The pathogenesis of gram-negative bacjll&ry meningitis: Review of th~ literature · · RICHARDS. GOODSTEIN, D.O., (Capt.), USAF, MC Loring AFB, Maine

A review of the literature shows that gram-negative bacillary meningitis remains a threat to the newborn infant and the neurosurgical patient. It also may occur in the alcoholic man and the neutropenic patient, especially if he or she is hospitalized. The intrinsic immunologic factors that predispose the newborn infant to this illness are explored. With neonatal E. coli meningitis, strains with the Kl antigen show the greatest invasiveness, with morbidity and mortality related to the amount and duration of Kl antigen in serum or cerebrospinal fluid. The development of nosocomial gram-negative bacillary meningitis in neurosurgical patients seems to be related to m~tiple procedures, sharing of operative suites, and lack of intraoperative sterilization. The phys~ologic basis for the susceptibility of the alcoholic patient with cirrhosis to gram-negative bacillary meningitis is discussed.

Historically, gram-negative bacillary meningitis has been thought to be fairly well confined to the newborn infant and the neurosurgical patient. As the following paper will show, gram-negative bac­terial meningitis occurs in others as well, although such cases are nowhere near as common. For ex­ample, a 5-year retrospective stuqy at the Yale­New Haven Medical Center showed that only 0.5 percent of the meningitis cases other than those in neurosurgical or neonatal patients were caused by gram-negative bacilli. 1 Similarly, Crane and Lerner2 in their study from Detroit's three inner­city hospitals reported an incidence of 1.0 percent fo'r gram-negative bacillary meningitis in non­traumatic cases in adults.

The purpose of this paper is to explore the patho­physiology of gram-negative bacillary meningitis

Pathogenesis of gram-negative bacillary meningitis

and to re-emphasize its existence in an era which may possibly see an increased incidence of this en­tity, especially in the compromised host.

Neonatal ~eningitis In the neonate, gram-negative bacillary meningi­tis accounts for 42 percent of the neonatal menin­gitides, 1 with the premature infant being at four times the risk of the full-term neonate.3 The men­ingitis is usually s~condary to infected circumci­sion, postmaturity, upper respiratory tract infec­tions, or an umbilical infection in the otherwise normal neonate.4

•5 The literature cont~ins reports

of outbreaks of meningitis in ·nurseries with a sin­gle serotyped pathogen, a situation suggesting nosocomial spread, a real threat to any neonatal unit.5

·

In the neonate, intrinsic immunologic and ex­trinsic antigenic factors play predisposing roles. The neonate is deficient in IgM.3 IgM is poorly transferred across the placenta to tht:l neonate. The IgM (198) antibody is the most efficient bacterici­dal and opsonizing antibody against the somatic (0) antigen of the Enterobacteriaceae.3

•4 It is not

until the end of the fourth month oflife that detect­able levels of somatic antibodies specific to Escher­ichia coli are found in the serum of infants, ·a time­sequence that correlates well with the age-related decreasing susceptibility to E . coli meniytgitis. The neonate must have complement to be effective in phagpcytizing and ulti:rnately killing these e11cap­sulated Enterobacteriaceae. The neonate is defi­cient in Cl, C2, C4,6-8 so its classic complement pathway is defective. Sinpe the neonate also is de­fective in factor B or the C3 proactivator (glycine­rich 13-gly~oprotein) , the alternate pathwa,y for in­duction of opsonifiGation thus is abrogated.9

On the other hand, it is thought that the breast­fed neonate does· procure some de'gree of passive and active defense against the Enterobacteria­ceae. There are high concentrations of secretory IgA especially in the colostrum. 10 Although the mechanism of action of IgA is not known, it prob­ably protects the lumen of the neonatal gut from bacterial invasion. 10 The significance of this fea­ture only attains its true import when taken into the context of a study by Glode and cpworkers11 in

557/103

which meningitis developed in 4 7 percent of bac­teremic newborn rats deprived of colostrum and fed a highly virulent (K1 strain) E. coli, whereas meningitis occurred in only 15 percent of their counterparts fed the K1 strain but allowed to suck­le. Their finding of a 65 percent colonization rate for the K1 strains of E . coli in a single stool culture after the strains were fed to the newborn rats points out the ubiquity of the K1 strains.11 Passive transfer oflgA is significant in neonatal protection in that E . coli invasion was shown to be age relat­ed, with decreasing colonization and bacteremia rates with increasing age and defense develop­ment.11 Breast milk is also high in lactoferrin, which inhibits bacterial growth of E. coli by bind­ing iron necessary as a metabolic cofactor.12

Neonates are further limited in that their poly­morphonuclear leukocytes (PMN) have decreased opsonizing and phagocytic abilities. 13 Breast-fed neonates receive a quantity of maternal, fully ac­tive PMNs.

