Apr 23, 1986 - in 90% ofcases"3 although recovery may take several years12. No improvement ... disc diffusion testing on Direct Sensitivity Test. (DST) agar.
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with respiratory insufficiency. The prognosis is good in 90% of cases"3 although recovery may take several years12. No improvement was seen in our patient during the 9 months between investigations. It is important to monitor such cases, so that if deterioration should later occur, nocturnal ventilatory support can be considered. This case demonstrates that a patient with diaphragm weakness may have only mild orthopnoea and minimal breathlessness on exertion14 and that unless the diagnosis is considered it may easily be overlooked. Acknowledgments: A Mier is supported by the Medical Research Council and C Brophy is funded by Napp Laboratories. References 1 Newsom-Davis J, Goldman M, Loh L. Diaphragm function and alveolar hypoventilation. Q J Med 1976;45: 87-100 2 Allen SM, Hunt B, Green M. Fall in vital capacity with posture. Br JDis Chest 1985;79:267-71 3 Wilson SH, Cooke NT, Edwards R, Spiro S. Predicted normal values for maximal respiratory pressures in caucasian adults and children. Thorax 1984;39:535-8 4 Agostoni E, Rahn M. Abdominal and thoracic pressures
Two neutropenic patients with multiple resistant Pseudomonas aeruginosa septicaemia treated with ciprofloxacin
J W A Bendig MB P W Kyle MRCPath P L F Giangrande BSc MRCP D M Samson MD MRCPath B S Azadian BSc MRCPath Departments ofMicrobiology and Haematology, Charing Cross Hospital, London W6 Keywords: leukaemia, Pseudomonas aeruginosa, septicaemia, ciprofloxacin
Ciprofloxacin, a new 4-quinolone with a wide range of antibacterial activity' -3, appears to be a promising antibiotic for the treatment of severe multiple resistant Pseudomonas aeruginosa infections. The drug is available in the UK on a named patient basis for intravenous use and the manufacturer's recommended dosage is 200 mg 12-hourly. We describe 2 neutropenic patients with serious Ps. aeruginosa infection in whom ciprofloxacin was used and serum levels monitored.
Case reports Case 1: A 67-year-old woman with acute myeloid and neutropenia commenced cytotoxic leukaemia 0141-0768/87/ 050316-02/$02.00/0 chemotherapy on 17.8.84, and remained neutropenic (0.5 x 109/l) until 26.9.84 when she recovered follow° 1987 ing successful remission induction. During this time The Royal she developed a spreading cellulitis of her right foot Society of Medicine originating from an abrasion of the little toe. On
at different lung volumes. J Appl Physiol 1960;15: 1087-92 5 Miller J, Moxham J, Green M. The Maximal sniff in the assessment of diaphragm function in man. Clin Sci 1985;69:91-6 6 Loh L, Goldman M, Newsom-Davis J. The assessment of diaphragm function. Medicine (Baltimore) 1977;6: 165-9
7 Newsom-Davis J. Phrenic nerve conduction studies in man. JNeurol Neurosurg Psychiatry 1967;30:420-6 8 Mier A, Brophy C, Moxham J, Green M. Phrenic nerve conduction time in normals. Clin Sci 1985;70:70P 9 Graham AN, Martin PD, Haas LF. Neuralgic amyotrophy with bilateral diaphragmatic palsy. Thorax 1985;40:635-6 10 Billings R, Grahame R. Neuralgic amyotrophy with hemidiaphragmatic paralysis. Rheumatology and Rehabilitation 1975;14:260-1 11 Spillane JD. Localised neuritis of the shoulder girdle. Lancet 1943;ii:532 12 Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial plexus neuropathy: report on 99 cases. Arch Neurol 1972;27:109-17 13 James JL, Miles DW. Neuralgic amyotrophy: a clinical and electromyographic study. Br Med J 1966;ii:1042-3 14 Mier A, Brophy C, Moxham J, Green M. Diaphragm weakness and orthopnoea. Thorax 1985;40:631-2
(Accepted 23 April 1986)
27.8.84 she became unwell with a fever of 37.8°C. A swab from the toe grew anaerobic streptococci and Ps. aeruginosa, the latter resistant to gentamicin, tobramycin, azlocillin, piperacillin, ticarcillin, ceftazidime, cefotaxime and sensitive only to amikacin and ciprofloxacin. Sensitivities were determined by disc diffusion testing on Direct Sensitivity Test (DST) agar. Blood cultures at this point were negative. Amikacin (500 mg 12-hourly) and metronidazole (500 mg 8-hourly) were started, and there was some initial improvement in the foot and reduction of the fever. However, in spite of peak amikacin levels of 20-30 mg/l, the toe became progressively worse and by 7.9.84 her temperature again rose to 390C. Blood cultures at this time grew the same resistant Ps. aeruginosa present in the toe. Both isolates were indistinguishable by serology, though untypable by phage typing. The patient became increasingly unwell, and on 10.9.84 she was clinically shocked with a fever of 39.50C. Ciprofloxacin was commenced at a dose of 200 mg intravenously 12-hourly in addition to amikacin and metronidazole. Daily granulocyte transfusions were also given over the next week. Minimum inhibitory concentrations (MICs) of ciprofloxacin and amikacin to the Ps. aeruginosa were 0.25 mg/l and 4.0 mg/l respectively. These were determined using Iso-sensitest broth. By 12 hours after starting ciprofloxacin there was a definite clinical improvement and after 4 days she became afebrile. All antibiotics were stopped on 18.9.84 (after 8 days of ciprofloxacin). The toe gradually healed following surgical debridement, but the resistant Ps. aeruginosa was not eradicated from the site. A widespread rash developed 6 days after starting ciprofloxacin but was not severe enough to necessi-
Journal of the Royal Society of Medicine Volume 80 May 1987
tate discontinuing the drug. It resolved rapidly after stopping ciprofloxacin.
