Greece. ZDepartment of Otolaryngology, University of Patras, Patras, Greece.
Eur. J. Clin. Microbiol. Infect. Dis.
occluded drainage plus a poorly vascularized mucosa. Pefloxacin is a new fluorinated quinolone which is reported to have potent antimicrobial activity against Enterobacteriaceae and Pseudomonas aeruginosa, including strains resistant to other classes of antibiotics, and is also active against Haemophilus spp. and methicillin-susceptible staphylococci (2-8). Its activity against methicillin-resistant staphylococci is disputed however, (9) while increasing resistance of Pseudomonas aeruginosa has been reported in some countries (10). Bacteroides fragilis and Bacteroides melaninogenicus oralis are generally resistant to pefloxacin (2). The absorption of pefloxacin following oral administration is excellent. The serum half-life is 12 hours, while less than 10 % of the administered dose is excreted in the urine in unchanged form and about 40 % as two major metabolites (11, 12). In view of these properties and the satisfactory tolerance of pefloxacin when administered orally (6), we evaluated its pharmacokinetics in maxillary sinus cavity and nasal secretions.
Patients and Methods. Thirty-nine patients (14 males and 25 females) whose ages ranged from 18 to 46 years (mean 33.1 -+ 12.5, median 32) were entered in the study. All patients were suffering from an exacerbation of CMS. The diagnosis was verified in every case by reviewing the clinical course of the disease which in all cases exceeded a duration of one year (13). All patients presented with protracted nasal congestion, purulent nasal discharge and facial pain or toothache. Air-fluid levels or completely opaque sinuses were observed on conventional x-ray examination in all patients. The infection was unilateral in 27 patients and bilateral in 12, while 5 patients had concomitant frontal sinus involvement. Before starting therapy, undiluted antral secretions were obtained by aspiration with a trocar inserted through the inferior nasal meatus. Quantitative aerobic and anaerobic cultures of all specimens were performed by conventional methods. Having obtained maxillary secretions by aspiration, a thin plastic catheter was inserted through the trocar into the maxillary sinus while the trocar was removed. The catheter remained in place throughout the period of collection of samples for pharmacokinetic studies. Purulent nasal secretions were also obtained by aspiration from the floor of the nose and from the area of the middle meatus where drains the anterior ethmoid complex.
Vol. 11, 1992
829
Pefloxacin was administered in two doses of 400 mg p.o. given 12 hours apart. Following the second oral dose of pefloxacin, sinus and nasal secretion specimens were obtained 0, 3, 6, 9 and 12 hours post-dose. Blood specimens were also obtained concomitantly. Pefloxacin levels were then measured by an agar-well diffusion bioassay with isotonic Sensitest agar (Oxoid 471, Oxoid, UK) using Escherichia coli (ICB 4004) as the indicator microorganism. Sinus or nasal samples containing visible blood were discarded.
Results and Discussion. The culture results are shown in Table 1. Overall, 48.7 % of the infections were characterised as pure aerobic, 15.4 % as pure anaerobic and 20.5 % as mixed aerobicanaerobic, while in 15.4 % sterile effusions were found, mainly in cystic sinus fluid. Staphylococcus spp. (35.4 %), Streptococcus spp. (22.5 %) and Haemophilus influenzae (22.5 %) were the most frequently isolated pathogens among the aerobes while Bacteroides spp. were the most frequently isolated pathogens among the anaerobes. Sinus fluid and nasal secretion samples obtained from six patients were not assayed because they contained blood. Mean peak pefloxacin levels (Table 2), which were observed 3 hours after the second dose in all types of specimens, were 5.0 -+ 1.3 mg/1, 6.9 +- 1.08 mg/l, 7.1 ± 1.34 mg/l and 9.1 :t 0.21 mg/1 in serum, sinus fluid, cystic fluid and nasal secretions respectively.
Table 1: Results of culture in 39 patients with an exacerbation of chronic maxillary sinusitis. Pathogen
Number
Aerobes Streptococcus pneumoniae Viridans streptococci Enterococcus f aecalis Group D streptococci Staphylococcus aureus Staphylococcus epidermidis Klebsiella oxytoca Escherichia coli Pseudomonas aeruginosa Haemophilus influenzae Branhamella catarrhalis
3 1 1 2 4 7 1 2 2 7 1
Anaerobes Bacteroides fragilis Other Bacteroides spp. Propionibacterium aches Peptostreptococcus spp. Mieroaerophilie cocci Fusobacterium spp.
