of 2 /2
520 realised in clinical use. 2,6, Recently the explanation for the synergy seen in vitro between sulphonamides and tri- methoprim has been questioned with new evidence that sulphonamides may also inhibit dihydrofolate reductase in addition to their established ability to compete with para-aminobenzoic acid earlier in this pathway.8 That sulphonamides can also inhibit mammalian dihydro- folate reductase might explain some of their toxicity to man.’° Perhaps certain individuals possess variant bone- marrow with a particular affinity for some or all of the sulphonamides. Another argument for combining tri- methoprim with sulphonamides is that the simultaneous use of two drugs would prevent the emergence of resis- tance. However, several reports indicate that the fears of trimethoprim resistance appearing with the single agent have been overstated. 11-13 There is little evidence that resistance will be a specific problem with trimetho- prim-certainly not more so than with the combination. Of course, as with all chemotherapeutic agents, the inci- dence of resistance can often be related to their total consumption, so trimethoprim should be used for speci- fic indications supported wherever possible by accurate clinical and microbiological evidence. At present tri- methoprim is available in the U.K. for the prevention and treatment of urinary-tract infections, but could well in the future replace the combinations for treating respir- atory-tract infections, since the concentrations of trimethoprim in sputum and lung tissue seem adequate - about four times the minimum inhibitory concentra- tion for the anticipated pathogens.14 Clinical trials in this area are needed. Some infections due to bacteria that are relatively resistant to trimethoprim-e.g., Neis- seria gonorrhœæ—may still warrant combination ther- apy, although various other single agents are available (penicillin for the predominant penicillin-sensitive strains, or spectinomycin, cefuroxime, or cefoxitin). Despite the emergence of trimethoprim as an effective antibacterial agent in its own right, the efficacy of com- binations of trimethoprim with rifampicin (’Rifaprim’) and of tetroxoprim with sulphadiazine (’Sterinor’) have been explored.15 Tetroxoprim (He781) is chemically related to trimethoprim and likewise becomes bound to 6. Greenwood O, O’Grady F. Activity and interaction of trimethoprim and sul- phamethoxazole against Escherichia coli. J Clin Path 1976; 29: 162-66. 7. Greenwood D. Relevance of in vitro synergy to therapy: does synergy between diaminopyrimidines and sulphonamides operate at concentrations achievable in urine? J Antimicrob Chemother 1979; 5: suppl. B, 85-89. 8. Poe M. Antibacterial synergism: a proposal for chemotherapeutic potentia- tion between trimethoprim and sulphamethoxazole. Science 1977; 194: 533-35. 9. Lacey RW. Mechanism of action of trimethoprim and sulphonamides: rele- vance to synergy in vivo. J Antimicrob Chemother 1979; 5: suppl. B, 75-83. 10. Golde DW, Bersch N, Quan SG. Trimethoprim and sulphamethoxazole inhi- bition of hæmatopoiesis in vitro. Br J Hœmatol 1978; 40: 363-67. 11. Kasanen A, Anttiba M, Elfving R, Kahela P, Saarimaa H, Sandquist H, Tik- kanen R, Toivanen P. Trimethoprim: pharmacology, antimicrobial acti- vity and clinical use in urinary tract infection. Ann Clin Res 1978; 10: suppl. 22, 12. Pearson NJ, Towner KJ, McSherry H, Cattell WR, O’Grady F. Emergence of trimethoprim-resistant enterobacteria in patients receiving long term co-trimoxazole for the control of intractable urinary-tract infection. Lan- cet 1979; ii: 1205-08. 13. Huovinen P, Toivanen P. Trimethoprim resistance in Finland after five years’ use of plain trimethoprim. Br Med J 1980; i: 72-74. 14. Hughes DTD, Bye A, Hodder P. Levels of trimethoprim and sulphamethoxa- zole in blood and sputum in relation to treatment of chest infections. In: Advances in Antimicrobial and Antineoplastic Chemotherapy, vol I. New York: University Park Press, 1971: 1105-06. 15. Liebenow W, Prikryl J. Structural relationships of new 2,4-diamino-5-benzyl pyrimidines. J Antimicrob Chemother 1979; 5: suppl. B, 15-18. bacterial dihydrofolate reductase. These combinations have been tried mainly in urinary infection; few workers, if any, have compared the combination with trimethoprim alone. It is hard to see any likely advantage of tetroxo- prim over trimethoprim, either singly or in combi- nations, since tetroxoprim is only about a fifth as potent as trimethoprim,16,17 and any postulated advantage for tetroxoprim seems slight. The toxicity of rifampicin must also limit the usefulness of rifampicin-trimetho- prim combinations. Which agents should be prescribed now? For the treatment and prevention of urinary-tract infections, the arguments for favouring trimethoprim alone are per- suasive. Until trial evidence accumulates, a reasonable dosage for acute infections in adults is 200 mg twice daily for 5 days and for prophylaxis 100 mg daily. A syrup formulation is awaited. For the treatment of many other infections clinical trials are required. When a com- bination drug is under consideration the prescriber will have to assess the slight potential benefit of the ad- ditional sulphonamide against its toxicity and cost. The occasional fatalities associated with co-trimoxazole ther- apy include agranulocytosis18 and renal failure19—side- effects typical of sulphonamides. It is regrettable that no adequate trials comparing trimethoprim with trimetho- prim/sulphonamide combinations had been published when co-trimoxazole was introduced. Since the two res- pective components of both co-trimoxazole and co-tri- mazine are not necessarily used together, it is question- able whether each combination merits an approved pharmaceutical name. The procedure for such approval requires examination. SEVERE HYPOKALÆMIA ROUTINE requests for biochemical profiles of patients admitted to hospital are a mixed blessing. The satisfac- tion of a smart diagnosis of, say, hypercalcxmia or para- proteinaemia has been replaced by the dilemma of decid- ing whether symptomless often elderly patients with hyperparathyroidism or myeloma require treatment, but, despite the increasing load on laboratory facilities, most of the requests are justified. For instance, everyone knows that hypokalxmia may cause sudden cardiac death which should be avoidable, hence the demand for plasma electrolyte determinations, but just how common is dangerous hypokalæmia and who is likely to have it? Capitalising on their biochemistry department’s com- puterised record system, Lawson and his colleaguesl in Glasgow have analysed the electrolyte concentrations of 58 000 patients in hospital. In three years they found 3 patients with plasma potassium concentrations below 2 mmol/1 and a further 472 patients with concentrations between 2 and 2 4 mmol/1—an overall incidence of 1 ‘. As might be expected, mortality was much greater 111 16. Wiedermann B. Activity of tetroxopnm and sulphadiazine alone and in com- bination on Gram-negative bacteria. J Antimicrob Chemother 1979, 5 suppl. B, 45-47. 17. Bywater MJ, Holt HA, Reeves DS. Activity m vitro of tetroxoprim-sulpha- diazine. J Antimicrob Chemother 1979; 5: suppl. B, 51-60. 18. Inman WHW. Studies of fatal marrow depression with special reference phenylbutazone and oxyphenbutazone, Br Med J 1977; i: 1500-05. 19. Richmond JM, Whitworth JA, Fairley KF, Kincaid-Smith P. Co-trimoxazole nephrotoxicity. Lancet 1979; i: 493-93. 1. Lawson DH, Henry DA, Lowe JM, Gray JMB, Morgan HG. Severe hypoka- lemia in hospitalized patients. Arch Intern Med 1979; 139: 978-80

