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SINUSITIS, BRONCHITIS, AND MYCOPLASMAL PNEUMONIA* GEORGE A. PANKEY, M.D. Head, Section of Infectious Diseases Ochsner Medical Institutions Clinical Professor of Medicine Tulane University School of Medicine New Orleans, Louisiana

T HE tetracyclines were the first effective antibiotics available to treat sinusitis, bronchitis, and mycoplasmal pneumonia, and even today they remain one of the few effective agents against Mycoplasma

pneumoniae.1 However, over the years the dominant role of tetracyclines in the treatment of sinusitis and bronchitis has been challenged by ampicillin. This is understandable, because it was once believed that pneumococci were the prime etiologic organisms in these respiratory infections, and reports suggested widespread pneumococcal resistance to tetracyclines. Recent findings suggest that the problem of pneumococcal resistance to tetracyclines was exaggerated. For example, a recent study by Finland and his colleagues found that all of 33 pneumococcal strains tested were susceptible to the tetracyclines.2 Newer analogues such as methacycline, doxycycline, and minocycline displayed higher activity than the parent compound. A similar situation was observed in 35 strains of Hemophilus influenzae strains tested. In our own experience, tetracyclines have remained active against pneumococcal and H. influenzae strains. However, because these respiratory infections are usually treated on an outpatient basis and because they are usually not life-threatening, antibacterial efficacy is only one factor important for successful antibiotic therapy. Safety is equally important. A low potential for hypersensitivity reactions and other adverse effects (e.g., diarrhea, colitis, rash, dizziness, and accumulation of the drug in patients with renal failure) is necessary. Convenient dosage is desirable for patient compliance. *Presented as part of A Symposium on the Tetracyclines: A Major Appraisal sponsored by the New York Academy of Medicine in cooperation with Science and Medicine Publishing Co., Inc. under a grant from Pfizer Laboratories, New York, N.Y., and held at the Academy October 15, 1977. Address for reprint requests: Ochsner Clinic, 1516 Jefferson Highway, New Orleans, La. 70121.

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SINUSITIS Infection of the paranasal sinuses is a troublesome, often recurrent condition estimated to occur in at least 25% of adults.3 Although these patients rarely require hospitalization, we estimate, using estimates from Great Britain, that more than 1,000,000 work days are lost in the United States each year because of sinusitis.4 Often associated with chronic bronchitis, some believe that sinusitis is a reservoir of organisms responsible for acute bronchial infections. The diagnosis of acute sinusitis is usually based on clinical findings, although radiologic studies may provide additional information. Gram stain and cultures of nasal secretions are unreliable because they are often contaminated by organisms resident in the nasopharynx. Thus, the antibiotic treatment of acute sinusitis is empirical, based on knowledge of the likely pathogens and ability of the drug to concentrate in sinus mucosa and secretions. Streptococcus pneumoniae and Hemophilus influenzae have long been implicated in acute and chronic sinusitis. In recent years, however, several studies have demonstrated that in some instances anaerobic organisms also play an important etiologic role.5'6 Frederick and Braude reported that 52% of patients had anaerobic organisms in chronically infected sinus secretions. These anaerobes-peptostreptococci, fusobacteria, Bacteroides, and Veillonella-were commonly found mixed with the aerobic organism. Fungi and viruses occasionally infect the sinuses. Mycoplasma sp. and Chlamydia sp. may contribute to sinus infection, although their role is less well defined. In addition to microorganisms, allergy, such congenital abnormalities as a deviated nasal septum, or both are considered important contributing factors. The newer analogues, doxycycline and minocycline, have the advantage of higher activity against both aerobic organisms.2'7 They are more completely absorbed from the gastrointestinal tract and achieve antibacterial levels in infected sinus muscosa and secretions, presumably because their high lipid solubility eases transport into and across cell membranes.8'9 This property is important, because for an antibiotic to be effective in sinusitis, concentration in the mucous membrane itself as well as in secretions is important. Doxycycline is our antibiotic of choice for sinusitis. Although minocycline has also proved effective, because vestibular dysfunction is frequent we do not use it in outpatients.10 A favorable feature of doxycycline, as opposed to tetracycline hydro-

