Postgrad. med. J. (November 1968) 44, 844-847. Postgrad Med J: first published as 10.1136/pgmj.44.517.844 on 1 November 1968. Downloaded from

Experiences with carbenicillin in the treatment of septicaemia and meningitis A. E. RIcHARDsoN CONSTANCE R. SPITTLE* M.B., F.R.C.S. M.B., M.C.Path. St George's Hospital Neurosurgical Unit, St George's Hospital Neurosurgical Unit, London London K. W. JAMnst 0. P. W. ROBINSON M.A., M.B., D.T.M.R.T. M.B., B.S. Clinical Research Department, Medical Department, Royal Marsden Hospital, London Beecham Research Laboratories, Brentford Summary ity against strains of Pseudomonas aeruginosa Experiences in the use of carbenicillin, a new and those strains of Proteus normally resistant penicillin active against Pseudomonas aeruginosa to ampicillin, for example, Proteus rettgeri, and other Gram-negative bacteria in the treatment Proteus morganii and Proteus vulgaris. Carbeni- of septicaemia and meningitis are described. Blood cillin also has some Gram-positive activity levels of carbenicillin in excess of the levels required although considerably less than that possessed by Protected by copyright. to inhibit the infecting organisms were obtained ampicillin or penicillin G and is not active against using intravenous infusions of large doses to- penicillinase-producing staphylococci, since it is gether with probenecid by mouth. High cerebro- destroyed by staphylococcal penicillinase. spinal fluid levels of carbenicillin were ensured Strains of Pseudomonas aeruginosa are sensi- in the meningitis patients with daily intrathecal tive to 12*5-250 ,ug/ml of carbenicillin, the or intraventricular injections. Carbenicillin un- majority being sensitive to 50 ,ug/ml (Knudsen doubtedly controlled the course of Ps. aeruginosa et al., 1967). Although this degree of activity is septicaemia in two patients. considerably less than that generally accepted for Rapid sterilization of the cerebrospinal fluid a useful systemically administered antibiotic the was achieved in both meningitis patients with high urinary concentrations of carbenicillin clinical improvement. obtainable following intramuscular dosage have No evidence of toxicity was seen and daily enabled Pseudomonas aeruginosa infections of intrathecal injections were well tolerated. the urinary tract to be treated successfully (Brum- fitt, Percival & Leigh, 1967).

Introduction The successful treatment of severe systemic in- http://pmj.bmj.com/ Carbenicillin (BRL 2064, Pyopent)-disodium fections such as septicaemia and meningitis, how- a-carboxybenzyl penicillin-is a new semi-synthe- ever, depends on the attainment and mainten- tic penicillin having a wide spectrum of antibacter- ance of blood levels at least as high as the ial activity. It is not absorbed following oral minimum inhibitory concentration. In the case of administration and must therefore be given by Pseudomonas aeruginosa strains, therefore, blood injection (Acred et al., 1967). Animal studies have levels in the region of 100,ug/ml are required. shown carbenicillin to be virtually non-toxic. Transient levels of this order may be achieved fol- Knudsen, Rolinson & Sutherland (1967). lowing 1-g intravenous doses of carbenicillin on October 2, 2021 by guest. Carbenicillin is active against Gram-negative (Knudsen et al., 1967), but the maintenance of such organisms including Escherichia coli, and Proteus a level requires either repeated intravenous injec- strains. Its main interest, however, lies in its activ- tions or continuous infusion. The low toxicity of *Present address: Central Pathological Laboratory, carbenicillin enables large doses to be given with Stanley Royd Hospital and Pinderfields General Hospital, safety and if probenecid is given by mouth in Wakefield. addition-sustained blood levels sufficiently high to tPresent address: Medical College ofVirginia, Department inhibit strains of Pseudomonas aeruginosa and of Medicine, Richmond, Virginia, U.S.A. other Gram-negative *Pyopen is the registered trade name for carbenicillin organisms may be achieved produced by Beecham Research Laboratories England and (Robinson & Sutherland, 1967). Beecham Products Inc. U.S.A. Carbenicillin, like other penicillins does not Carbenicillin in treatment ofsepticaemia and meningitis 845 Postgrad Med J: first published as 10.1136/pgmj.44.517.844 on 1 November 1968. Downloaded from pass readily into the cerebrospinal fluid (CSF) concurrently. Over a period of days the patient and the successful treatment of meningitis will, improved and became apyrexial, and carbenicil- in view of the high concentrations required to lin was discontinued after 2 weeks. At this stage inhibit Pseudomonas aeruginosa strains, require he developed clinical signs of broncho-pneu- local injection into the cerebrospinal fluid in monia for which he was given a 5-day course addition to systemic therapy. of chloramphenicol. This resolved and he was This paper describes our experiences with discharged. Subsequently he was readmitted 4 carbenicillin in septicaemia and meningitis. Pseu- weeks later with a Pseudomonas aeruginosa domonas septicaemia was confirmed in one patient urinary infection which responded to intramuscu- and strongly suspected in another, whilst in the lar colistin 4 mega-units daily. The strain of Pseu- meningitis patients the infecting organism was domonas aeruginosa isolated had unchanged sensi- Pseudomonas aeruginosa in one and a paracolon tivity to carbenicillin. organism in the other. Case 3 Case 1 A 50-year-old woman was admitted uncons- An 18-year-old man previously treated for cious to St George's Hospital Neurosurgical Unit Hodgkin's disease relapsed and was admitted to with a 5-week history of frontal sinusitis and the Royal Marsden Hospital with splenomegaly recent incision of a left frontal swelling, and and fever. In spite of intensive therapy with was found after investigation to have a left cytotoxic drugs and steroids he deteriorated and subdural abscess. This was drained through became jaundiced. He developed severe marrow frontal and temporal burr-holes. No organisms depletion and required intensive platelet infusion were grown from the pus obtained from the support. Pseudomonas aeruginosa was isolated abscess although Gram-positive cocci were obser-

