Recurrent Salmonella Meningitis in a Compromised Host

RICARDO BOLIVAR, MD,' GERALD P. BODEY, MD,' AND WILLIAM S. VELASQUEZ. MDt

A 26-year-old woman with Hodgkin's disease had recurrent episodes of meningitis caused by Salmonella enteritidis serotype poona, which responded well to antimicrobial therapy. An extensive investigation failed to reveal a focus of infection. A defective cellular immune response and the intracellular location of these microorganisms probably accounted for the pattern of infection seen in this patient. The need for long-term therapy in compromised patients with this type of infection is stressed.

Cancer 50:2034-2036, 1982.

ALMONELLA MENINGITIS is Usually a disease of chil- S dren,' occurring only sporadically in adults.' Re- current bacterial meningitis is most commonly seen in association with underlying anatomic defects3 Here we describe an adult with Hodgkin's disease and recurrent Salmonella meningitis in whom no source of bacteremia or anatomic defect was identified.

Case Report

A 26-year-old woman previously in good health was diag- nosed as having Hodgkin's disease in September 1976. At that time a Iaporatomy and splenectomy were done. The patient was staged 111 A and was given radiation therapy consisting of 4400 rad to the upper mantle and 4000 rad to the abdomen. The radiotherapy was completed in December 1976. In Feb- ruary 1977, radiation pneumonitis and pericarditis were de- tected and she was given prednisone and isoniazid prophylac- tically. The dose of prednisone was initially 60 mg/day which was slowly tapered thereafter.

Five courses of chemotherapy with nitrogen mustard. vin- cristine, procarbazine, and prednisone (MOPP) were given between June and November 1977. In December 1977, the patient traveled to Honduras where she developed a nonspe- cific febrile illness of three days duration. She recovered un- eventfully and on a follow-up outpatient visit had no evidence of disease except for symptoms attributable to radiation peri- carditis and pneumonia. She continued to receive prednisone at a dose of 5 mg/day. In January 1978, she was admitted to the hospital because of fever, chills, and neck stiffness which had developed during the preceding 24 hours. On physical examination the patient appeared toxic, the temperature was 102.4"F, the pulse was 104. blood pressure was 100/80, and

From the Departments of *Developmental Therapeutics and tMed- icine, The University of Texas Cancer Center, M. D. Anderson Hos- pital and Tumor Institute, Houston, Texas.

Address for reprints: Ricardo Bolivar, MD, M. D. Anderson Hos- pital and Tumor Institute, Department of Developmental Therapeu- tics, 6723 Bertner, Houston. TX 77030.

Accepted for publication September 17, 198 1.

signs of meningeal imtation were present; the remainder of the physical examination findings were unremarkable. Her leu- kocyte count was 9300 with 96% polymorphonuclear leuko- cytes, the hemoglobin was 11.5 gr/100 ml and the hematocrit was 34.9%. Electrolytes, glucose, and creatinine levels were within normal limits. The urinalysis was normal. The cerebro- spinal fluid (CSF) analysis results are listed in Table I . Initial treatment consisted of aqueous penicillin G (20 million units) and chloramphenicol ( 1 g, intravenously [IV] every 6 hours). A gram-negative bacteria was cultured from a blood specimen which was susceptible to chloramphenicol, ampicillin, tri- methoprim sulfamethoxazole, and tetracycline. When these results became available, penicillin was stopped and chlor- amphenicol continued. The organism was later identified by the City of Houston Health Department as Salmonella enter- itidis, group G. serotype poona. After two weeks of therapy, the CSF values (Table 1 ) had improved, and at the time of discharge the patient was asymptomatic.

One week after discharge the patient presented with fever, chills, and headache. During examination signs of meningitis were again detected. CSF findings and culture results are seen in Table 1. An organism with the same susceptibility pattern was isolated in culture. Chloramphenicol ( I gram IV every 6 hours) was initiated. The patient responded well to this therapy and once again improvement was documented both clinically and by analysis of the CSF. Upon discharge, oral therapy with trimethroprim sulphamethoxazole ( 160/800 mg three times daily) was recommended. Following this episode, the patient was admitted three times in less than a four-month period with evidence of meningitis. The dates, sequence and details of each episode are outlined in Table 1 . During the fifth hospitaliza- tion, the patient was treated with chloramphenicol 4 g/day IV and showed a good response, but because of bone marrow depression it was decided to discontinue the drug. Four days after discontinuation of the antibiotic, a relapse occurred. Once again she responded to treatment and was discharged on tri- methroprim sulphamethoxazole ( I60/800 mg three times daily) therapy which was to continue for an indefinite period of time.

During the course of her several hospitalizations, an exten- sive investigation was camed out to determine the source of

OOO8-543X/82/ I I 1512034 $0.95 0 American Cancer Society

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No. 10 RECURRENT SALMONELLA MENINGITIS - Bolivar et al. 2035

TARE 1 . Selected Laboratory Results

CSF findings

Cultures Hospital Glucose (blood Protein Peripheral WBC admission Dates WBCImm’ %PMNL glucose) mddl mddl W BC/m m3 %PMNL Blood CSF

# I 1124-217 3.900 90 7 (79) 243 9.300 96 -t

#2 2/ 15-41 1 16.500 99 1 (80) 635 19.400 85 + i #3 417-518 3.290 89 46 ( 1 21) 103 10.500 95 #4 51 14-5/30 1.800 91 14 (145) 111 9.300 16 -t t #5 6127-819 6.320 91 19 (145) I45 9.100 14 + i

Post therapy 10 18 58 ( 1 10) 33

-

Relapse 1/16 920 89 40 (100) 90 Postparenteral 1/23 0 61 (120) 22

therapy

CSF cerebrospinal fluid; WBC: leukocyte count; PMNL: polymorphonuclear leukocytes.

