Flavobacterium odoratum ventriculitis treated with intraventricular cefotaxime

Journal of Infection (I985) IX, 233-238

CASE REPORT

Flavobacterium odoratum ventriculitis treated with intraventricular eefotaxime D. E. Macfarlane,* P. B a u m - T h u r e e n , t and I. Crandon~

*Departments of Microbiology, af Child Health and :~Surgery, University Hospital of the West Indies Mona, Kingston 7, Jamaica Accepted for publication ~r January r985 Summary A 6-week-old infant admitted to the University Hospital of the West Indies with hydrocephalus later developed ventriculitis. A heavy growth ofFlavobacterium odoratum susceptible to gentamicin and cefotaxime was recovered from the ventricular fluid. Since intraventricular therapy was envisaged, a Pudenz reservoir was installed and ventricular fluid aspirated every 24 h to monitor treatment. Initial therapy consisted of intravenous cefotaxime, 5o mg/kg q.i.d, for 4 days. No significant reduction in the number of organisms in the ventricular fluid was achieved with this regimen. Intravenous therapy was therefore discontinued. On day 5 intraventricular therapy began with 5 mg cefotaxime 24 h for 6 days, followed by r mg/24 h for 4 days. Daily monitoring of intraventricular fluid indicated a high degree of antibacterial activity with rapid elimination of bacteria. Ventricular fluid remained sterile Io days after therapy stopped. The Pudenz reservoir was removed, a ventriculoperitoneal shunt installed, and the patient discharged from hospital 4 days later without noticeable sequelae.

Introduction T h e treatment of ventriculitis, with or w i t h o u t concomitant meningitis, presents a p r o b l e m w h e n the infecting organism is a G r a m - n e g a t i v e enteric bacillus because it is extremely difficult to achieve adequate concentrations of appropriate antibiotics in the cerebrospinal fluid b y means of parenteral a d m i n i s t r a t i o n ) L u m b a r intrathecal administration has not shown any consistent advantage over systemic therapy in terms of either increased concentrations of antibiotic or i m p r o v e m e n t in the patient's c o n d i t i o n : This is especially so for h y d r o c e p h a l u s w h e n penetration of antibiotic into the ventricles is u n p r e d i c t a b l e ? Direct installation of antibiotics into the ventricles has been p r o p o s e d as a possible solution to some of these p r o b l e m s ? In a multicentre trial which c o m p a r e d systemic with intraventricular therapy for treating neonatal meningitis and ventriculitis, M c C r a c k e n and colleagues reported a dramatic increase in mortality associated with the use of intraventricular a m i n o g l y c o s i d e s : In a m o r e recent study, h o w e v e r W r i g h t and colleagues reported a mortality rate of 5"5 % with intraventricular aminoglycoside therapy c o m p a r e d with 4o % for systemic therapy in children with meningitis caused b y G r a m - n e g a t i v e bacteria. T h e s e favourable results were attributed to careful o613-4453/85/o6o233 +06 $o2.oo/o

© x985 The British Society for the Study of Infection

234

D. E. M A C F A R L A N E E T A L .

Table I C S F values prior to insertion of ventriculoperitoneal shunt

Day Specimen I

CSF glucose (mmol/1)

Cell count ( x io6/1)

Protein (rag/l) Culture

6.2

i-8

8

(lumbar puncture) 4 CSF (ventricular tap)

4"2

I'5

I7

8

3'2

I.I

IO6

I5OO

No growth

3'8

I'O

3

I87O

5 x IO4 CFU/1

13

CSF

Blood glucose (mmol/1)

CSF (ventricular tap) CSF (ventricular tap)

900

No growth

lO6O No growth

Flavobacterium odoratum

monitoring of antibiotic concentrations and numbers of bacteria in the cerebrospinal fluid (CSF) during treatment. 3 We wish to report on the treatment with intraventricular cefotaxime of a patient with meningitis caused by Flavobacterium odoratum. Treatment was monitored by aspirating ventricular fluid daily in order to determine bactericidal and bacteriostatic concentrations as well as the number of bacteria.