from his throat, nose, hands and urine and sub- ved in the smear and it was felt advisable to Protected by copyright. sequently he developed numerous skin lesions administer cloxacillin, chloramphenicol and ster- which were considered to be septic emboli from oids systemically and subdurally. The patient a Pseudomonas aeruginosa septicaemia since a improved temporarily but subsequently devel- blood culture showed the presence of this organ- oped a swinging fever and her general condition ism. He was given carbenicillin 24 g daily by deteriorated. Cerebrospinal fluid culture at this intravenous infusion and probenecid 1 g 8-hourly time grew Pseudomonas aeruginosa. Carbenicil- by mouth, following which there was a tempor- lin was given intravenously starting with a dosage ary improvement, but 9 days after the patient's of 6 g daily and increasing to 20 g daily together blood culture was obtained he died as a result with probenecid orally, 1 g twice daily. Carbeni- of the development of terminal oedema and cillin 40 mg daily was also given by intraventricu- ascites associated with right lower lobe pneu- lar and intrathecal routes. monia. A blood-culture taken prior to death grew There was an immediate improvement follow- Esch. coli and Klebsiella pneumoniae. ing this therapy with fall in pyrexia, sterilization Case 2 of CSF and fall in white cell count. On discon- tinuation of treatment A 35-year-old man admitted to the Royal the patient continued to http://pmj.bmj.com/ Marsden Hospital with acute stem-cell leukaemia improve although she was left with a residual was treated with cytotoxic drugs and steroids and neurological defect. eventually went into remission. Subsequently he Case 4 became pyrexial following a catheterization for A 19-year-old girl admitted to St George's acute retention at a time when Pseudomonas Hospital Neurosurgical Unit with symptoms of aeruginosa was repeatedly being isolated from an intracranial space-occupying lesion was found his stools and throat as well as from dermatitis on investigation to have a retrosellar solid of the perineum. He transiently improved with tumour. Following craniotomy and ventricular on October 2, 2021 by guest. intramuscular colistin, 4 mega-units daily, but his drainage a deterioration in the patient's condi- pyrexia increased and he became hypotensive. tion was apparent and a paracolon organism was Although his blood culture at this time was isolated from the CSF. There was no response sterile he was assumed to have Pseudomonas to treatment with high intravenous dosage of aeruginosa septicaemia and a further course of ampicillin together with intrathecal ampicillin and colistin with steroids was given. Since he con- steroids, cultures from the CSF remaining posi- tinued to deteriorate colistin was discontinued tive. Bacteriological sensitivity tests showed that and he was treated with 24 g carbenicillin daily the organism was considerably more sensitive to by intravenous infusion increasing to 30 g daily. carbenicillin than to ampicillin. Carbenicillin Probenecid 1 g 8-hourly by mouth was given was therefore given in a dose of 24 g daily 846 A. E. Richardson et al. Postgrad Med J: first published as 10.1136/pgmj.44.517.844 on 1 November 1968. Downloaded from by intravenous infusion together with 50 mg 8- being effective antibiotic therapy must be institu- hourly intraventricularly. Probenecid 1 g 8-hourly ted on a presumptive diagnosis. Frei et al. (1965) was given also by mouth. The infection was showed that the median survival time from the rapidly controlled, the CSF becoming sterile in first positive blood-culture was only 2 days and 3 days with fall in cell count. The patient that only two patients out of twenty-three lived subsequently collapsed and died. Necropsy find- more than 7 days after the first positive blood ings revealed a sterile cerebrospinal fluid and a culture had been obtained. third ventricular malignant glioma growing into Case 1 in this study in fact survived 9 days the hypothalamus and left temporal lobe. after his first positive blood-culture and his temporary clinical improvement could only be Laboratory investigations attributed to carbenicillin before he developed Venous blood samples were taken at intervals terminal Esch. coli and Klebsiella pneumoniae together with aliquots of several 24-hr urine septicaemia. collections on different days whilst patients were Case 2 almost certainly had Ps. aeruginosa septi- having carbenicillin treatment. Cerebrospinal fluid caemia and had progressively deteriorated in samples were taken before the next dose of spite of hydrocortisone and colistin therapy. The carbenicillin was due in Cases 3 and 4. The separ- administration of an intravenous carbenicillin in- ated serum, urine and CSF samples were fusion resulted in a gradual improvement in his immediately stored at -10°C to await assay at condition and he was able to be discharged in Beecham Research Laboratories. remission following a short course of chloram- The minimum inhibtory concentration (MIC) phenicol for a clinical bronchopneumonia infec- of carbenicillin was determined by conventional tion. tube dilution technique using a 1: 100 dilution In both Cases 1 and 2 blood-levels consider- of an overnight culture of the infecting organism. ably higher than those required to inhibit theProtected by copyright. Serum, urine and CSF concentrations were deter- strain of Pseudomonas aeruginosa (25 ,ug/ml) were mined using a conventional agar diffusion assay consistently obtained. It is interesting that both technique employing a highly sensitive strain of these patients, however, continued to harbour the Pseudomonas aeruginosa as assay organism. The organism on the skin, throat or nose during treat- summarized results of these investigations are ment and that Case 2 subsequently developed shown in Table 1. Blood counts and liver func- a Pseudomonas infection of the urinary tract. tion tests were repeated during and after the There was, however, no suggestion of any de- course of carbenicillin treatment. creased sensitivity to carbenicillin of the later isolates. Although no Pseudomonas aeruginosa Results and discussion could be isolated from blood culture during treat- The onset of Pseudomonas aeruginosa septi- ment from Case 1, superinfection occurred with caemia is almost invariably a fatal complication K. pneumoniae which is invariably resistant to of any illness since by the time the organism is carbenicillin. The sensitivity of the Esch. coli identified an overwhelming infection is present. strain isolated was not determined.