It has been well documented that the specific an­tigenicity of the E. coli plays the major role in the development of neonatal gram-negative bacillary meningitis. Among E. coli strains there are 154 so­matic (0) antigens, 100 capsular (K) antigens, and 34 flagellar (H) antigens.11 Of the E . coli strains that cause neonatal meningitis, 84 percent contain the K1 antigen. 14 It is found in stool samples of only 12 percent of neonates without enteritis and in blood samples of only 39 percent of neonates with E . coli septicemia without meningitis .1 4

Among neonates with E. coli meningitis , the K1 antigen caused greater morbidity and mortality than non-K1 antigens.15 The outcome was directly related to the amount and duration of K1 antigen in cerebrospinal fluid or serum. The mean median lethal dose ofK1 E. coli organisms in meningitis in a mouse model for 31 of Robbins and associates'14

cerebrospinal fluid isolates was 168 organisms as compared to 58,000 organisms in cerebrospinal fluid isolates from 10 non-Kl cases. The path­ogenicity of the K1 antigen has been shown in other kinds of infection in older patients as well; it was present more often and in higher proportions in invasive infections such as pyelo­nephritis than in the less invasive infections such as cystitis.14

•15

The K1 capsular antigen is a polysaccharide, a polymer of sialic acid, shown to be chemically ho­mogeneous with the polysaccharide capsular anti­gen of meningococcus group B.15 Experimentally, protection has been established to the K1 E . coli somatic antigen via passive injection of the puri­fied meningococcal group B capsular antibody. 14

The antigens most often associated with E. coli K1

558/104

meningitis were somatic (0 ) antigens 01, 06, 07, and 018ac.15

In neonates with galactosemia, the incidence of infection is high. 16 Galactosemia is an inborn error of galactose metabolism involving a deficiency of galactose-1-phosphate uridyl transferase. The dis­ease in its full expression involves cataracts, men­tal retardation, jaundice, weight loss, and hepato­megaly in the infant and, if the infant survives to early childhood, cirrhosis.17

Galactosemia deserves special attention in this review of gram-negative bacillary meningitis in that it is a model for the most common underlying pathologic disorder in the adult with gram-nega­tive bacillary meningitis not related to trauma: liver disease.

In a screening program for galactosemia in new­born infants in Massachusetts from 1964-1965 and 1966-1977, 8 neonates with "classic" galactosemia were found.18 Of these, 4 (50 percent) had infec­tions; 3 of the 4 had gram-negative bacillary men­ingitis and died; and the single infected survivor had pyelonephritis. In the uninfected neonates, galactosemia was diagnosed prior to initiation of feeding so that the insult to the liver that results in a massive, cytotoxic, hepatocellular necrosis was avoided.18 The resulting hepatitis and hepato­megaly causes an alteration in the portal circula­tion, similar to that described by Conn19 in his pa­per on spontaneous peritonitis and bacteremia in the patient with Laennec's cirrhosis.

Gram-negative bacteria are the predominant microorganisms in the galactosemic patient.18 The predominance of the gram-negative bacilli , their inherent virulence, and an induced alteration in the portal circulation with bypass of the Kupffer 's cells in the liver put the galactosemic neonate at a high risk for gram-negative bacillary septicemia and meningitis.

Certainly not limited to the neonate are the cases of meningitis secondary to contiguous infec­tion of mastoids and/or the inner ear. The associ­ation of gram-negative bacterial meningitis to spi­nal malformations such as meningomyelocele or spina bifida5 is also a circumstance common to the infant, increased in frequency during this period in that surgical correction of these lesions are usu­ally attempted as early as possible.

