Journal of Neurology, Neurosurgery, and Psychiatry, 1972, 35, 903-908 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.6.903 on 1 December 1972. Downloaded from

Klebsiella meningitis report of nine cases

D. J. E. PRICE' AND J. D. SLEIGH From the Institute of Neurological Sciences, Killearn Hospital, Glasgow

SUMMARY During a serious epidemic of chest and urinary infections due to Klebsiella aerogenes in a neurosurgical unit, several patients developed klebsiella meningitis after trauma or surgery. Despite all attempts to control the epidemic and treat the meningitis with antibiotics, eight of the nine patients died. It was not until all antibiotics used to treat respiratory and urinary infections had been totally withdrawn that no further patients developed klebsiella meningitis.

Recent advances in antibiotic therapy have re- Lancet, 1970). Such outbreaks in neurosurgical sulted in a great reduction in mortality from units may result in patients developing menin- many infections and pyogenic meningitis is no gitis or serious wound infections which may en- exception. Klebsiella species are an uncommon danger life (Ayliffe, Lowbury, Hamilton, Small, cause of pyogenic meningitis, but this infection Asheshov, and Parker, 1965). still carries a high mortality. This paper reports Until 1971, the Glasgow Institute of Neuro- guest. Protected by copyright. nine patients in a neurosurgical unit who devel- logical Sciences was situated at Killearn Hospi- oped this form of meningitis within one year. tal, some 16 miles from Glasgow, and during Only one patient survived. the winter of 1967-68, antibiotic-resistant coli- In recent years an increasing number of hos- form organisms producing mucoid colonies, later pital epidemics due to antibiotic-resistant Gram- identified as Klebsiella aerogenes, were isolated negative bacilli have been reported (Lancet, 1966; from sputum and urine specimens in increasing numbers. By July 1968, this organism 1 Reprints from Mr. D. J. E. Price, Department of Neurosurgery, could be General Infirmary, Leeds. recovered from the sputum of 12% of the % PATIENTS WITH KLEBSIELLA ORGANISMS IN SPUTUM 30

25

FIGURE Occurrence of http://jnnp.bmj.com/ 20 meningitis in relationz to isolation of klebsiella 15 organisms from sputum.

10

5 on September 24, 2021 by

903 904 D. J. E. Price and J. D. Sleigh J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.6.903 on 1 December 1972. Downloaded from

patients in the intensive care ward (Figure). Full .3 --, Li .E. xo 0 ur 0 0 O realization of the seriousness of the problem Q _) en .- :13 4.1 came with the death from klebsiella meningitis ccn '-, of a 12 year old boy admitted with cerebrospinal fluid (CSF) rhinorrhoea after a moderately severe + + head injury.

>. >X O E ea L 0. 4) PATIENTS c .2 0 00 There were six male and three female patients; two were children, one a young adult and the remaining + ++ + + six adults aged from 45 to 60 years (Table). Three patients (cases 1, 2, and 8) had sustained serious head injuries with compound fractures of the skull involv- + 4- ing sphenoidal or frontal air sinuses. Two patients (cases 7 and 9) had undergone aneurysm surgery and at both procedures mucosa was breached during the +) approach: the frontal sinus at frontotemporal + craniotomy for a middle cerebral aneurysm and the pharyngeal mucosa at a transcervical approach to a + + + + + basilar aneurysm. Two patients (cases 3 and 5) (A developed meningitis after operations for benign z intracranial tumours-an acoustic neuroma and a guest. Protected by copyright. pituitary adenoma. The remaining two patients 0. (cases 4 and 6) had relatively minor procedures-a z 0 : . e. m m 0 0 ventriculoperitoneal shunt for hydrocephalus and [,L Z stereotaxic surgery for Parkinsonism. Three patients (cases 3, 4, and 5) had localized Ov 0 0 ~ wound infections at the operative site in addition to w -1 the meningitis. Klebsiella was persistently isolated 0 0 O from the sputum and throat of one patient (case 9) 0 t O ^ m O~~~~4O during the period of four weeks between operation z and development of meningitis, but it was only o 8 8 °>~~~4 ° °o 4 0n 0 found in the sputum or throat of five patients and en also the urine of two of these patients only in the 48 hours preceding clinical recognition of the menin- gitis. Blood cultures were taken from three patients during the 48 hours after meningitis was diagnosed.

One (from case 9) was sterile but from the other two 40 C4. (from cases 3 and 4), KI. aerogenes was isolated. > > > > 4>

4.-S. 1 L. &.4- .0 4 4 . o 4) 4) a 40 4).