Case r e p o r t

A 6-week-old black male infant was admitted to hospital with a history of poor feeding since birth, vomiting after feeds for 2 weeks, and swelling of the head for IO days. He was born with vertex presentation at 34 weeks gestation by spontaneous vaginal delivery to a pre-eclamptic mother in premature labour. Since the mother had abandoned the child, details of the birth were unknown but the infant was admitted to hospital for 3 weeks because of prematurity. On examination, he was alert but very irritable. His temperature was 37 °C, pulse rate I4o/min and respiration rate 4o/min but not laboured. Head circumference was 34 cm, length 46 cm and weight 2"3 kg. All growth parameters were at the third percentile for gestational age, but the circumference of the head was significantly larger than expected for length and weight of the body. Examination was remarkable for widely splayed sutures with large, bulging fontanelles and a prominent venous pattern over the scalp. Neurologically the baby was within normal limits, with good muscle tone, symmetrical deep tendon reflexes, and appropriate sucking, rooting, grasping and Moro reflexes. On admission, a lumbar puncture was performed. T h e low glucose and high protein levels indicated the possibility of meningitis with concomitant ventriculitis. Antimicrobial therapy was started with a combination of penicillin and gentamicin and continued for IO days. Four days after admission IO ml clear sterile fluid was aspirated from the left ventricle. Two further samples of ventricular fluid were withdrawn on days 8 and I3 in order to confirm

Treatment of F. odoratum ventriculitis

235

Table II Bacterial colony counts and bacteriostatic and bactericidal dilutions

of ventricular fluid samples aspirated during cefotaxime therapy Day 29 3°

Bacterial c o u n t s cfu/1

Bacteriostatic dilution

Bactericidal dilution

Antibiotic

x IO 8 X IO 7 x Io 6 x IO 7

I in 8 I in 8 -I in 32

0 0 -I in 4

Intravenous c e f o t a x i m e 5o m g / k g q.i.d

32

I 7'5 7"5 3"5

33 34

7"0 x lO 7 3"0 x lO 4

I in 64 I in 64

I in 32 I in 64

Intraventricular cefotaxime 5 rag/z4 h

35

4"0 × I01

36 37 38

I - o x IO l NG NG

I in 64 , in I 2 8 x in 128

I in 32 I in 64 r in 64

4o 41 43 48

NG NG NG NG

I in 512 i in 256 i in i 2 8 --

I in 256 I in 128 I in 64 --

31

--

--

Intraventricular cefotaxime i mg/24 h

NG = no growth.

sterility of the ventricles. On day 23 a ventriculoperitoneal shunt was inserted, and a further sample of ventricular fluid taken. A Gram stain of this sample revealed many pus cells and Gram-negative bacilli. T h e distal shunt tubing was removed and a Pudenz reservoir connected to the proximal intraventricular catheter. As a prophylactic measure, 5 mg gentamicin was instilled into the reservoir during surgery. Initial therapy consisted of 50 m g / k g of cefotaxime Iv q.i.d, for 4 days. Treatment was monitored by daily aspiration of ventricular fluid, determination of CSF bacteriostatic and bactericidal titres and by counting colonies of F. odoratum found in the CSF. After 4 days intravenous cefotaxime therapy was discontinued and 5 mg cefotaxime injected daily into the Pudenz reservoir for 6 days, followed by a further four daily injections of i mg cefotaxime. T h e ventricular fluid was checked for sterility I week after completing therapy. T h e Pudenz reservoir was removed 2 weeks later. T h e intraventricular catheter was cultured for organisms by washing it with I ml nutrient broth. A colony count was performed on the nutrient broth. T h e four initial samples of CSF (Table I) revealed low glucose and increasingly elevated protein concentrations. T h e cell count, however, was low in all samples except the third which came from a traumatic tap. Organisms were not recovered from the first three samples but a light growth of a Gram-negative bacillus was obtained from the fourth sample. T h e organism was identified by standard biochemical tests and API 2oE as F. odoratum. T h e sample of ventricular fluid removed during insertion of the ventriculoperitoneal ishunt contained I'5 × Io ~ colony forming units (CFU)/1 of the same organism. T h e baseline sample of ventricular fluid aspirated on day 29 after insertion of the Pudenz reservoir contained IO8 CFU/1 of F. odoratum (Table II). This sample was bacteriostatic at a dilution of I in 8 but was not bactericidal.

236

D.E. MACFARLANE ETAL.

After 4 days of intravenous cefotaxime therapy, there was no significant change in the numbers of organisms in the ventricular fluid, although the bactericidal dilution had increased from o to I in 32 (Table II). Within 24 h of commencing intraventricular therapy, the numbers of organisms decreased rapidly from 7 × xoT/1 to 3 x Io4/1, and 4 days later the CSF from the ventricles was sterile (Table II). T h e bactericidal dilution of the ventricular fluid increased from I in 4 to I in 64 and reached a peak of I in 256 after 6 days of intraventricular therapy (Table II). A sample of ventricular fluid aspirated 6 days after completion of therapy remained sterile. T h e Pudenz reservoir was removed on day 62 and fluid aspirated from the right ventricle at this time was sterile. Fluid from the left ventricle yielded 5 x IO4 CFU/1 of F. odoratum, and culture of the intraventricular catheter grew in excess of 4 x I o 5 CFU/1 of the same organism. A repeat sample of ventricular fluid taken I week later was sterile. Discussion