The patient with either uremia or hyposplenism is also predisposed to gram-negative enteric men­ingitis. Because the uremic patient has ineffective chemotaxis and phagocytosis, the response against encapsulated pathogens is ineffective. This attains an added significance in the gram-negative bacilli, which are frequent pathogens in the uremic pa­tient. The infant with sickle cell disease or non-

Apri l 1982/Journal of AOA/vol. 81/no. 8

traumatic surgical asplenia is deficient in lgM, which is made in the spleen's germinal center and is bactericidal for the gram-negative bacillus so­matic antigens. 20 These patients also are deficient in properdin and tuftsin, peptides necessary for op­sonization that are synthesized in the spleen.21 The spleen's ultrastructure ordinarily serves as a sieve entrapping intravascular particulate matter (that is, bacteria), thereby reducing the possibility of bacteremia. The hyposplenic infant thus is pre­disposed to bacteremia, especially that caused by E. coli, pneumococcus, and Hemophilus influen­zae. Because of the ease of access via the infant's blood-brain barrier, the increased frequency of bacteremia predisposes to meningitis.

Adult meningitis Meningitis caused by gram-negative enteric bacil­li in the adult is associated with underlying dis­ease, most commonly alcoholism with resultant liver disease, neutropenia, or neurosurgical proce­dures.

Prevalence in alcoholism In a review of non traumatic cases of meningitis in the Detroit city hospitals during the period of 1964 to 1974, there were 785 cases of meningitis of which 8 (1.0 percent) were caused by gram-nega­tive enteric microorganisms.2 Of the 5 patients with community-acquired infections, all were chronic alcoholics. The patient with cirrhosis re­sponds less effectively against encapsulated bacte­ria. 22 This factor may be related to the reduction in the liver's production of complement necessary for the opsonization and destruction of encapsulated bacteria. Conn19 cited evidence that in advanced cirrhosis, 80 percent of the pelvic venous blood by­passes the Kupffer cells, part of the liver's reticu­loendothelial system. Through portovenous or por­tohepatic arterial shunts the majority of pelvic flow escapes filtration. 19

It is not difficult to understand the significance \ of such an anatomic alteration when one considers that P. aeruginosa, E. coli, and Klebsiella species, the common causes of gram-negative enteric men­ingitis, are frequently associated with the urinary tract infections.1·21 The likelihood is increased when the cirrhotic patient undergoes urogenital manipulation such as cystoscopy. In the male, the prostate and the corpus spongiosum are richly in­vested with venous plexuses that are ultimately filtered in the normal person by the Kupffer cells. When one considers that the majority of cirrhotic persons are males, these factors combined explain the prevalence ofnontraumatic gram-negative en­teric meningitis in the adult male alcoholic. 2 In

Pathogenesis of gram-negative bacillary meningitis

addition, blood from the left renal vein and pelvic organs drains into the lumbar plexus (Batson's), which have anastomoses with the intracranial ve­nous sinuses, so that bacteria may bypass the liv­er. 2·21 The point to be made is that it is rather sur­prising that the proportion of meningitides that are nontraumatic and caused by gram-negative, enteric microorganisms (1.0 percent as reported by Crane and Lerner2) is not higher.

Nosocomial infections in neutropenic patients Neutropenia, especially that associated with ma­lignant disease, carries a marked risk for Pseudo­monas septicemia.22 In 1973 Bodey and Rodri­guez23 reported that P. aeruginosa accounted for 25 percent of all gram-negative bacillary septicemias in leukemia patients at the M.D. Anderson Hospi­tal and Tumor Institute. The major contributing factor was obviously the neutropenia, but the sec­ondary factor was length of hospital stay. As the neutropenic patients' hospitalization approached 4-6 weeks, 4 7 percent of this patient population were colonized with Pseudomonas species.23 No statistics on the number of these septicemic pa­tients who go on to develop meningitis via hema­togenous spread are available. It has been estimat­ed, however, that Pseudomonas meningitis has a 66 percent mortality.22 The translation of these statistics to practical patient care can only under­line the need to keep the leukemic and otherwise neutropenic patient out of the hospital as much as is feasible .