Case 2: A 17-year-old boy was treated with intensive cytotoxic chemotherapy for a second relapse of acute lymphoblastic leukaemia. A week after finishing chemotherapy, on 2.7.85, the patient was profoundly neutropenic (0.3 x 10 '/I). A nodule, 2 cm in diameter with a central necrotic area and surrounding cellulitis, developed in the right axilla. The patient developed a fever of 38.80C associated with rigors. Three sets of blood cultures and a swab from the lesion grew Ps. aeruginosa, resistant to gentamicin, tobramycin, piperacillin, ceftazidime, cefotaxime and sensitive only to amikacin and ciprofloxacin. The patient was accordingly started on amikacin (350 mg 12-hourly) and ciprofloxacin (200 mg 12hourly). In addition he received a 5-day course of granulocyte transfusions. MICs of ciprofloxacin and amikacin to the Ps. aeruginosa were 0.25 mg/l and 0.5 mg/l respectively. After 5 days' treatment the patient became afebrile, and after a further 3 days the lesion in the axilla had shrunk, and the cellulitis had completely resolved. Ciprofloxacin was discontinued after a further week. A further 5-day course of cytotoxic chemotherapy was given since the patient was still not in remission, and he remained severely neutropenic (0.2 x 10 '/I). He remained on amikacin with satisfactory blood levels (peak level of 18.5 mg/l). On 27.7.85, 9 days after stopping ciprofloxacin, the lesion in the axilla flared up. The patient developed a fever of 40°C, and once again Ps. aeruginosa was isolated from two sets of blood cultures. This isolate had the same antibiotic sensitivities as previously. All isolates were subsequently shown to be indistinguishable by serology though untypable by phage typing. Ciprofloxacin was restarted at a dose of 200mg 12-hourly, but in the absence of clinical improvement the dose was increased to 200 mg 8hourly two days later. No remission was obtained and the patient remained neutropenic. His general condition deteriorated and he died on 13.8.85. During his first course of ciprofloxacin and amikacin the patient had developed a widespread rash. This resolved soon after stopping the antibiotics and did not recur when ciprofloxacin was used a second time. Discussion In the first patient, a resistant Ps. aeruginosa spread from the toe despite adequate blood levels of amikacin to which it was sensitive in vitro. At the time of starting ciprofloxacin she was seriously- ill with a pseudomonal septicaemia. The addition of ciprofloxacin and granulocyte transfusions to the amikacin and metronidazole was undoubtedly effective in her recovery. The part played by the granulocyte transfusions is impossible to determine in this case. The efficacy of granulocyte transfusions in neutropenic patients remains controversial'. In the second patient, the combination of ciprofloxacin, amikacin and granulocyte transfusions was at least initially effective in that it cured the first episode of septicaemia. However, the skin lesion never completely healed and, following his second course of cytotoxic chemotherapy, all antibiotics failed. Both patients tolerated ciprofioxacin well, with no significant rise in plasma aspartate transaminase, alkaline phosphatase, urea or creatinine during their treatment.
10.0 _
3.0
-
E
'
1.0
Patient 1
0.5
IPatient 2\%~ 0. 3
0.1 1
0
2
4 6 8 Time (hours)
%M.I.C. (0. 25 mg/I.) 10
12
Figure 1. Serum levels after 200 mg i.v. ciprofloxacin
Although both developed rashes, ciprofloxacin could not be definitely incriminated, particularly as in the second patient the rash did not recur during his second course of ciprofloxacin. In both patients, serum concentrations of ciprofloxacin were measured by high pressure liquid chromatography (Figure 1). Both graphs show that the half-life of ciprofloxacin given intravenously was of the order of 2 hours. Furthermore, with the dose of 200 mg, the serum levels fell to the MIC (0.25 mg/l) after 10 and 6 hours in the first and second patient respectively. We suggest, therefore, that an 8-hourly regimen may be more appropriate than 12-hourly (as was tried in the last 2 weeks of the second patient's illness). Gonzalez et al.5, in a study of the pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers, also concluded that an 8hourly, rather than 12-hourly, regimen should be considered for serious pseudomonal infections. Acknowledgments: We thank Mr L E Cherrington for technical assistance; Bayer UK Ltd for supplying ciprofloxacin; Dr L 0 White, Department of Microbiology, Southmead Hospital, Bristol, for ciprofloxacin levels; and Public Health Laboratory Service, Colindale, for type identification of Pseudomonas aeruginosa. References 1 Shrire I, SaundersJ, TraynorR, etal. A laboratory assessment of ciprofloxacin and comparable antimicrobial agents. Eur J Clin Microbiol 1984;3:328-32 2 Hoogkamp-KorstanjeJAA. Comparative in vitro activity offive quinolone derivatives and five other antimicrobial agents used in oral therapy. Eur J Clin Microbiol 1984;8: 333-8 3 Van Caekenberghe DL, Pattyn SR. In vitro activity of ciprofloxacin compared with those of other new fluorinated piperazynil - substituted quinolone derivatives. Antimicrob Agents Chemother 1984;25:518-21 4 Buckner CD, Clift RA. Prophylaxis and treatment of infection of the immunocompromised host by granulocyte transfusions. Clin Haematol 1984;13:557-71 5 Gonzalez MA, Moranchel AH, Duran 5, et al. Multipledose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers. Antimicrob Agents Chemother 1985;28:23&9
(Accepted 19 March 1986)
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