C http://jnnp.bmj.com/ 0 U4. 04 0 DEVELOPMENT OF MENINGITIS -'A0. 0. 0 0. L. In all but one patient, persistent pyrexia of 39-40' C ~ 0

developed within the 24 hours before recognition of o4o meningitis: the remaining patient (case 8), however, ).044 -C had an intermittent fever for a week. The time between 1 the presumed penetration of the dural defect (at injury or surgery) by Kl. aerogenes and the develop- ment of meningitis varied from three to 10 days in all on September 24, 2021 by but one patient. In this exception (case 9) the period was four weeks. Only five patients had neck stiffness or Kernig's sign before the diagnosis was proven at lumbar puncture. The clinical presentation was in Kiebsiella meningitis-report ofnine cases 905 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.6.903 on 1 December 1972. Downloaded from

fact as varied as any other purulent meningitis in Gentamicin: 2 mg Twice neurosurgical patients, and we concur with Thomp- daily son, Williams, Williams, and Anderson (1952) that Intrathecaln for two days the clinical features of klebsiella meningitis are Ifollowedfolwdbby indistinguishable from any other type. Colistin: 50,000 units once daily When the diagnosis was substantiated by examina- (half of the dosage into a ventricle and half into the tion of the CSF, the initial white cell counts ranged lumbar theca). from 1,300 to 7,000 cells per cu.mm. Sugar deter- minations were made on the CSF of six of the RESULTS OF patients and results were all low, and, in fact, sugar TREATMENT was absent in four. Ventricular taps confirmed ven- Only five patients were treated. Of the remaining triculitis in all six patients who had this examination four, three were diagnosed only within a few and ventricular CSF white cell counts ranged from hours of death so that no more than one dose of 90 to 25,000 cells per cu.mm. Gram-stained films colistin and could be showed large numbers of polymorphs and Gram- gentamicin given and in the negative bacilli. Culture yielded a heavy growth of other case (case 6) the diagnosis was made only lactose fermenting coliform organisms which pro- at necropsy. duced mucoid colonies. Full biochemical investiga- Three of the patients who were treated died tion proved that they were Ki. aerogenes. In one five, 30, and 19 days after isolation of the organ- patient (case 6) there was an increasing CSF leuco- ism from the CSF (cases 3, 4, and 5). In these cytosis but organisms were not seen in the smears patients, the CSF became sterile within four days nor were they isolated in culture until necropsy. but it remained purulent. In the other two treated patients (cases 1 and 9) lumbar and ventricular CSF rapidly became sterile and the cell counts guest. Protected by copyright. CHEMOTHERAPY steadily fell to below 20 cells per cu.mm. One of these PROPHYLACTIC At the time of this epidemic, no patients recovered (case 9) but the other defined policy restricting the use of antibiotics had finally died of pneumonia while remaining un- been formulated. It was common practice to pre- conscious a month after the meningitis had scribe routinely broad-spectrum antibiotics to pa- subsided. tients thought to be at high risk of meningeal infec- Necropsy was performed on six of the eight tion after suspected dural breaches at the site of patients who died. All had florid meningitis with compound fractures or when the upper respiratory tenacious pus in the subarachnoid space over the tract mucosa was opened at craniotomy. The most convexities and filling the basal cisterns. In addi- commonly used antibiotic regime was the combina- tion, four of them had evidence of tion of ampicillin and cloxacillin. Of the seven persisting patients ventriculitis, two had subdural abscesses, and given prophylactic chemotherapy, two were one had given additional intramuscular colistin and despite encephalitis. Three of the patients had the fact that all strains ofKl. aerogenes were sensitive herniation of the unci or cerebellar tonsils indi- in vitro to this drug, both patients developed menin- cating raised intracranial pressure. gitis after eight days of administration at normal dosage. DISCUSSION THERAPEUTIC Although the strains of Ki. aerogenes INCIDENCE Klebsiella species have been re- http://jnnp.bmj.com/ isolated differed in their sensitivity to many anti- ported as an uncommon cause of purulent biotics, all proved to be sensitive to both gentamicin meningitis in several series. Ransmeyer and and colistin. The therapy for adults who were treated Major (1943) investigating the literature found was standardized as follows: that this was the causal organism of only three Gentamicin: patients out of a total of 3,714 cases of purulent 40 mg twice daily* meningitis. In reviews of published cases, kleb- on September 24, 2021 by Systemic siella meningitis was twice as common in men as in women. It usually affected infants or adults Colistin: 1 mega unit 4-hourly and was most uncommon between the ages of 3 * and 20 years (Ransmeyer The recommended dose of gentamicin is now 80 mg three times a and Major, 1943; day. Thompson et al., 1952). A 12 year old boy was 906 D. J. E. Price and J. D. Sleigh J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.6.903 on 1 December 1972. Downloaded from