2 3 3 2 2 1
In the treatment of sinusitis the choice of antibiotics should be based not only on the expected bacteriological findings and the antibiotic susceptibility patterns, but also on the pharmacokinetie behaviour of the agents in sinus secretions. The concentration of various older oral antibiotics (penicillin, ampicillin, cephradin, tetracycline, spiramycin and erythromycin) in the sinus cavity has been studied by several authors (14-17). Few investigators have, to the best of our knowledge, examined the ability of newer quinolones to penetrate into the sinus and nasal secretions and mucosa (18-20). The mean concentration of ciprofloxacin in maxillary sinus mucosa has been found to be 0.44 + 0.18 mg/l which is almost twice that of the simultaneous mean level of drug in serum (18). The concentrations of enoxacin in nasal secretions exceeded plasma levels whereas concentrations in saliva, tears and sweat were lower than those in plasma (19). However, enoxacin levels in sinus secretions were lower than serum levels (1.4 ± 0.4 mg/1) (20). From the results of the present study it is evident that pefloxacin penetrates well into purulent sinus fluid, levels varying around 6.9 mg/1.3 hours after the second 400 mg dose. Slightly higher mean levels (7.1 mg/l) were detected in cystic f u i d and even higher levels in nasal secretions (9.1 mg/1). The higher levels of pefloxacin in sinus secretions, which are higher than the simultaneous levels in the plasma, could reflect uptake of drug by phagocytic cells. Such accumulation within phagocytic cells would not necessarily mean a high level of antimicrobial activity (21). In bacteriological studies carried out in these patients after sinus puncture and aspiration the following pathogens were found: Haemophilus
influenzae, Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Enterobacteriaceae and Bacteroides spp. The choice of a newer quinolone such as pefloxacin for the therapy of CMS seems appropriate since HaemophiIus influenzae and Staphylococcus aureus are usually involved in sinusitis, while the rate of beta-lactamase producing strains of Haemophilus influenzae is increasing as well as the rate of Enterobacteriaceae resistant to oral antibiotics. However it should be pointed out that pefloxacin is not active against anaerobes which are frequently involved in sinusitis (2), and that methicillin-resistant Staphylococcus aureus strains are very often resistant to the newer fluoroquinolones (9).
830
Eur. J. Clin. M i c r o b i o l . Infect. D i s .
Table 2: Mean concentrations of pefloxacin in body fluids measured at different intervals after two oral doses of 400 mg given 12 hours apart in 33 patients with chronic maxillary sinusitis. Mean(±SD)eoneentration(m~l) ~me
Oh
3h
6h
9h
12h
Serum
1.5±0.I6 (n = 2)
5.0±1.3 (n = 6)
3.1±1.0 (n = ~
2.7±0.7 (n = 2)
2.2 (n = 1)
Sinus fluid
2.3 ± 0.99
6.9 + 1.8
3.7 + 0:67
3.5 ± 0.96
2.8 :t:1.41
(n = 2)
(n = 6)
(n = 6)
(n = 3)
(n = 4)
Cystic fluid Nasal secretions
2.3
7.1 ± 1.34
4.03 ± 0.81
4.2 ± 0.69
4.1 ± 1.6
(n = 1)
(n : 2)
(n : 3)
(n = 3)
(n = 2)
1.9 (n=l)
9.1 ± 0.21 (n=2)
3.7 + 0.66 (n=2)
3.0 (n=l)
2.8 (n=l)
In conclusion, this study shows that pefloxacin selectively a c c u m u l a t e s in the inflamed sinus cavity at c o n c e n t r a t i o n s exceeding b l o o d levels. T h e r e f o r e it m i g h t be suitable for the t h e r a p y o f C M S w h e n multiresistant a e r o b i c g r a m - n e g a t i v e bacteria o r methicillin-resistant s t a p h y l o c o c c i are implicated. I n view of the f r e q u e n t i n v o l v e m e n t o f a n a e r o b e s in C M S the c o m b i n a t i o n of pefloxacin with an antimicrobial agent possessing activity against a n a e r o b e s is indicated however. References