-

the recurrent infection. In addition to the routine laboratory evaluation, numerous other diagnostic studies were performed. Specimens were obtained of stool, urine, and bile (endoscopic canulation of bile duct), and Salmonella sp. was cultured from none of them. Roentgenographs were obtained of the skull, mastoids and paranasal sinuses, as were a bone series, myelo- gram, oral chloecystogram, and upper gastrointestinal series, including small bowel evaluation. Results of all of these studies were normal. Radionuclide scans of bone and gallium and ’ I I Indium scintillation cystemography were performed, all showed no abnormalities. An echocardiogram showed no ev- idence of valvular vegetations. Delayed hypersensitivity testing with dermatophyton, Candida, varidase, mumps, and PPD (purified protein derivative) were all negative. Complement and immunoglobin concentrations were within normal limits. The organism repeatedly isolated in culture showed the same antibiotic susceptibility pattern during the course ofthis illness.

One month after her discharge from the hospital the patient was seen in the outpatient clinic, at which time she had no fever or headache and was doing well. After this visit she moved to another city and was lost to follow-up.

Discussion

Although Salmonella is not a frequent cause of men- ingitis and less than 1% of the cases of Salmonella in- fection are associated with this c~mplication,~ numerous cases of Salmonella meningitis have been reported in children.’,’ In contrast, according to a recent review,2 only 14 cases of Salmonella meningitis in adults have been recorded in the English literature. Most of the adult cases were caused by Salmonella typhi and none by the serotype found in this case. Although infections caused by these organisms are not unusual in cancer patients, the occurrence of meningitis is rare. Only one case of meningitis’ was described in 190 cancer patients with salmonella infections from four large series.’-I0

It is well established that a greater susceptibility to Salmonella infections occurs in extremes of age, chronic diseases, hemolytic disorders, and hematologic malig-

nancies,6 and following immunosuppressive therapy.’~~ Among patients with underlying malignancies, Salmo- nella infections are much more common in patients with leukemia and lymphoma.’ In these patients, defects in leukocyte function, cellular immunity,” and defective regulation of inflammatory mediators12 could explain the increased susceptibility. This patient’s susceptibility to infection by Salmonella organisms and the compli- cated course were most likely related to the underlying disease, as manifested by impaired delayed hypersensi- tivity reaction and possibly further compromised by ste- roid therapy. It is difficult to ascertain the role that sple- nectomy played in this patient’s clinical picture, since the risk of infection in asplenic patients is usually as- sociated with other microorganism^.'^

The first contact with the infecting organism could not be determined exactly since, as in most adult pa- tients with Salmonella meningitis preceding symptoms of gastroenteritis or sepsis are usually absent.2 Although the oral route is by far the most common way of ac- quiring the organisms, there are unusual circumstances in which the infection may occur as a complication of transfusion of blood products.I4

It is striking that after approximately a total of 14 weeks of therapy, albeit interrupted, the patient contin- ued to relapse. Most cases of recurrent bacterial men- ingitis are associated with anatomic defects, either post- traumatic or postoperative, or to the presence of a para- meningeal focus of infe~t ion.~ In the patient discussed here, despite extensive investigation, a site of infection could not be clearly defined. Although the gastrointes- tinal tract was considered an important potential source for the organism, bacterial cultures off and on antibiotic failed to reveal it. The recurrent infection of the central nervous system suggests the possibility of ventriculitis. Other cases of recurrent salmonella meningitis have been usually associated with well-defined septic foci such as brain abscesses,’’ coexistence of ventriculitis,16 or in-

2036 CANCER November 15 1982 Vol. 50

fected operative sites.I7 Fitzgerald el al. I 7 described an adult patient with postoperative meningitis due to Sal- monella choleraesuis who relapsed six times until an infected subarachnoid cyst was removed.

The ability of Salmonella to cause recurrent infection probably has to do with the fact that it is an intracellular facultative organism. Collins ef al. ‘’ have ascribed an important role to cell-mediated aspects of immunity in protecting against infections caused by intracellular or- ganisms, such as Salmonella. Prolonged camer states and failure of short courses of treatment may be related to the persistence of Salmonella in tissue. The fact that the organism isolated during these episodes maintained the same susceptibility pattern is in agreement with the postulate of Levison and Kaye’’ that therapeutic failures are usually associated with persistence and not to the emergence of antibiotic-resistant strains. Transforma- tion of microorganisms to L forms and failure of drug delivery to intracellular sites are some mechanisms pro- posed to explain microbial persistence.20

Considering the pathogenic mechanisms involved in infections caused by Salmonella and the interaction with compromised hosts, the need for long-term therapy be- comes apparent. In this case, it is possible that the com- pliance of the patient to a long-term oral and uninter- rupted antimicrobial regimen might have prevented the recurrent episodes of infection. The experience from a recent report” of gram-negative meningitis offers an- other explanation for the prolonged course. The relapse rate in patients with Salmonella meningitis was high even after prolonged courses of chloramphenicol; in contrast, patients treated with ampicillin responded well. Perhaps the predominant bacteriostatic activity of chlor- amphenicol compared to the bactericidal activity of am- picillin accounts for this phenomenon. We feel that in compromised hosts, especially patients with defective cellular immunity, recurrent Salmonella meningitis probably requires a minimum of four weeks of contin- uous parenteral antibiotics with bactericidal activity, fol- lowed by oral therapy for two to three months with a close follow-up after completion of treatment.

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