T h e clinical diagnosis of hydrocephalus, and the low glucose and high protein concentrations in the CSF, raised suspicion ofventriculitis in this child, despite a low cell count, and the failure to recover any organism from the first three samples. T h e neurosurgeons were anxious to exclude the possibility of ventriculitis before they inserted a ventriculoperitoneal shunt, hence three ventricular taps were performed. Although a light growth of F. odoratum was obtained from the third sample of ventricular fluid, the absence of pus cells and the unusual identity of the organism led to the conclusion that it was a contaminant. This was unfortunately incorrect, and by the time the ventriculoperitoneal shunt was installed there was evidence of definite ventriculitis, with numerous pus cells, and a heavy growth of F odoratum in the ventricular fluid. It is possible that the organism was introduced by repeated sampling of the ventricles. As it seemed likely that intraventricular therapy would be necessary in this patient, and monitoring of ventricular fluid would be an important aspect of treatment, an intracranial Pudenz reservoir was inserted and connected to a ventricular catheter. T h e choice of antimicrobial drugs was limited to an aminoglycoside or to cefotaxime, because of the antibiogram of the infecting organism. Cefotaxime was selected on the basis of its superior penetration into the CSF 6 and its relative lack of toxicity. Previous experience with the aminoglycosides has indicated poor penetration into the C S F and possible ventricular toxocity. 8 T h e initial attempt at systemic therapy was not succesful. T h e bacteriostatic activity of the CSF in the baseline sample may be attributed to the 5 mg gentamicin instilled into the Pudenz reservoir after insertion since CSF does not normally possess significant intrinsic antibacterial activity. 9 T h e decision to commence intraventricular therapy was based on the failure of systemic cefotaxime to reduce the bacterial counts in the ventricular fluid despite a modest increase in both the bacteriostatic and bactericidal concentrations in the CSF. The sample taken immediately before the start of intraventricular therapy indicated a significant bactericidal concentration in the ventricular

Treatment of F. odoratum ventriculitis

237

fluid, thereby suggesting that cefotaxime was beginning to accumulate in the ventricles. T h r e e days after the start of intraventricular therapy, the C S F was sterile. This compares favourably with the 4-5 days required to sterilise the ventricles with 5 m g / d a y of intraventricular amikacin. 3 In spite of the high degree of antimicrobial activity maintained in the reservoir for at least IO days (Table II), significant numbers of organisms managed to persist, either in the reservoir, or in the intraventricular catheter. Furthermore, they had begun to recolonise the left ventricle which contained the catheter. A sample taken 7 days after removal of the reservoir, however, showed the ventricles to be sterile and ventriculitis did not recurr. Direct instillation into the cerebral ventricles would seem to be the only sure m e t h o d of achieving adequate concentrations of some antibiotics in the C S F of patients with ventriculitis. This is particularly true in those with hydrocephalus, when C S F hydrodynamics are unpredictable. Some recent studies, however, have raised doubts about the safety of this procedure. Watanabe and colleagues have shown that intracisternal administration of a single z. 5 m g / k g dose of gentamicin in rabbits was associated with an 80 % mortality within 2 h of injection. 1°-12 T h e same authors have recently demonstrated that repeated intraventricular administration of gentamicin to rabbits at a daily dose of 0"5 m g / k g resulted in ventriculitis, ventricular dilation, abnormal postural reflexes and ataxia.8 In the study by M c C r a c k e n and colleagues intraventricular plus systemic administration of gentamicin to children with meningitis and ventriculitis was associated with a 42 % mortality compared with I2"5 % in the systemic therapy g r o u p ? A total of 28 children received intraventricular therapy and there were IZ deaths, six of these occurring after the administration of only one dose of gentamicin. This would seem to indicate either a high degree of gentamicin ventricular toxicity or a poor prognosis before the start of treatment. Included among the I2 deaths were three patients with gentamicinresistant organisms, one patient who died 36 days after the start of therapy from aspiration pneumonia, and a patient who suffered a reinfection of the meninges with Haemophilus influenzae. T h e C S F concentrations of gentamicin in this study ranged from Io to I3o mg/1, and were similar to those which have been shown to cause ventriculitis, neurological abnormalities and death in rabbits.8.10 Wright and colleagues have reported a prospective and retrospective study of children with Gram-negative meningitis who received intraventricular aminoglycosides compared with children who received systemic therapy alone? T h e mortality in the intraventricular group was 5"5 % (I/18) compared with 4o % (IO/25) in the systemic group. Gentamicin, tobramycin and amikacin were used in doses ranging from I to 5 mg, with several patients receiving loading doses of 5 mg. T h e r a p y was continued for at least 7 days in all cases. Ventricular concentration of amikacin in eight patients were consistently > Ioo m g / l . T h e r e w e r e n o t o x i c m a n i f e s t a t i o n s a s s o c i a t e d w i t h i n t r a v e n t r i c u l a r aminoglycoside therapy in this study. It has been suggested that failure to adjust aminoglycoside therapy by monitoring ventricular fluid may have been one reason for the poor results in the McCracken study. ~ T h e fact that six patients died after receiving one dose of 2"5 mg gentamicin does not support this hypothesis. It is extremely difficult to reconcile the results of these two studies, but it is evident that aminoglycosides should be used with caution, if