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chloride and the other analogues, is that it does not accumulate in the presence of renal impairment. Thus, neither renal function studies nor dosage adjustments before instituting therapy are necessary, as they are with the other tetracyclines. However, dosage changes are necessary in patients receiving such antiepileptic drugs as carbamazepine, diphenylhydantoin, and phenobarbital. The metabolism of doxycycline by the liver is enhanced by these agents and larger dosages are needed to maintain effective blood and tissue levels.1" Because its serum half-life is 18 to 22 hours, doxycycline can be taken only once a day after the initial loading dose of 100 mg. twice the first day. Depending on the patient's weight, we generally follow this with 100 mg., once or twice daily, for 14 days. This is longer than my previous recommendation'2 but necessary to eradicate the more difficult anaerobic bacteria. We usually instruct patients to take doxycycline with meals, because this reduces the chance of nausea and does not significantly impair the drug's absorption. However, divalent cations such as the ferrous ion do impair absorption, and two to three hours should separate the administration of all tetracyclines and ferrous sulfate. Most patients with acute sinusitis do very well on a combination of doxycycline and local systemic decongestant therapy. However, surgical drainage may occasionally also be necessary, particularly when symptoms are severe and there is radiologic evidence of sinus clouding. In patients with chronic sinusitis, surgical intervention is often required for polyps, cysts, or other pathological changes that impair sinus drainage. Following these procedures, treatment with doxycycline (100 mg./day) may be initiated for four to six weeks. On the whole, results of antibiotic therapy in chronic sinusitis are not as dramatic as in acute disease except during periods of acute exacerbation. BRONCHITIS As with sinusitis, acute bronchial infection is common in the adult population. Many elderly patients also suffer from chronic bronchitis, emphysema, or both, and have acute exacerbations of bronchitis. Because sputum cultures are frequently unreliable in defining etiologic organisms, the initial diagnosis of acute bronchitis is usually clinical. Sputum Gram stain and culture are of greater importance for the occasional patient who does not rapidly respond to initial antibiotic therapy. Bull. N.Y. Acad. Med.

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Common pathogens associated with acute bronchitis in patients with underlying chronic bronchitis or chronic obstructive pulmonary disease are S. pneumoniae and H. influenzae. M. pneumoniae and various viruses also play a role in some patients. All of these organisms may occur alone or in combination.13 Anaerobic bacteria do not appear to be associated with acute exacerbations of chronic bronchitis. 14 While ampicillin is widely used, unlike doxycycline, it is ineffective against M. pneumoniae, penetrates purulent sputum poorly, must be taken frequently, may sensitize the patient to penicillin, and causes an idiosyncratic rash in some hyperuricemic patients receiving allopurinol. Amoxicillin penetrates purulent sputum and apparently does not have the idiosyncratic rash problem, but adults usually must take 500 mg. every eight hours, and we prefer to reserve it for the rare patient who fails to respond to doxycycline. Chodosh has demonstrated that doxycycline and amoxicillin appear to be equivalent in efficacy.15 Perhaps this is related to the bronchial mucosal concentration as well as to purulent and mucoid secretion concentration of these drugs. 16,17 The safety of doxycycline in patients with renal impairment is significant in patients with chronic bronchitis, many of whom have some degree of renal dysfunction.18 The progressive decrease in renal function with aging (already 30% at age 65)19 also must be considered when selecting an antibiotic for these outpatients. Thus, in my view, tetracyclines other than doxycycline should be avoided in such cases. Like most physicians treating chronic bronchitis, it is our practice to write a prescription for patients to use with acute exacerbations, instructing them to start antibiotic therapy as soon as signs of infection develop, such as increased cough and purulent sputum production. Rather than ampicillin, doxycycline is used to treat these acute exacerbations. We use 100 mg. every 12 hours for two doses, followed by 100 mg./day for at least 10 days or for several days after the sputum has become nonpurulent. Patient compliance is usually satisfactory with this once-daily dosage schedule. If symptoms do not improve within 48 hours, patients are instructed to report for examination and sputum evaluation. In such cases there is the chance that a virus or tetracycline-resistant Gram-negative bacilli such as Pseudomonas aeruginosa, Klebsiella, and Proteus are the pathogens. Although bronchial infections due to the latter organisms are infrequent, the physician should always be alert to the possibility. In our experience, they are most likely in adult cystic fibrosis patients, patients with bronchiectasis Vol. 54, No. 2, February 1978