1. Lundberg C, Engquist S: Localization of bacteria and the cause of tissue destruction in maxillary sinusitis. Acta Otolaryngologica 1984, Supplement, 407: 30-32. 2. King A, Phillips I: The comparative in vitro activity of pefloxacin. Journal of Antimierobial Chemotherapy 1986, 17, Supplement B: 1-10. 3. Verhlst L: In vitro activity of pefloxacin against microorganisms multiply resistant to beta-taetam antibiotics and aminoglycosides. Journal of Antimicrobial Chemotherapy 1986, 17, Supplement B: 11-17, 4. Auekenthaler R, Michea-Hamzehpour M, Perhere JC: In vitro activity of newer quinolones against aerobic bacteria. Journal of Antimicrobial Chemotherapy 1986, 17, Supplement B: 29-39. 5. Fuss ILl, Helsel VL: In vitro antistaphyloeoccal activity of pefloxacin alone and in combination with other antistaphylococcal drugs. Antimierobial Agents and Chemotherapy 1987, 31: 1457-1460. 6. Giamarellou H, Perdikaris G, Galanakls N, Davoulos G, Mandragos K, Sfikakis P: Pefloxaein versus ceftazidime in the treatment of a variety of gram-negative bacterial infections. Antimierobial Agents and Chemotherapy 1989, 33: 1362--1367. 7. Neu HE" Quinolones in perspective. Journal of Antimicrobial Chemotherapy 1990, 26, Supplement B: 1-5. 8. Giamarellou H, Mandragos K, Bechrakls P, Rigas K, Bilalis D, Sfikakis P: Pefloxaein versus imipenem in the therapy of nosocomial lung infections of intensive care unit patients. Journal of Antimicrobial Chemotherapy 1990, 26, Supplement B: 117-127.
9. Barry AL, Fuchs PC: Antistaphylocoeeal activity of the fluoroquinolones CI-960, DP 131628, sparfloxacin, ofloxacin and ciprofloxacin. European Journal of Clinical Microbiology and Infectious Diseases 1991, 10: 168-171. 10. Hooper DE, Wolfson JS: Bacterial resistance to the quinolone antimicrobial agents. American Journal of Medicine 1989, 87, Supplement 6C: 17-23. 11. Barre M, Houin G, Tillement JP: Dose dependent pharmacokinetic study of pefloxacin a new antibacterial agent in humans. Journal of Pharmaceutical Sciences 1984, 73: 1379-1382. 12. Frydman AM, LeRoux Y, Lefervre MA, Djebbar F, Fourtillan JB, Gaillot J: Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg bid) in young healthy volunteers. Journal of Antimierobial Chemotherapy 1986, 17, Supplement B: 65-79. 13. Charles L, Daley A, Merle S: The runny nose: infection of the paranasal sinuses. Infectious Diseases Clinics of North America 1988, 2: 131-147. 14. Axelsson A, Brorson JE: Concentration of antibiotics in sinus secretion. Doxyeyline and spiramycin. Annals of Otology, Rhinology and Laryngology 1973, 82: 4448. 15. Axelsson A, Brorson JE: The concentration of antibiotics in sinus secretions. Ampieillin eephradine and erythromyein estolate. Annals of Otology, Rhinology and Laryngology 1974, 83: 323-330. 16. Lundberg C, Gullets K, Malbborg AS: Antibiotics in sinus secretions. Lancet 1968, ii: 107. 17. Paavolainen M, Kohonen A, Palva T, Rendkonen VO: Penetration of erythromycin stearate into maxillary sinus mucosa and secretion in chronic maxillary sinusitis. Aeta Otolaryngologica 1977, 84: 292-295. 18. Dan M, Englander M, Corea A, Havel M, Berger AS: Concentrations of eiprofloxacin in external ear granulation tissue and maxillary sinus mucosa. Reviews of Infectious Diseases 1989, 11, Supplement 5: 1080. 19. Zucher J, Jaehde U, S0rger F, Naberk K, Schumacher H, Kraus C, Schunaek W: Distribution of enoxacin and its main metabolite oxo-enoxacin into saliva, nasal secretions, tears and sweat of healthy volunteers. Reviews Infectious Diseases 1989, 11, Supplement 5: 1136.