Postoperative cases In a 15-year retrospective study it was found that 80 percent of the meningitides at the Montreal Neurological Hospital were caused by gram-nega­tive bacilli.24 Of the 10,634 cases, there were 23 of nosocomial meningitis, an incidence of0.2 percent. This is an extremely low statistic, but not totally unexpected when one considers that the Hospital only does neurosurgical procedures; the operating rooms are not shared by other surgical subspecial­ties. Nineteen of the cases were caused by gram­negative bacilli. Of these 19, 18 were craniotomy cases; none were emergency (that is, trauma) cases. Meningitis following emergency procedures tended to be caused by Staphylococcus species. In comparison, Yale-New Haven Medical Center re­ported a 0.5 percent overall incidence of meningi­tis after neurosurgery of which 69 percent of cases were caused by gram-negative bacilli , with E . coli and K. pneumoniae accounting for 70 percent of the gram-negative bacilli.1 Multiple procedures, the sharing of operative suites, and the lack of in­traoperative sterilization techniques all seem to

559/105

predispose to nosocomial gram-negative bacillary meningitis. 1•2

4 Peripartum spinal anesthesia, ver­tebral closed heedle aspiration bone biopsy, and contaminated intrathecally injected drugs (such as amphotericin

1}3) have all beeh reported as causing

gram-negative bacillary meningitis.25-27 In the

Montreal study, only a singie case of meningitis caused by gram-negative bacilli was reported after laminectomy.24 Obviously, the continuity and in­tegrity of the dura make the difference between the low incidence of meningitis after laminectomy and that following spinal anesthesia or intrathecal injections.

Comment The rather lengthy view taken on this subject is of more than academic interest. In gram-negative bacillary meningitis there is a striking difference in mortal-ity based on the infection's origin. In gram-negative bacillary meningitis the result of distant spread (as in the alcoholic) mortality ap­proach s 33 percent, whereas in meningitis spreading from contiguous structures, as in mas­toiditis, otitis media, or a craniotomy site, mortal­ity approaches 70 percent.28

Appreciation is expressed to Gerald Blackburn, D.O., for his advice.

.. 1. Mangi , R.J. , Quintiliani, R. , and Andriole , V.T.: Gram-negative bacil-lary meningitis. Am J Med 59:829-36, Dec 75

2. Crane, L.R., and Lerner, A.M.: Non-traumatic gram-negative bacilla­ry meningitis in the Detroit Medical Center, 1964-1974 (with special mention of cases due to Escherichia coli). Medicine 57:197-209, May 78

3. Wilfert, C.M.: E. coli meningitis . K1 antigen and virulence. Annu

Rev Med 29:129-36, 1978

4. Headings, D.L., and Overall, J.C., Jr.: Outbreak of meningitis in a newborn intensive care unit caused by a single Escherichia coli K1 sero­type. J Pediatr 90:99-102, Jan 77

5. Stanley, M.M.: Cited by DeClerck, Y.: Primary Pseudomonas aerugin­

osa meningitis in a two-year-old boy. Can Med AssocJ 117:1066-7,5 Nov

77 6. Fishel, C.W., and Pearlman, D.S.: Comp)ement components of paired mother-cord sera. Proc Soc Exp Bioi __ Med 107:695-9, Jul61

7. Fireman, P. , Zuchowski, D.A., and Taylor, P.M.: Development of hu­man complement system. J Immunol103:25-31, Jul 69

8. Propp, R. , and Alper, C.A.: C'3 synthesis in the human fetus and lack of transplacental passage. Science 162:672-3, 8 Nov 68

9. Stossel , T.P. , Alper, C.A. , and Rosen, F.S.: Opsonic activity in the new­born. Role of properdin. Pediatrics 52:134-7 , 1973

560/106

10. South, M.A. : Enteropathogenic Escherichia coli disease. New devel­opments and perspectives. J Pediatr 79:1-11, Jul 71

11. Glade, M.P., et a l.: Pathogenesis of neonatal Escherichia coli menin­gitis. Induction of bacteremia and meningitis in infant rats fed E. coli Kl. Infect Immun 16:75-80, Apr 77

12. Bullen, J.J., Rogers, H.J., and Leigh, L.: Iron-binding proteins in milk and resistance to Escherichia coli infection in infants. Br Med J

