02 September, 2008

First clinical trials of penicilin for bacterial meningitis

Photo: The withdrawing apparatus of culture media used at Oxford
(quoted from Lancet, August 16, p179, 1941)

First clinical trial of penicillin for bacterial meningitis.

Below is the original description of case 4.

A 4-year-old boy with meningitis due to Staphlococcal aureus.
In this case, the total of 6.8g penicillins were administered.
In other words, it required 6,800 litters of culture media of
Penicillium mould.

I think that this culture volumes are beyond the capacity of
one laboratory level. In fact, 10 technicians worked for large

Unfortunately, 4 years old boy accidentally die and the autopsy
showed that the rupture of brain aneurysm was noted and
the infection was cured.

CASE 4. -----Boy, aged 41/2 years.

May 13, 1941. admitted with Cavernous-sinus thrombosis from septic spots on left
|||||||| eyelid and face following measles 5 weeks before. Had received 30g
|||||||| sulphapyridine in 14 days before admission. Semi-comatose, incontinent of
|||||||| urine and feces. Gross oedema both eyelids(fig. 6a), especially Left, with
|||||||| bilateral proptosis. Complete bilateral external ophthalmoplegia and 2 dioptres
|||||||| of papilloedema; neck rigidity; bilateral Kernig's sign and extensor plantar
|||||||| response. Moist sounds both base.
|||||||| Liver edge two finger-breadths below costal margin. Blood-culture sterile.
|||||||| Lumber puncture gave a faintly yellow cloudy fluid under high pressure(see table ||||||||  III).
May 13: intravenous infusion of citrate saline at 10c.cm. an hour(rate maintained with
|||||||| slight variation for 9 days, the site of infusion being changed 4 times).
|||||||| Penicillin injected into infusion ; dose 100mg.hourly. for two doses,
|||||||| 50mg.hourly for four doses, then 25mg. hourly.
May 14: pus from incision made into left eyelid and swab from nose grew Staph. aureus.
|||||||| X rays:opacity of left antrum, ethmoids clear.
May 15: blood sample an hour after dose of penicillin showed no anti-bacterial activity;
|||||||| dose increased to 50mg. hourly. General improvement.
May 16: obviously better; swelling of eyelids largely subsided. Blood taken just before
|||||||| injection showed trace of antibacterial activity.
May 19: general and local condition vastly improved(see fig. 6b); bilateral 6th nerve palsy
|||||||| and extensor plantar response remained. penicillin reduced to 50mg. 3-hourly.
|||||||| Small corneal ulcer left eye treated with penicillin 1 in 5000, which caused no 
||||||||  discomfort.
May 22: improvement maintained, patient talking and playing with toys.
|||||||| Chest clinically normal. Slight pyrexia still thought to be due to pyrogen in penicillin
|||||||| or to reaction from thromboses in veins used for injections(see fig.7). penicillin ||||||||stopped.
May 26. progress good. Temperature normal. General condition excellent. eye movements
|||||||| returning. X ray of sinuses:only slight clouding left antrum; chest; patch of ||||||||consolidation
|||||||| left apex and small ring shadow right mid-zone. These thought to be embolic sighs but
|||||||| general condition so good that no further penicillin needed.
May 27: 1 A.M. vomited and had general convulsions. Lumber puncture gave uniformly
|||||||| blood -stained fluid under high pressure. Became comatose with neck rigidity,s
|||||||| positive Kernig' sigh and spastic limbs.
May 28: temperature began to rise again.
May 29: appearance much as on admission. penicillin 2g. given in next 36 hours,
|||||||| but died May 31.

Date pressure Protein Red cells White cells Culture
May13 Raised 110 v. few 109 Staph.aureus
14 Normal 100 v. few 372 Staph.aureus
19 Normal 60 v. few 110 Staph.aur. and alb.
22 Normal 95 v. few 45 Sterile
27 Raised # 120 14,600 56 Sterile
------ omission
# Cell-count done after fluid had stood for several hours

Autopsy(dr.A.H.T. Robb-Smith).-------- Brain showed no thrombosis of main venous
sinuses; adhesion and old hemorrhage in hypophysical region. Considerable old and
recent hemorrhage in region of pons and cerebellum due to rupture of aneurysm on
left vertebral artery. Cavernous-sinus region and left orbit occupied by oedematous
granulation tissue; left carotid arter partially occluded by thrombus in its cavernous
course and completely occluded in its bony course. Both lungs showed scattered
abscess cavities, larger ones being air-containing cysts lined by yellowish membrane;
smaller ones containing yellowish material not exactly resembling pus. other organs
not remarkable.

Histologically granulation tissue is essentially similar whether in lung abscess, orbital
tissues or covernous regions(fig.8). There is a small central area of necrosis sometimes
containing a few gram-positive cocci; around this is an oedematous exudate with lipoid
-containing histiocytes;surrounding this is a granulation tissue formed largely of histiocytes
containing lipoid and blood-pigment, lymphocytes and plasma cells with a very occasional
neutrophil leucocyte; this tissue is well vascularized and there is some fibroblastic
proliferation, greatest in periphery.

In the cavernous region some of the veins contain organising thrombus; the left carotid
and vertebral arteries show organising thrombi which do not appear to be infected,
but as there are large breaks in the media and elastica of the walls of both these vessles
it must be presumed that they are the late results of an acute arteritis probably of bacterial
origin. The other organs show no significant change.

The autopsy showed that the infection in the cavernous sinus, orbits and in the lung had
been almost entirely overcome, and that healing processes were well advanced.
Death was due to the ruptured mycotic aneurysm and not to a recrudescence of the
infection. Before this vascular accident the patient had been restored from a moribund
condition to apparent convalescence. No toxic effects from the penicillin were noticed.

Any questions: write to Keiji Hagiwara, M.D., Kami-Ube Pediatric Clinic