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20. Malmborg AS, Kumlien J, Samueison A, Svennerus K" Concentration of enoxaein in sinus secretions. Reviews Infectious Diseases 1989, 11, Supplement 5: 1205-1206. 21. Desnotles JF, Jacotot F, Bruel J, Bassoullet MT, Niel G' Effects of pefloxacin on phagoeytosis function of rat macrophages and polymorphonuelear leucocytes. Journal of Antimicrobial Chemotherapy, 1986,17,Supplement B: 53-57.
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Infective Endocarditis with Involvement of the Tricuspid Valve due to Capnocytophaga canimorsus H.K. A n d e r s e n 1., M. P e d e r s e n 2
A case of endocarditis with vegetations on the tricuspid valve caused by Capnocytophaga canimorsus is described. Extensive diagnostic investigations preceded the diagnosis, including blood cultures, 34 of which were sterile. A possible role of the pulmonary circulation in the negative blood cultures is discussed.
Capnocytophaga canimorsus, formerly designated dysgonic fermenter 2 (DF2), was first described in 1976 (1) and has been associated with septicaemia, meningitis, wound infection and endocarditis (1). It has been found in immunocompromised patients, especially asplenic patients, and alcoholics, but also in previously healthy persons (1). We report a case of infective endocarditis with vegetations on the tricuspid valve caused by Capnocytophaga canimorsus in a previously healthy male.
Case Report. A 56-year-old previously healthy man with no history of drug abuse was admitted to hospital on 19 August 1990 with a history of intermittent high fever for two months and a weight loss of 22 pounds, a slight cough, functional dyspnoea and malaise. On admission his temperature was 39 °C. There was a stasis of the veins of the collum. The haemoglobin level was 6.1 mmolll and the total leucocyte count 48.8 x 106/ml, with an increased proportion of immature 1Department of Clinical Microbiology, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark. 2Department of Medicine and Haematology, Gentofte Hospital, Universityof Copenhagen, Gentofte, Denmark.
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cells. The erythrocyte sedimentation rate was 80 mm/h. Auscultation of the heart and lungs was normal but the ECG showed elevation of the S-T segment. On the basis of these findings exudative pericarditis was suspected. However, the echocardiogram suggested endocarditis with changes in the lateral portion of the tricuspid valve. Blood cultures performed on Colorbact medium (Statens Seruminstitute, Denmark) were negative. Cefuroxime plus gentamicin were administered; penicillin was not given because of a history of exanthema during previous penicillin treatment. The following day the echocardiographic findings were discounted as a sign of endocarditis and the antibiotics were discontinued. Infiltrative changes were seen on chest roentgenogram, and perfusion/ventilation scintigraphy was performed which indicated the presence of a pulmonary embolism. Anticoagulant treatment was initiated. In the following five months the patient received no antibiotics, and blood cultures of a total of 34 samples were all negative. Two and a half months after admission endotoxinaemia was observed with petechial haemorrhages on the legs. Intensive diagnostic investigations excluded carcinoma of the lung, periarteritis nodosa, hypernephroma, malignant lymphoma, Good Pastures syndrome or Wegeners granulomatosis. During these five months the patient continued to have intermittent episodes of chills and raised temperature. On 23 January 1991 a repeat echocardiogram showed dilatation of the right side of the heart, especially the right atrium, and the lateral portion of the tricuspid valve was seen to have three excrescences. Furthermore, an atrial septum secundum defect was seen. Blood cultures were repeated, and penicillin plus gentamicin were administered with no adverse reactions. Four days later two of four blood cultures were positive with a slender fusiform gram negative rod forming yellowish, fringe-like colonies. The organism showed gliding motility, was oxidase, catalase and ONPG positive, and melbiose negative. It was facultatively anaerobic but grew slowly in an anaerobic atmosphere, preferring an atmosphere with 5 % carbon dioxide. The microorganism was identified as Capnocytophaga canimorsus (DF2) this identification being confirmed by the Statens Seruminstitute, Copenhagen. After six weeks of penicillin treatment the patient showed no elevation of temperature, leucocyte