1:69-75,8 Jan 72

13. Miller, M.E.: Phagocytosis in the newborn infant. Humoral and cel­lular factors . J Pediatr 74:255-9, Feb 69

14. Robbins, J.B. , et al.: Escherichia coli K1 capsular polysaccharide as­sociated with neonatal meningitis. N Eng! J Med 290:1216-20, 30 May

74 15. McCracken, G.H., Jr., et al.: Relation between Escherichia coli K1 capsular polysaccharide antigen and clinical outcome in neonatal men­ingitis. Lancet 2:246-50, 3 Aug 74

16. Donnell, G.N., Bergren, W.R., and Cleland, R.S.: Galactosemia. Pe­diatr Clin North Am 7:315-32, May 60

17. Holzel, A., Komrower, G.M., and Schwarz, V.: Galactosemia. Am J Med 22:703-11, May 57

18. Levy, H.L. , et al. : Sepsis due to Escherichia coli in neonates with ga­lactosemia. N Eng! J Med 297:823-5, 13 Oct 77

19. Conn, H.O.: Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. 1'). relatively common but rarely recognized syndrome. Ann Intern Med 60:568-80, Apr 64

20. Eichner, E.R.: Splenic function. Normal, too much and too little. Am J Med 66:311-20, Feb 79

21. Siroky, M.B. , et al.: Metastatic infection secondary to genitourinary tract sepsis. Am J Med 61:351-60, Sep 76

22. Turgeon, P.L., Laverdiere, M. , and Perron, L.: Successful treatment of Pseudomonas meningitis and septicemia in a leukemic neutropenic adult. Am J Clin Pathol63:135-41, Jan 75

23. Bodey, G.P., and Rodriguez, V.: Advances in the management of Pseudomonas aeruginosa infections in cancer patients. Eur J Cancer 9:435-41, Jun 73

24. Buckwold, FJ., Hand, R., and Hansebout, R.R.: Hospital-acquired bacterial meningitis in neurosurgical patients. J Neurosurg 46:494-500, Apr77 25. Corbett, J.J. , and Rosenstein, B.J. : Pseudomonas meningitis relat­ed to spinal anesthesia. Report of three cases with a common source of in­fection. Neurology 21:946-50, Sep 71

26. Rarrigopal, V. , and Geller, M.: Iatrogenic Klebsiella meningitis fol­lowing closed needle biopsy of the lumbar spine. Report of a case andre­view of the literature. Wis Med J 76:41-2, Mar 77

27. Sarubbi, F.A., Jr., et al.: Nosocomial meningitis and bacteremia due to contaminated amphotericin B. JAMA 239:416-8,30 Jan 78

28. Nunn, S.L. , and Wellman, W.E.: Pseudomonas meningitis. Report of a case. J Med Clin N Amer 44:1075-8, Jul60

Accepted for publication January 1982. Updating, as neces­sary, has been done by the author.

At the time this paper was written, Dr. Goodstein was a resi­dent in internal medicine at Flint Osteopathic Hospital, Flint, Michigan, of which Jerry L. Dutton, D.O., is chairman of the department. He is now a member of the Department oflnternal Medicine and Director of Medical Education at USAF Hospital, Loring AFB, Maine.

Dr. Goodstein, Capt. USAF, MC, 2113A Tennessee Circle, Lor­ing AFB, Maine 04751.

Aprill982/Journal of AOA/vol. 81/no. 8

IN ANGINA PECTORIS* ...

ISOROI[ (ISOSORBIDE DINITRATE)

ACTIVITY RECONFIRMED BY THALLIUM SCINTIGRAPHY

How isosorbide dinitrate affects stress-induced abnormal myocardial perfusion in angina pectoris 1

PROTOCOL In 14 patients with coronary artery disease, thallium 201 scintigrams were obtained on appearance of angina pectoris during stress-testing and four hours after stress-testing , and then again four to six weeks later following a single 10 mg sublingual dose of isosorbide dinitrate (ISDN) . In each patient six left ventricular segments were evaluated, for a total of 84 segments . RESULTS • Of 39 segments with exercise-induced perfusion

defects, 25 were normalized after ISDN. • ISDN reduced the segments with new or enlarged

exercise-induced defects by 64% . • ISDN increased the number of segments without new

or larger stress defects by 55% . • Angina and ST depression prevented in 11 of 14

patients .