-the only patient within this age range in this appeared to be a critical level of about 10% series and we found the same sex ratio. above which meningitis occurred, and as soon as the isolation rate fell below this level there PORTAL OF ENTRY Thompson et al. (1952) in a were no further meningeal infections (Figure). comprehensive review of all the known reported Regular routine bacteriological monitoring cases at that time observed that the most com- within an intensive care area can give warning mon primary foci of klebsiella infection were of an impending outbreak of infection. This infections of the middle ear, mastoid, nasal organism may have been transmitted via the air sinuses, lungs, and wounds, and they concluded from patients with tracheobronchitis (Price and that this organism is rarely a primary invader of Sleigh, 1970) and all attempts to isolate infected the meninges. When blood cultures were taken, patients from those at high risk should be en- 7000 were positive. forced. Recent information regarding the epi- In this series, we isolated the organism from demiology of Klebsiella infections (Lancet, 1971) the sputum or throat before or at about the suggests that gastrointestinal colonization with same time as from the CSF in five patients, sug- Klebsiella precedes infection and faeces may be gesting a spread from the upper respiratory tract. an important reservoir in an epidemic situation. It is a matter of conjecture as to whether the Shooter, Faiers, Cooke, Breaden, and O'Farrell organisms reached the meninges from the (1971) have shown that in hospital patients some respiratory tract by direct spread (as probably of the intestinal Gram negative bacilli, including in cases 1, 2, 7, 8, and 9). Klebsiella, originate in their food. It is possible that in the other cases trans- mission may have been mediated by the blood PROPHYLAXIS The isolation of Klebsiella aero-guest. Protected by copyright. stream as is normal in meningococcal menin- genes from sputum, nose and throat was recog- gitis. Genest, Bingham, and Hamilton (1963) nized in one patient to indicate the potential reported a patient with klebsiella urinary infec- risk of meningitis (case 9). Nevertheless prophy- -tion with presumed blood stream spread after laxis by systemically and locally given antibiotics urethral dilatations to infect bilateral chronic failed to prevent migration to the meninges. The subdural haematomata. Septicaemia was recog- failure of systemic colistin to prevent meningitis nized in two ofthe three patients on whom blood may well be due to the fact that, as with many culture had been performed, but since these cul- antibiotics, they fail to attain therapeutic levels tures had not been taken until after the onset of in the CSF when the meninges are normal (Boger meningitis, this investigation does not clarify the and Gavin, 1961). Price and Impey (1971) record route of spread. that, even when colistin is administered in five In a neurosurgical unit, the risk of severe in- times the normal dose to non-meningitic patients, fection of the ventricles and meninges by Gram CSF levels are much lower than concurrent negative bacilli appears inseparable from opera- muscle and serum levels. Boger and Gavin (1961) tive procedures (Newman and Holt, 1967). found the mean colistin levels in lumbar CSF Spivack, Eisenberg, Weiss, and Flippin (1957) and serum to be similar (0-27 ,ug/ml. and 0 35 reported one patient who developed klebsiella ,ug/ml. respectively) six hours after a single dose meningitis after a craniotomy at which the frontal of 500,000 u. Patients on continuous very highhttp://jnnp.bmj.com/ sinus mucosa which was already infected with dosage of colistin (26 mega units a day) attained the organism was breached. Lewin (1948) re- a mean lumbar CSF level of 2-6 pg/ml. compared ported an incidence of meningitis of 10% com- with the mean serum level of 71 Vg/ml. The brain plicating a series of wartime penetrating head levels (mean 10 ,g/g) compared more favourably wounds and found a quarter of these to be due with the concurrent muscle levels (mean 43 to Gram negative bacilli but none to Klebsiella. Vg/g). All attempts at chemoprophylaxis of klebsiella on September 24, 2021 by BACTERIAL ENVIRONMENT The incidence of kleb- meningitis failed and the epidemic was controlled siella meningitis appeared to be directly related only when all antibiotics, both therapeutic and to the number of patients whose respiratory prophylactic, were withdrawn. This resulted in tracts were colonized by the organism. There the organism virtually disappearing from the Klebsiella meningitis-report ofnine cases 907 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.6.903 on 1 December 1972. Downloaded from unit and a considerable reduction in the overall characteristically tenacious and it has been sug- infection rate (Price and Sleigh, 1970). When an gested that this prevents adequate antibiotic epidemic develops, the prescribing policy for penetration and may explain why the organism antibiotics requires to be reviewed. may be sensitive to an antibiotic in vitro but However, in the non-epidemic situation when resistant in vivo. infection with resistant Gram