Relapsing pneumococcal meningitis: Isolation of an organism with decreased susceptibility to penicillin G

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B r i e f clinical and laboratory observations

Canfield CJ: Malaria: Host defense mechanisms and complications, Ann Intern Med 73:295, 1970. Heineman HS: The clinical syndrome of malaria in the United States. A current review of diagnosis and treat-

R elapsing pneumococcal meningitis: Isolation of an organism with decreased susceptibility to penicillin G Sirus Naraqi, M.D., Garland P. Kirkpatrick, M.D., and Sherwin Kabins, M.D.,* Chicago, IlL

UNTIL RECENTLY, p n e u m o c o c c i

isolated from human beings were uniformly highly sensitive to penicillin. B e g i n n i n g in 1967, a few p n e u m o c o c c i w i t h d e c r e a s e d s u s c e p t i b i l i t y to penicillin G were isolated from patients, the majority of whom had received penicillin G o n m u l t i p l e occasions. 1, 2 W e isolated a p n e u m o c o c c u s with d e c r e a s e d s u s c e p tibility to penicillin G , f r o m a p a t i e n t with sickle cell a n e m i a a n d m e n i n g i t i s . A f t e r initial i m p r o v e m e n t , clinical signs o f m e n i n g i t i s r e c u r r e d associated w i t h rep e a t e d isolation o f p n e u m o c o c c i f r o m blood a n d cereb r o s p i n a l fluid. R e l a p s e o c c u r r e d despite u n i n t e r r u p t e d t r e a t m e n t with h i g h d o s e s o f penicillin G. W e b e l i e v e t h e relapse was d u e in p a r t to d e c r e a s e d s u s c e p t i b i l i t y o f t h e p n e u m o c o c c u s to periicillin G.

CASE R E P O R T A 3-year-old black boy, with sickle cell anemia, developed cough, rhinorrhea, fever, irritability, and sore throat. On May 4, 1973, a lumbar puncture done in the emergency room at Michael Reese Medical Center yielded clear cerebrospinal fluid that was normal except for 10 mononuclear cells and 206 red blood cells per m m 3. Gram stain of the sediment was negative. He was given 600,000 units of intramuscular procaine penicillin G and sent home. He was admitted six hours later following a gener~alized seizure. From the Division o f lt!fectious Diseases, Department o f Medicine, Michael Reese Hospital and Medical Center, and the Department o f Medicine, University o f Chicago, Pritzker School of Medicine. *Reprintaddress:Department OfMedicine, Michael Reese Hospital and Medical Center, 29th St. at EllisA re., Chicago, IlL 60616.

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ment for American 'physicians, Arch Intern Med 129: 607, 1972. 10. The Medical Letter: Drugs for parasitic infections, 16 (No. 2, Issue 392): 8, 1974.