CONCLUSION The administration of ISDN results in a reduced but more homogeneous myocardial perfusion after stress, indicating a reduction in myocardial oxygen consumption. The authors believe this reduction reflects the peripheral action of ISDN.

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References l Wolf R, Prelschner P, Engels HJ, Hundeshagen H. Lichllen PR: The eflecl of isosorbide dinitrate on stress-induced abnormal myocardial perfusion in coronary disease, substantiated by 201-thallium scintigraphy. Zeitschrih filr Kardiologie 68:676-686, 1979. 2. Data on file, lves Laboratories.

*Indications: Based on a review of this drug by the National Academy of Sciences­National Research Council and/ or other information, FDA has classified the indications as follows: "Probably" effective: When taken by the sublingual or chewable route, lsordil Sublingual and Chewable Tablets are indicated for the treatment of acute anginal attacks and for prophylaxis in si tuations likely to provoke such attacks. "Possibly" eflective: When taken by the oral route, lsordil is indicated for the relief of angina pectoris (pain of coronary artery disease). It is not intended to abort the acute anginal episode, bul is widely regarded as useful in the prophylactic treatment of angina pectoris. Final classification of the less-than-eflective indications requires further investigation.

Contraindication: Idiosyncrasy to this drug. Warnings: Data supporting lhe use of nitrites and nitrates during the early days of the acute phase of myocardial infarction (the period during which clinical and laboratory findings are unsta­ble) are insuflicient to establish safety. Precautions: Tolerance to this drug and cross- tolerance to other nitrites and nitrates may occur. In patients with functional or organic gastrointestinal hypermotility or malabsorption syndrome, it is suggested that orallitradose tablets. sublingual or chewable tablets, or Tembids capsules be the preferred therapy because a few patients have reported passing partially dissolved Tembids tablets in their stools. This phenomenon is believed to be on the basis of physiologic variability and to reflect rapid gastrointestinal transit of the tablet. Adverse Reactions: Cutaneous vasodilation with flushing . Headache is common and may be severe and persistent. Transient episodes of diuiness and weakness as well as O\her signs of cerebral ischemia associated with postural hypotension may occasionally develop. This drug can act as a physiological antagonist to norepinephrine, acetylcholine, histamine. and many other agents. An occasional individual exhibits marked sensitivity lo the hypotensive eflects of nitrite, and severe responses (nausea, vomiting. weakness, restlessness, pallor, perspiration and collapse) can occur even with the usual therapeutic dose. Alcohol may enhance this eflect. Drug rash and/ or exfoliative dermatitis may occasionally occur. Consult direction circular before prescribing.

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• 50% of overall four-week improvement of depression occurred during the frrst week of treatment.1 * Optimal antidepressant effect may not be evident for 2-3 weeks.

• Somatic improvement parallels antidepressant response.2

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• Effective over a wide range of depressed patients.7

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Antidepressant effectiveness with a single h. s. doset

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Rapidly emerging fro111 depression · with SINEQUAN® (doxepin HCI)

References: 1. Barranco SF. Thrash ML. Hackell E. et al (Pf1zer Pharmaceuticals, Pf1zer Inc .. New York. N.Y.). Early onset of response to doxep1n treatment , J Cfm Psych1atry 40:265-269. 1979. 2. Barranco SF. Thrash ML, Hackett E. et at (Pf1zer Phar­maceuticals , PfiZer Inc .. New York. N.Y.) Correlation of re­sponse of somattc and affecttve symptoms 1n treatment of depression w1 th doxep1n, 1n. Somat1c Depresston- lnstghts for Prrmary Care Physrc1ans . Postgraduate Med1c1ne Communl­cat,ons. Spec1al Report . March 1979. pp. 5Q-58. 3. Ward NG. Bloom VL. Fnedel RO The effectiveness of tncyclic antide­pressants tn the treatment of coexisting pain and depresston