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associated with chronic bronchitis, and patients with chronic obstructive pulmonary disease who develop acute bronchitis while in the hospital. The role of intermittent or continuous antibiotic therapy in suppressing acute exacerbations of chronic bronchitis is still not established. There is some evidence that this therapy reduces morbidity, but insufficient data are available to answer whether it helps retard destruction of lung tissue. A major concern is that continuous antibiotic therapy may result in bacterial strains resistant to antibiotics. ADJUVANT THERAPY

Obviously, the importance of preventing or lessening bronchial irritation must be emphasized. Especially important is the avoidance of air pollutants (including cigarette, cigar, and pipe smoke), humidification of inhaled air, and postural drainage. Bronchodilators are useful in some patients, but the role of expectorants is less well established. MYCOPLASMAL PNEUMONIA

The organism M. pneumoniae is estimated to cause more than one third of all pneumonias among civilian populations. It is also an etiologic agent in pharyngitis and bronchitis. Mycoplasmal pneumonia can occur at any age, but it is more common among adolescents and young adults and is unusual after the age of 50. The clinical course is usually self-limiting, but it can result in prolonged disability and, occasionally, serious complications such as meningitis and hemolytic anemia.21 Like sinusitis and bronchitis, the initial diagnosis of mycoplasmal pneumonia is clinical, and its antibiotic treatment is empirical because culture techniques may not be available and serologic tests require both acute and convalescent sera to confirm the diagnosis. It is characteristic of mycoplasmal pneumonia that symptoms such as fever, cough, malaise, and headache develop slowly over a period of days. Sputum Gram stains reveal insignificant numbers of bacteria, although the sputum may be purulent. Certainly, any adolescent or young adult who presents with such symptoms and signs should have a chest roentgenogram. If a diagnosis of a "walking" pneumonia is made, M. pneumoniae is the most likely agent, although other organisms, such as Mycobacterium tuberculosis, must be considered in the differential diagnosis. The tetracyclines and erythromycin are the most appropriate antibiotics to treat mycoplasmal pneumonia. Both have in vitro activity against M. Bull. N.Y. Acad. Med.

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pneumoniae and are equally effective clinically. Clindamycin has been shown to be ineffective,22 but the in vitro development of resistance against erythromycin has not been a problem clinically.23 Unlike many bacterial infections, antibiotic therapy of M. pneumoniae appears to have no effect on eradication of the organism, but it does shorten the duration of symptoms and signs, which results in decreased morbidity. Whether tetracycline or erythromycin prevents complications of mycoplasmal pneumonia has not been determined. We regard one of the tetracyclines as the antibiotic of choice because these drugs are effective against such rickettsial and chlamydial disease as Q fever and psittacosis, which can mimic mycoplasmal pneumonia. Our pneumococcal isolates have remained susceptible in vitro to tetracycline. In addition to the safety factors, doxycycline concentrates well in the lung and is our tetracycline of choice for mycoplasma pneumonia. The dosage in ambulatory patients is 100 mg. every 12 hours for one week. Symptomatic improvement usually occurs within 48 to 72 hours, although clearing of chest roentgenograms is frequently slower. Although equally effective, erythromycin tends to cause more gastrointestinal side effects and requires a dosage schedule of four times a day. In the patient who requires hospitalization, intravenous doxycycline (200 mg./day administered in a 400 cc. infusion) may be used if there are symptoms of nausea and vomiting. However, because oral administration of this drug provides equivalent serum and tissue levels, the usual oral dosage is resumed once gastrointestinal symptoms have abated. DISCUSSION