At age two, hemoglobinalysis had revealed 98% hemoglobin S and 2% hemoglobin F. Aside fi'om receiving penicillin two or three times for upper respiratory infections, he had been well. At admission, he was pale, irritable and alert. Temperature was 100.6~ pulse 166/rain, respirations 64/rain, blood pressure 110/60 mm Hg, weight 12.2 kg, and height 97 cm. His neck was supple. A systolic murmur was audible over the precordium. The lungs, abdomen, extremities, and a neurologic examination were normal; meningeal signs were absent. Hemoglobin concentration was 7.5 gin, hematocrit 23%, WBC 20,300/mm 3 with 75% neutrophils, 2% bands, 20% lymphocytes, and 3% monocytes. Peripheral blood smear revealed 2+ polychromatophilia, 2+ sickling and Howell-Jolly bodies. Cardiomegaly and normal lungs were noted on a chest r0entgenogram. Abbreviations used CSF: cerebrospinal fluid MIC: minimal inhibitory concentration Salient features of the hospital course are depicted in Fig. 1. The patient was given intravenous penicillin G, 100,000 units, every six hours and phenobarbital for 24 hours. The next day, he became lethargic, developed nuchal rigidity, and a positive Brudzinski sign. At this point, CSF and blood cultures taken the day before in the emergency room grew Diplococcus pneumoniae. The dose of penicillin G was increased to 500,000 units/kg/day, given in divided doses every four hours. He became afebrile by the third day and free of irritability and nucha! rigidity by the fifth day. Fever on days six and seven was attributed to thrombophlebitis at the intravenous site. At this time, there were no meningeal signs. The fever and thrombophlebitis abated simultaneously by the ninth day. On the tenth day headache, nuchal rigidity, irritability, fever, and a positive Kernig's sign recurred. Careful review revealed that no doses of penicillin G had been missed. Repeat lumbar puncture yielded cloudy fluid which contained 80 white blood cells per m m 3, 95% of which were mononuclear, 65 mg/dl protein and 64 mg/dl glucose. Gram stain of spinal flui~l was negative. Echoencephalogram and brain scintiscan were normal. Three to four per second occipital slow waves and abortive spikes were present on electroencephalogram. A positive Brudzinski's sign developed on the eleventh day when cultures of CSF and blood obtained the day before grew D. pneumoniae. One unit of packed red blood cells was given, and the dose of penicillin G was increased to one million units/kg/day, given in divided doses every two hours. The next day, he was afebrile

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Brief clinical and laboratory observations

The Journal of Pediatrics November 1974 our patient than the ten random isolates (Table I). The pneumococcus lacked beta-lactamase (penicillinase) activity. Levels of penicillin G in blood and CSF were assayed by a conventional serial twofold dilution technique (Fig. 1). Blood specimens were obtained midway between doses of penicillin G. The first specimen of CSF was assayed after 24 hours of refrigeration. The remaining specimens were assayed immediately after collection.

I

CSF

BLD 106 ~"

105

~-r.-

~:

104

io3

"u'l' 101"

DISCUSSION

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o.@.. ;00" 9998-

I7

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0"056 ' 2 ' 4 ' 6 ' 8

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10 12 14 16 18 20 22 30 35 40 DAY

Fig. 1. Response to therapy. Patient's pneumococcus required 0.25 /~g penicillin G per ml for inhibition. 32,500 units of penicillin G per kg were given on day one. Table I. Diplococcus pneumoniae sensitivity studies

Patient's organism* (Ixg/ml) MIC [ MBC Penicillin G Ampicillin Cephaloridine

0.25 0.6 0.15

0.25 1.2 0.3

Ten wi/d strains'~

(~glm/) MIC

MBC

0.015 - 0.03 0.015 - 0.03 0.04 - 0.08 0.04 - 0.08 0.02 - 0.04 0.02 - 0.04

MIC = Minimal inhibitory concentration; MBC = Minimal bactericidal concentration. *Identical results were obtained with both blood isolates and the second cerebrospinal fluid isolate. ]'Range of results. and free of headache and nuchal rigidity. Repeat cultures of CSF and blood on the twenty-first day were sterile. Therapy with penicillin G was discontinued on the thirty-seventh day. The child was discharged the next day after receiving an intramuscular injection of 600,000 units benzathine penicillin G. He has remained free of serious infection during the ensuing year. Pneumococci isolated from blood and CSF were type 23 (determined by Dr. H. M. Sommers at the Department of Microbiology, Northwestern Memorial Hospital, Chicago, Illinois). They, with ten random pneumococcal isolates were assayed by serial twofold dilutions of antibiotic. Eight to 17 times more penicillin G and ampicillin and 4 to 7 times more cephaloridine were required to inhibit the pneumococcus from