Pam 7 331-341 . 1979. 4. Karacan I, Blackburn AB. Thornby Jl . et al: The effect of doxepm HCI (Sinequan) on sleep patterns and cllmcal symptomatology of neurot1c depressed patients

w1th sleep d1sturbance. 1n Mendels J (ed): Smequan•(Ooxe­pm HCI), A Monograpf> of Recent Cf1mcaf Studres. Excerpta Med1ca . 1977. pp. 4-22 5. Renshaw DC Doxep1n treatment of

sexual dysfunctions assoc1ated with depress1on: 1n Mendels (ed) Smequan. A monograph of recent clin1cal stud1es. p . 23

(Excerpta Med1ca. Amsterdam 1975) . 6. Tra1tz JJ. Bla1ne G. Georg1a EH: Evaluation of gastro1ntest1nal symptomatology 1n psychoneurot1cally depressed outpat1ents. Presented at the

Southern Med1cal Assoc1at1on . 79th Annual Meetmg. New Or­leans (November 1976). 7. P1nder RM. Brogden RN. Spe1ght TM, et al Doxep1n up-to-date· A rev1ew of 1ts pharmacological

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BRIEF SUMMARY SINEOUAN• (doxepin HCI) Capsules/ Oral Concentrate Contraindications. SINEOUAN 1s contramd1cated m individu­als who have shown hypersens1t1vity to the drug . Poss1b111ty of

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mind . SINEQUAN 1s contra1nd1cated m patients w1th glaucoma or

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tant tn patients receivmg other medtcal!ons w1th anti ­

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and may rema1n so unt1l Significant Improvement has oc­curred, pat1ents should be closely superv1sed dunng the early course of therapy. Prescnpt1ons should be wnllen for the

smallest feas1ble amount Should 1ncreased symptoms of psychosis or sh1ft to man1c

symptomatology occur. 1t may be necessary to reduce dosage or add a ma1or tranquiliZer to the dosage reg1men . Adverse Reactions. NOTE: Some of the adverse reacllons noted below have not been spec1flcally reported w1th SINEQUAN (doxep1n HCI) use . However. due to the close pharmacological S1m11ant1es among the tncychcs. the reac­llons should be cons1dered when prescnb1ng SINEOUAN.

Antichofrnergrc Effects Dry mouth , blurred VISIOn , constlpa­

llon. and urinary retenllon have been reported . If they do not subs1de w1th cont inued therapy. or become severe . 11 may be necessary to reduce the dosage.

Central Nervous System Effects Drows1ness 1s the most commonly not1ced side effect. Th1s tends to d1sappear as

therapy 1s continued . Other Infrequently reported CNS s1de effects are confuSIOn. d1sonentat1on. hallucinations, numb­ness . paresthes1as. atax1a, and extrapyramidal symptoms and

seizures . Cardiovascular: Cardiovascular effects 1nclud1ng hypoten­

SIOn and tachycardia have been reported occas1onally. Aflerg1c Sk1n rash. edema. photosensltlzallon, and pruntus

have occasionally occurred . Hematofogrc · Eos,noph1l1a has been reported 1n a few pa­

tients. There have been occasional reports of bone marrow

depress1on man1festmg as agranulocytosis , leukopenia, thrombocytopenia, and purpura .

Gastromtestinaf. Nausea. vom1t1ng . 1nd1gest1on. taste dis­

turbances. d1arrhea. anorex1a, and aphthous stomatitiS have been reported . (See anllchol,nerg'c effects.)

Endocrrne. Ra1sed or lowered lib1do. test1cular swell1ng . gynecomastia 1n males. enlargement of breasts and galac­

torrhea 1n the female , rais1ng or lowenng of blood sugar levels

have been reported w1th tncychc adm1nistrat1on . Other D1wness, t1nn1tus . we1ght ga1n , sweat1ng . ch1lls .

fat1gue . weakness. flushmg , jaundice. alopec1a, and

headache have been occas1onally observed as adverse

effects. Dosage and Administration. Far most pat1ents w1th 1llness of mild to moderate seventy. a starting daily dose of 75 mg is

recommended . Dosage may subsequently be 1ncreased or decreased at appropnate Intervals and accord1ng to 1ndiv1dual

response. The usual opt1mum dose range 1s 75 mglday to 150 mgtday.

In more severely 111 pallents h1gher doses may be reqUired w1th subsequent gradual1ncrease to 300 mg day 1f necessary.