238

D. E. MACFARLANE ET A L .

at all, in t h e t r e a t m e n t o f v e n t r i c u l i t i s . I n t r a v e n t r i c u l a r c e p h a l o s p o r i n s are r e c o m m e n d e d f o r t r e a t i n g s t a p h y l o c o c c a l s h u n t - a s s o c i a t e d v e n t r i c u l i t i s , 13 a n d t h e n e w b r o a d - s p e c t r u m t h i r d - g e n e r a t i o n c e p h a l o s p o r i n s w o u l d s e e m to b e a logical a l t e r n a t i v e to a m i n o g l y c o s i d e s in t h e t r e a t m e n t o f G r a m - n e g a t i v e v e n t r i c u l i t i s . W e h a v e n o t b e e n able to locate a n y p r e v i o u s r e p o r t s o n t h e i n t r a v e n t r i c u l a r a d m i n i s t r a t i o n o f c e f o t a x i m e in t h e t r e a t m e n t o f v e n t r i c u l i t i s . T h e f a v o u r a b l e r e s u l t s o b t a i n e d in t h e t r e a t m e n t o f this p a t i e n t s h o u l d encourage further investigation.

References I. McCracken G H Jr. The rate of bacteriologic response to antimicrobial therapy in neonatal meningitis. Am J Dis Child I972; I23: 547-553. 2. McCracken G H Jr. A controlled study of inrathecal antibiotic therapy in gram negative enteric meningitis in infancy. J Pediatr I976; 89: 66--72. 3. Wright PF, Kaiser AB, Bowman CM, McKee K T Jr, Trusillo H, McGee ZA. The pharmokinetics and efficacy of an aminoglycoside administered into the cerebral ventricles in neonates: implications for further evaluation of this therapy in meningitis. J Infect Dis 1981; 143: 141-147. 4. Kaiser AB, McGee ZA. Aminoglycoside therapy of Gram-negative bacillary meningitis. N Eng!J Med 1975; 293: 1215-122o. 5. McCracken G H Jr, Mize SG, Threlkeld N. Intraventricular gentamicin therapy in gram negative bacillary meningitis of infancy. Lancet 198o; i: 787-79 I. 6. Belohradsky BH, Bruch K, Geiss D, Kafetzis D, Marget W, Peters G. Intravenous cefotaxime in children with bacterial meningitis. Lancet 198o; i: 61-63. 7- Rodriques V, Stewart D, Bodey G. Gentamicin sulfate distribution in body fluids. Clin Pharmacol Ther 197o; I I : 275-279. 8. Hodges GR, Watanabe I, Singer Pet al. Central nervous system toxicity ofintraventricularly administered gentamicin in adult rabbits. J Infect Dis 1981; 143: 148-155. 9. Fourtellotte W. On cerebrospinal fluid immunoglobulin G (Ig. G) quotients on multiple sclerosis and other diseases. J Neurol Sei 197o; IO: 279-285. IO. Watanabe I, Hodges GR, Dworzack DL, Kepes JJ, Duensing GF. Neurotoxicity of intrathecal gentamicin; a case report and experimental study. Ann Neuro11978; 4: 564-572. I I. Watanabe I, Hodges GR, Dworzack DL. Chemical injury of the spinal cord of the rabbit after intracisternal injection of gentamicin. J Neuropathol Exp Neurol 1979; 38:lO4-113. 12. Hodges GR, Watanabe I. Chemical injury of the spinal cord of the rabbit after intracisternal injection of gentamicin; an ultra-structural study. J Neuropathol Exp Neuro 198o; 39: 453-475. 13. Simpson PP Jr, Warron GC, Smith RR. Intraventricular cephalothen in childhood ventriculitis. Surg Neurol 1975; 4: 279-286.