DR. L. D. SABATH. You commented that it was worthless to examine the purulent postnasal drip for selecting therapy, and then later you mentioned that patients who failed to respond to therapy prescribed over the phone for bronchitis should come into the office to have the sputum examined. Just how helpful is it to culture purulent secretions in selecting

therapy? DR. PANKEY. If patients with sinusitis do not respond, we ask them to come back in 48 hours for roentgenograms of the sinuses. Frequently, surgical drainage is required. In chronic bronchitis, where the acute exacerbation does not respond, we frequently find that we are dealing with other Gram-negative rods, as in the cystic fibrosis patient. Perhaps we are dealing with an area of bronchiectasis associated with chronic bronchitis, Vol. 54, No. 2, February 1978

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and the patient, in fact, now has Pseudomonas aeruginosa or resistant Klebsiella sp. or Proteus sp. Obviously, the immunosuppressed patient is entirely different, as is the patient who has been in the hospital. Most of the time the cultures done in 48 hours for the patient who does not respond initially are not helpful, as you have suggested. DR. HAROLD C. NEU. You did not mention how long you treat these various entities: the sinusitis, the mycoplasmal pneumonia, and the bronchitis. DR. PANKEY. With the recognition of the role of the anaerobes in sinusitis, we prolong our treatment to two weeks because anaerobic infections, by nature, require long therapy. Obviously, some patients are going to have surgery, which is the prime therapy with very few exceptions for any anaerobic infection. With bronchitis we treat 10 days, or at least two or three days beyond the disappearance of the purulent sputum. We treat mycoplasmal pneumonia for one week. Of course, the length of therapy is arbitrary for all of these infections. DR. NEU. If the patient's sputum becomes purulent during a time of year when this is common, would you arbitrarily tell them to resume therapy? DR. PANKEY. Yes. The hospital or office visit for culture and sensitivity testing for one organism may cost the patient $20 to $30. If patients do not have a prescription to fill in order to start therapy, they will not come into the office until they get seriously ill. Many of our patients travel a lot; they may be in another city when the acute exacerbation occurs and not know where to go for treatment. From a practical standpoint, giving them a prescription has worked very nicely. One has to be careful about what antibiotics one prescribes in a refillable prescription. We do not like to prescribe ampicillin or any of the penicillins in refillable prescriptions except for people who receive prophylaxis for rheumatic fever. DR. FRANK M. CALIA. It may be that I see a different patient population at a Veterans Administration hospital, but when our patients fail to respond to tetracycline, very often it is not entirely due to the infection. We get all kinds of aerobic Gram-negative rods and occasionally Staphylococcus aureus from sputum cultures, which are the result of colonization, but our patients do not respond, because they continue to smoke or have a very poor pulmonary toilet. If we manipulate those situations rather than the chemotherapy, they do respond. DR. PANKEY. I think that is critical. The other therapy is just as Bull. N.Y. Acad. Med.