In a study of 314 r a n d o m l y selected p n e u m o c o c c i , 99.4% w e r e inhibited by 0.04/xg of penicillin G per ml. 3 O n e strain required 0 . 2 / x g / m l for inhibition. T h e minimal inhibitory c o n c e n t r a t i o n (MIC) of 0.25 /xg penicillin G per ml for our patient's p n e u m o c o c c u s was 8 to 17 times higher t h a n the MICs for 10 r a n d o m strains that we tested. P n e u m o c o c c i requiring 0.1 to 2.0/xg penicillin G per ml for inhibition were isolated in N e w G u i n e a f r o m 12% of 530 isolates from carriers and patients with p n e u m o n i a and meningitis w h o had repeatedly taken penicillin 4, 5 R e c u r r e n t meningitis, associated with repeated isolation of D. pneumoniae from CSF and blood, occurred in our patient on the eighth day of c o n t i n u o u s high-dose penicillin G therapy. A t this point, the penicillin G level in CSF was below the M I C of our patient's organism, b u t was greater than the MIC for 99.4% o f p n e u m o c o c ci. 3 The w e l l - k n o w n decrease in clearance f r o m blood of p n e u m o c o c c i due to faulty opsonization f o u n d in patients with sickle cell anemia may h a v e b e e n partially responsible for the relapse. 6 R e c u r r e n t p n e u m o c o c c a l meningitis in patients with sickle cell a n e m i a occurs as a separate infection or after cessation o f penicillin G t h e r a p y ] Relapse could have b e e n due to an u n d e t e c t e d parameningeal focus of infection. Such loci usually cause relapse after cessation o f therapy with antibiotics or delay or p r e v e n t the initial response of the patient to therapy. 8 Relapse while receiving high doses of penicillin G is u n u s u a l . T h e a p p a r e n t m i l d i n f l a m m a t o r y r e s p o n s e in CSF may not h a v e allowed sufficient antibiotic to cross the blood-brain barrier to eradicate a p n e u m o c o c c u s with decreased susceptibility to penicillin G. D o u b l i n g the dosage of penicillin G led to a near d o u b l i n g o f drug c o n c e n t r a t i o n s in blood and tripling of levels in CSF and to eradication of infection. This report suggests that p n e u m o c o c c a l infection in an u n f a v o r a b l e site in selected hosts by strains with d e c r e a s e d s u s c e p t i b i l i t y to p e n i c i l l i n G m a y r e q u i r e higher t h a n r e c o m m e n d e d dosage for cure. Since sensitivities of p n e u m o c o c c i to penicillin G are not routinely assayed, a periodic r e - e x a m i n a t i o n of the susceptibility o f the o r g a n i s m to antibiotics s e e m s advisable.

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REFERENCES 1, Hansman D, and Bullen MM: A resistant pneumococcus, Lancet 2:264, 1967. 2. Hansman D, Glasgow H, Sturt T, Devitt L, and Douglas R: Increased resistance to penicillin of pneumococci isolated from man, N Engl J Med 284:175, 1971. 3. Kislak JW, Razavi LMB, Daly AK, and Finland M: Susceptibility of pneumococci to nine antibiotics, Am J Med Sci 250:261, 1965. 4. Hansman D, Devitt L, and Riley I: Pneumococci with increased resistance to penicillin, Br Med J 3:405, 1973. 5. Hansman D, Glasgow HN, Sturt J, Devitt L, and Douglas

Peritonsillar infection and bacteremia caused by Fusobacterium gonidiaformans Ethan Rubinstein, M.D., New York, N. Y., Andrew B. Onderdonk, Ph.D., Sepulveda, Calif, and James J. Rahal, Jr., M.D.,* New York, IV. Y.