In order that treatment may stand a chance of In both meningitis patients (Cases 3 and 4) http://pmj.bmj.com/

TABLE 1 MIC to Carbenicillin levels (tg/ml) Case Age and Diagnosis Organism carbenicillin Daily carbenicillin dose sex (,ug/ml) Serum CSF Urine

1 18 years, Septicaemia Ps. aeruginosa 25 24 g i.v. daily 63-250 -

male (Probenecid I g 8-hourly) on October 2, 2021 by guest. 2 35 years, Septicaemia? Ps. aeruginosa 25 24-30 g i.v. daily 140-400 9000 male (Probenecid 1 g 8-hourly) 3 60 years, Meningitis Ps. aeruginosa 125 6-20 g i.v. daily 9-220 14-46 9100- female (Probenecid 1 g b.d.) (24-hr levels) 31,000 40 mg intrathecally + 40 mg intraventricularly daily 4 19 years, Meningitis Paracolon 2 5 24 g i.v. daily 17-5-125 Right ventricle female MIC to (Probenecid 1 g 8-hourly) 93-185 5400- ampicillin 25 mg 8-hourly into left left ventricle 15,700 50 tug/ml and right ventricle 480 (8-hr levels) Carbenicillin in treatment ofsepticaemia and meningitis 847 Postgrad Med J: first published as 10.1136/pgmj.44.517.844 on 1 November 1968. Downloaded from there was, following carbenicillin treatment, a Regular blood counts and liver function tests rapid return towards normality in the CSF find- revealed no evidence of any toxic effect due to ings, the results of which are shown in Fig. 1 carbenicillin. and 2. The Ps. aeruginosa strain isolated from Case 3 was fairly resistant to carbenicillin having Dosage of intravenous drugs an MIC of 125 ,ug/ml but serum levels in excess Ampicillin Carbenicillin of this figure were frequently obtained. Since the 24g/day K 24 g/day 24-hr CSF levels in this patient varied from 14 100,000 to 46,ug/ml levels prior to this must have been Culture positive considerably higher. This patient's CSF culture 25 mg 8-hourly into 25 mg 8-hourly into became sterile after the first intrathecal and sub- each ventricle each ventricle dural administration of carbenicillin and re- mained so. Her CSF cell count dropped from 1000 to 10/mm3 after 6 days and her clinical state improved. / 1 1 '\ / \Left venfricle 10,000 j /

Intravenous corbenicillin dose 6g 20g 12g

Intrathecally 40mg/doy A | ~~~~~~Rightventrcl Intravenously 40mg/day

1,000 1,000 \ I~\\ \ Protected by copyright.

to IE I I L 1 1 1 E ~~~~~~~~~ells E

100 / Protein \ 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 August E- o 50 FIG. 2. Case 4. 0 E Acknowledgments We are grateful to Dr G. N. Rolinson and his staff of the Microbiological Unit, Beecham Research Laboratories for a- the sensitivity studies and carbenicillin assay procedures carried out during the period of this investigation. Also to http://pmj.bmj.com/ 23 25 27 29 31 2 4 6 8 10 Dr R. L. Morgan and Dr P. E. Thompson Hancock of the 24 26 28 30 3 5 7 9 Royal Marsden Hospital for permission to study the patients May June under their care. FIG. 1. Case 3. References Case 4 ACRED, P., BROWN, D.M., KNUDSEN, E.T., ROLINSON, G.N. (Fig. 2) in spite of ampicillin therapy & SUTHERLAND, R. (1967) New semi-synthetic penicillin showed consistently positive CSF cultures, the active against Pseudomonas pyocyanea. Nature (Lond.), paracolon organism having an MIC of 50,ug/ml 215, 25. on October 2, 2021 by guest. to ampicillin. In view of the greater sensitivity BRumFrrr, W., PERCIVAL, A. & LEIGH, D.A. (1967) Clinical and laboratory studies with carbenicillin. A new penicillin of the organism to carbenicillin (25,g/ml) her active against Pseudomonas pyocyanea. Lancet, i, 1289. treatment was changed to this penicillin and the FREI, E., LEVIN, R.H., BODEY, G.P., MORSE, E.E. & CSF became sterile within 4 days; improvement FREIREICH, E.J. (1965) The nature and control of infections of cell counts became normal within 2 weeks. in patients with acute leukaemia. Cancer Res. 25, 1511. KNUDSEN, E.T., ROLINSON, G.N. & SUTHERLAND, R. (1967) Serum carbenicillin levels in this patient were Carbenicillin: A new semi-synthetic penicillin active against consistently higher than the level required to Pseudomonas pyocyanea. Brit. med. J. lii, 75. inhibit the infecting organism and the particu- ROBINSON, O.P.W. & SUTHERLAND, R. (1967) Absorption and larly high levels obtained in the cerebrospinal excretion of a new penicillin BRL 2064 (carbenicillin) in man. Vth International Congress of Chemotherapy. Verlag fluid occasioned no signs of cerebral irritation. der Wiener Medizinischen Akademie.