Addillonal therapeutiC effect 1s rarely to be obta1ned by ex­

ceeding a dose of 300 mg day. In pallents w1th very mild symptomatology or emollonal

symptoms accompanying organ1c d1sease. lower doses may

suff1ce. Some of these pallents have been controlled on doses

as low as 25-50 mg day. The total daily dosage of SINEQUAN may be g1ven on a

d1v1ded or once-a-day dosage schedule . If the once-a-day

schedule 1s employed the max1mum recommended dose 1s

150 mg day. Th1s dose may be g1ven at bedtime. The 150 mg capsule strength is intended for maintenance therapy only

and is not recommended for initiation of treatment.

Anti-anx1ety effect 1s apparent before the ant1depressar effect Opt1mal antidepressant effect may not be ev1dent fc two to three weeks. Overdosage. A S1gns and Symptoms

1. Mtld: Drowstness. stupor, blurred VISIOn, excesstve dr) ness of mouth .

2. Severe: Resptratory depression . hypotenston , comt convuls1ons. cardtac arrhythm1as and tachycardias.

Also. unnary retentton (bladder atony) , decreased gastro1r

test1nal mot1l1ty (paralytiC ileus). hyperthermia (or hypothe m1a) . hypertension. d1lated pup1ls . hyperact1ve reflexes . B. Management and Treatment

1. Mild. Observation and support1ve therapy 1s all that usually necessary.

2. Severe: Med1cal management of severe SINEOUA (doxep1n HCI) overdosage cons1sts ol aggress1ve support!\ therapy. If the pat1ent 1s conscious. gastnc lavage, w1th appro pnate precautions to prevent pulmonary asp1ration . should t performed even though SINEOUAN 1s rapidly absorbed . Tt use of activated charcoal has been recommended. as h< been continuous gastnc lavage with sal1ne for 24 hours more. An adequate a1rway should be established 1n comatm patients and ass1sted ven tilation used 1f necessary. EK monitoring may be requ~red for several days, s1nce retap1 after apparent recovery has been reported . Arrhythmi; should be treated w1th the appropnate ant1arrhythm1c agent has been reported that many of the cardiovascular and C~

symptoms of tncyclic antidepressant poisoning 1n adults m be reversed by the slow 1ntravenous admtmstratlon of 1 mg tc mg of physost1gm1ne salicylate. Because physost1gm1ne rapidly metabolized. the dosage should be repeated as 1 qUifed . Convuls1ons may respond to standard ant1convulso therapy, however. barbiturates may potentiate any resp,atc depress1on. D1alysis and lorced diures1s generally are not value in the management of overdosage due to high t1ssue a prate1n b1nd1ng of SINEQUAN. Supply. SINEQUAN 1s ava1lable as capsules conta1n1ng dO> p1n HCI equivalent to· tO mg. 75 mg, and 100 mg doxep bottles of 100. 1000. and un1t-dose packages of 100 ( 10 x 10' 25 mg and 50 mg doxep1n: bott les ol 100, 1000, 5000. a unit-dose packages of 100 (lOx 10's). 150 mg doxep1n: boll of 50. 500, and unit-dose packages of 100 (10 x 10' SINEOUAN Oral Concentrate 1s available 1n 120ml bottles w an accompanying dropper calibrated at 5 mg, 10 mg. 15 n 20mg. and 25 mg. Each ml conta1ns doxep1n HCI equ1valen 10 mg doxepin . Just pnor to adm1n~strat1on . SINEQUAN C Concentrate should be d1luted w1th approximately t 20 ml water. whole or sktmmed mtlk, or orange , grapefruit, tome prune or p1neapple JUice. SINEQUAN Oral Concentrate 1s phys1cally compatible w1th a number of carbonated b erages. Far those patients reqUifing antidepressant ther< who are on methadone maintenance, SINEOUAN Oral Co centrate and methadone syrup can be m1xed together v Gatorade:S lemonade , orange Juice, sugar water, Tang ~ water: but not w1th grape ju1ce. Preparation and storage of b dilutions 1s not recommended

More detailed professional information available on reqUI

ROeRIG(IJD A division of Pfizer Pharmaceuticals New York, New York 10017