negative bacilli is In retrospect, we believe that six of those who not feared, it is probably justifiable to practise died might have survived if they had not devel- antibiotic prophylaxis whenever there is a break oped meningitis, although four of them would of dura mater resulting in a communication with probably have been permanently disabled with the upper respiratory tract. dysphasia or hemiparesis. The other two would If the organism has also colonized or infected have died even if meningitis had not supervened. the respiratory or urinary tracts, it is reasonable We are aware that we have recommended a to consider using colistin in very high dosage to therapeutic regime, although eight of our nine eliminate the reservoirs within the patients and patients died. We are comforted to find that thus prevent reinfection. If so, renal function Spivack et al. (1957) in reporting the largest should be carefully monitored but nephrotoxicity single series believed that sulphonamide was the is reversible (Price and Graham, 1970). drug of choice, although 10 of their 11 patients succumbed. TREATMENT We wish to thank the consultant neurosurgeons at We do not feel confident to give advice concern- the Institute of Neurological Sciences, Glasgow, for ing the treatment of patients when reporting a permission to report on these patients under their guest. Protected by copyright. series with such a very high mortality. When no care and Professor J. Hume Adams for the necropsy antibiotics were available, all patients with this findings. infection died (Thompson et al., 1952). With the introduction of sulphonamides, streptomycin, REFERENCES chloramphenicol, and tetracycline, the overall Ayliffe, G. A. J., Lowbury, E. J. L., Hamilton, J. G., Small, J. M., Asheshov, E. A., and Parker, M. T. (1965). Hospital mortality had fallen to only 5000 (Soscia, Di infection with Pseudomonas aeruginosa in neurosurgery. Benedetto, and Crocco, 1974). Spivack et al. Lancet, 2, 365-369. (1957) commented that one reason for the high Boger, W. P., and Gavin, J. J. (1961). Absorption, excretion, mortality was the fact that the disease was often and distribution of colistin. Antimicrobial Agents and Chemotherapy, 429-435. fulminating. Newman and Holt (1967) published Genest, A. S., Bingham, W. G., and Hamilton, R. D. (1963). a series of four infants with klebsiella meningitis Bilateral subdural empyema. Report of a case with arterio- who all survived as a result of systemic and intra- grams. Journal of Neurosurgery, 20, 524-526. ventricular gentamicin. Lancet (1966). Pseudomonas aeruginosa. Lancet, 1139-1140. Although early recognition of meningitis is Lancet (1970). Bacteria in faeces and food. Lancet, 2, 805-806. Lewin, W. (1948). Gram-negative meningitis following head not always easy, there must be no delay in insti- wounds. British Journal of Surgery, 35, 266-280. tuting adequate chemotherapy as soon as the Marsden, H. B., and Hyde, W. A. (1962). Colistin methane sulphonate in childhood infections. Lancet, 2, 740-742. diagnosis has been substantiated by microscopic http://jnnp.bmj.com/ examination of the CSF. We believe that the Newman, R. L., and Holt, R. J. (1967). Intrathecal genta- micin in treatment of ventriculitis in children. British most aggressive therapeutic regime using both Medical Journal, 2, 539-542. colistin and gentamicin in conventional dosage Price, D. J. E., and Graham, D. I. (1970). Effects of large by systemic, lumbar thecal and intraventricular doses of colistin sulphomethate sodium on renal function. routes is essential, and perhaps this is the regime British Medical Joutrnal, 4, 525-527. Price, D. J. E., and Impey, A. (1971). Personal communica- of choice for meningitis caused by hospital tion. strains of coliform organisms before in vitro Price, D. J. E., and Sleigh, J. D. (1970). Control of infection sensitivities are available. Marsden and Hyde due to Klebsiella aerogenes in a neurosurgical unit by with- on September 24, 2021 by (1962) reported some success in treating infants drawal of all antibiotics. Lancet, 2, 1213-1215. Ransmeier, J. C., and Major, J. W. (1943). Friedliinder's with meningitis due to Gram negative organisms bacillus septicemia and meningitis. Archives of Internal with colistin. Medicine, 72, 319-328. Pus associated with klebsiella infections is Shooter, R. A., Faiers, M. C., Cooke, E. M., Breaden, A. L., 908 D. J. E. Price and J. D. Sleigh J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.6.903 on 1 December 1972. Downloaded from

and O'Farrell, S. M. (1971). Isolation of Escherichia coli, Spivack, A. P., Eisenberg, G. M., Weiss, W., and Flippin, Pseudomonas aeruginosa, and Klebsiella from food in hos- H. F. (1957). Klebsiella meningitis. American Journal of pitals, canteens, and schools. Lancet, 2, 390-392. Medicine, 22, 865-871. Soscia, J. L., DiBenedetto, R., and Crocco, J. (1964). Kleb- Thompson, A. J., Williams, E. B., Jr., Williams, E. D., and siella pneumoniae meningitis. Archives of Internal Medi- Anderson, J. M. (1952). Klebsiella pneumoniae meningitis, cine, 113, 569-572. Archives of Internal Medicine, 89, 405-420. guest. Protected by copyright. http://jnnp.bmj.com/ on September 24, 2021 by