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important as the antibiotic therapy. We have great difficulty with smoke and other air pollutants. We use bronchodilators if patients are wheezing, and we try to have air humidified. DR. NEU. It seems to me that one of our failures in administering these drugs in bronchitis is not giving a large enough dose to decrease the inflammatory response significantly. For instance, some of the Hemophilus MIC values are up around 1 to 1.5 ,ug./ml. With some people, if one is using a drug like doxycycline, perhaps the dosage should be 200 mg./day for the first two or three days. As for tetracycline hydrochloride, according to my review of the literature, if 2 gm. are not given for the first several days, it is no wonder that the regimen is not effective. Bronchial drainage, smoking cessation, bronchodilators, and air humidification are also very important, of course. But effective antibiotic therapy at the beginning of an illness decreases the number of bacteria and thus allows the secretions to become more viscid. REFERENCES 1. Barza, M. and Scheife, R. T.: AntimiWretlind, B.: Antibiotic concentrations crobial spectrum pharmacology, and in maxillary sinus secretions and in the therapeutic use of antibiotics: I. Tetrasinus mucosa. Chemotherapy 21:1, cyclines. J. Maine Med. Assoc. 67:368, 1975. 1976. 9. Worgan, D. and Daniel, R. J. E.: The 2. Finland, M., Garner, C., Wilcox, C.. penetration of minocycline into human and Sabath, L. D.: Susceptibility of sinus secretions. Scott. Med. J. 21:197, pneumococci and Haemophilus influ1976. enzae to antibacterial agents. Antimi- 10. Allen, J. C.: Minocycline. Ann. Intern. crob. Agents Chemother. 9:274, 1976. Med. 85:482, 1976. 3. Hanna, H. H.: Asymptomatic sinus 11. PenttilA, O., Neuvonen, P. J., Aho, K., disease in air crew members. Aerospace and Lehtovaara, R.: Interaction beMed. 45:77, 1974. tween doxycycline and some antiepilep4. Chronic sinusitis. Lancet 1:442, 1974. tic drugs. Br. Med. J. 2:470, 1974. 5. Frederick, J. and Braude, A. I.: 12. Pankey, G. A.: Sinusitis. In: Current Anaerobic infection of the paranasal Therapy, Conn, H. F., editor, Philadelsinuses. N. Engl. J. Med. 290:135, phia, Saunders, 1971. 1974. 13. Ellithorpe, D. B., Gonzalez, R., and 6. Evans, F. O., Jr., Sydnor, J, B., Mogabgab, W. J.: Antibiotic treatment Moore, W. E. C., et al.: Sinusitis of the of acute bronchial infections superimmaxillary antrum. N. Engl. J. Med. posed on chronic obstructive pulmonary 293:735, 1975. disease. Curr. Ther. Res. 20:121, 1976. 7. Meyer, R. D. and Finegold, S. M.: 14. Jordan, G. W., Wong, G. A., and Anaerobic infections: Diagnosis and Hoeprich, P. D.: Bacteriology of the treatment. South. Med. J. 69:1178, lower respiratory tract as determined by 1976. fiberoptic bronchoscopy and transtra8. Eneroth, C. M Lundberg, C., and cheal aspiration, J. Infect. Dis. 134:428,

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1:1133, 1971. 1976. 15. Chodosh, S. and Baigelman, W.: 20. Burrows, B. and Nevin, W.: Antibiotic management in patients with chronic Doxycycline Compared with Amoxicilbronchitis and emphysema. Ann. lin in Acute Bacterial Exacerbations of Intern. Med. 77:933, 1972. Chronic Bronchitis: Preliminary Report of a Double-Blind Crossover 21. Murray, H. W., Masur, H., Senterfit, L. B., and Roberts, R. B.: The protean Study. In: Doxycycline, Finegold, S. manifestations of Mycoplasma M., editor. Princeton, Excerpta pneumoniae infection in adults. Am. J. Medica, 1977, vol. 3, p. 1. Med. 58:229, 1975. 16. Hartnett, B. J. S. and Marlin, G. E.: Doxycycline in serum and bronchial se- 22. Smilack, J. D., Burgin, W. W., Jr., Moore, W. L., Jr., and Sanford, J. P.: cretions. Thorax 31:144, 1976. Mycoplasma pneumoniae pneumonia 17. Gartmann, J.: Doxycycline concentraand clindamycin therapy: Failure to tions in lung tissue, bronchial wall and demonstrate efficacy. J.A.M.A. bronchial secretions. Schweiz. Med. 228:729, 1974. Wochenschr. 102:1484, 1972. 18. Daggett, P.: An investigation of renal 23. Niitu, Y., Hasegawa, S., and Kubota, H.: In vitro development of resistance function in chronic bronchitis. Postto erythromycin, other macrolide antigrad. Med. J. 53:24, 1977. biotics and lincomycin in Mycoplasma 19. Siersbaek-Nielsen, K.: Rapid evaluapneumoniae. Antimicrob. Agents tion of creatinine clearance. Lancet Chemother. 5:513, 1974.

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Sinusitis, bronchitis, and mycoplasmal pneumonia.

156 SINUSITIS, BRONCHITIS, AND MYCOPLASMAL PNEUMONIA* GEORGE A. PANKEY, M.D. Head, Section of Infectious Diseases Ochsner Medical Institutions Clinic...
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