B A C T E R E M I A due to anaerobic organisms arising f r o m p l e u r o p u l m o n a r y , abdominal, and pelvic infections has b e e n recognized with i n c r e a s i n g , f r e q u e n c y during rec e n t years. 1"4 Prior to the clinical introduction of antibiotics, the o r o p h a r y n x was a f r e q u e n t initial site of anaerobic infection in children and y o u n g adults. Tonsillar or peritonsillar abscesses, parapharyngeal infections, and cervical adenitis led to t h r o m b o s i s of the jugular vein, bacteremia, and distant septic emboli. 5 G u n n , 6 in 1956, reported that one third of anaerobic b a c t e r e m i a s o r i g i n a t e d f r o m local i n f e c t i o n s in t h e oropharynx. Later series indicated a lesser frequency of tonsillar infections as the portal of entry, probably owing to the availability of several c h e m o t h e r a p e u t i c agents to which o r o p h a r y n g e a l species are s e n s i t i v e ) -4, 7-9 T h e following case s e r v e s as a r e m i n d e r that anaerotic peritonsillar and parapharyngeal infections still ocFrom the infectious Disease Division, New York Veterans Administration Hospital Department o f Medicine, New York Univep~ity School of Medicine, and b!fectious Disease Division, Sepulveda Veterans Administration Hospital. *Reprintaddress:New York VeteransAdmintstrationHospital Fit:ffA ve. and E. 24th St., New York,N. Y. 10010.

B r i e f clinical and laboratory observations

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RM: Pneumococci insensitive to penicillin, Nature (London) 230:407, 1971. 6. Johnston RB Jr, Newman SL, and Struth AG: Serum opsonins and the alternate pathway in sickle-cell disease, N Engl J Med 288:803, 1973. 7. Kabins SA, and Lerner C: Fulminant pneumococcemia and sickle cell anemia, JAMA 211:467, 1970. 8. Swartz MN, and Dodge PR: Bacterial meningitis-- a review of selected aspects. 1. General clinical features, special problemsl and unusual meningeal reactions mimicking bacterial meningitis, N Engl J Med 272:842, 1965.

cur and may lead to serious sequelae if not identified and treated promptly. CASE R E P O R T A 7-year-old boy was admitted to the hospital for tonsillectomy and adenoidectomy because of recurrent tonsillitis, otitis, and upper respiratory infections. There was no evidence of other chronic disease or immunodeficiency. Tonsillectomy was performed, and he was discharged from the hospital on the following day. Erythromycin ethylsuccinate, 40 mg/kg/day orally, was prescribed for treatment at home. Two days after the operation, fever occurred and therapy was changed to penicillin V, 25 mg/kg/day, and tlien to oxacillin, 40 mg/kg/ day, because a throat culture revealed Staphylococcus attreus. The temperature then rose to 106~ and he was hospitalized again. Physical examination revealed a large, firm tender mass in the left anterior cervical area and splenomegaly. The hemoglobin was ll.6 gm/dl and peripheral white cell count 7,100 with 66% neutrophiles, 21% lymphocyte s, 11% monocytes, and 2% eosinophiles. The platelet count was normal. An electrocardiogram and chest film were normal. Two blood cultures were taken, and the patient was treated with penicillin G, 12 million units, and oxacillin, 200 mg/kg, daily by intermittent intravenous infusion. On the third hospital day, both blood cul-tures contained gram-negative bacilli in the aerated bottles only (Difco, thiol). Gentamicin, 5 mg/kg/day, was administered by intramuscular injection. However, recurrent chills and fever of 103-104~ continued for three days. The hemoglobin fell to 8.2 gm/ml, a pericardial friction rub was heard, the electrocardiogram showed inversion o f T waves over the left precordium, and the child appeared critically ill. A blood culture was taken, penicillin and oxacillin therapy was withdrawn, and clindamycin, 35 mg/kg/day, plus chloramphenicol, 100 mg/kg/day, were given by intravenous infusion. On the following day, th e temperature remained below 102~ and the patient became more alert and comfortable. On the third day of chloramphenicol therapy, the peripheral leukocyte count fell to 4,300/ram 3 and this antibiotic was withdrawn. Treatment was maintained with clindamycin alone. The blood culture taken prior to chloramphenicol and clindamycin therapy was nega-