SEVERE HYPOKALÆMIA

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realised in clinical use. 2,6, Recently the explanation forthe synergy seen in vitro between sulphonamides and tri-methoprim has been questioned with new evidence thatsulphonamides may also inhibit dihydrofolate reductasein addition to their established ability to compete withpara-aminobenzoic acid earlier in this pathway.8 Thatsulphonamides can also inhibit mammalian dihydro-folate reductase might explain some of their toxicity toman.’° Perhaps certain individuals possess variant bone-marrow with a particular affinity for some or all of thesulphonamides. Another argument for combining tri-

methoprim with sulphonamides is that the simultaneoususe of two drugs would prevent the emergence of resis-tance. However, several reports indicate that the fears oftrimethoprim resistance appearing with the single agenthave been overstated. 11-13 There is little evidence thatresistance will be a specific problem with trimetho-prim-certainly not more so than with the combination.Of course, as with all chemotherapeutic agents, the inci-dence of resistance can often be related to their total

consumption, so trimethoprim should be used for speci-fic indications supported wherever possible by accurateclinical and microbiological evidence. At present tri-

methoprim is available in the U.K. for the preventionand treatment of urinary-tract infections, but could wellin the future replace the combinations for treating respir-atory-tract infections, since the concentrations of

trimethoprim in sputum and lung tissue seem adequate- about four times the minimum inhibitory concentra-tion for the anticipated pathogens.14 Clinical trials inthis area are needed. Some infections due to bacteriathat are relatively resistant to trimethoprim-e.g., Neis-seria gonorrhœæ—may still warrant combination ther-

apy, although various other single agents are available(penicillin for the predominant penicillin-sensitivestrains, or spectinomycin, cefuroxime, or cefoxitin).Despite the emergence of trimethoprim as an effective

antibacterial agent in its own right, the efficacy of com-binations of trimethoprim with rifampicin (’Rifaprim’)and of tetroxoprim with sulphadiazine (’Sterinor’) havebeen explored.15 Tetroxoprim (He781) is chemicallyrelated to trimethoprim and likewise becomes bound to

6. Greenwood O, O’Grady F. Activity and interaction of trimethoprim and sul-phamethoxazole against Escherichia coli. J Clin Path 1976; 29: 162-66.

7. Greenwood D. Relevance of in vitro synergy to therapy: does synergybetween diaminopyrimidines and sulphonamides operate at concentrationsachievable in urine? J Antimicrob Chemother 1979; 5: suppl. B, 85-89.

8. Poe M. Antibacterial synergism: a proposal for chemotherapeutic potentia-tion between trimethoprim and sulphamethoxazole. Science 1977; 194:533-35.

9. Lacey RW. Mechanism of action of trimethoprim and sulphonamides: rele-vance to synergy in vivo. J Antimicrob Chemother 1979; 5: suppl. B,75-83.

10. Golde DW, Bersch N, Quan SG. Trimethoprim and sulphamethoxazole inhi-bition of hæmatopoiesis in vitro. Br J Hœmatol 1978; 40: 363-67.

11. Kasanen A, Anttiba M, Elfving R, Kahela P, Saarimaa H, Sandquist H, Tik-kanen R, Toivanen P. Trimethoprim: pharmacology, antimicrobial acti-vity and clinical use in urinary tract infection. Ann Clin Res 1978; 10:suppl. 22,

12. Pearson NJ, Towner KJ, McSherry H, Cattell WR, O’Grady F. Emergenceof trimethoprim-resistant enterobacteria in patients receiving long termco-trimoxazole for the control of intractable urinary-tract infection. Lan-cet 1979; ii: 1205-08.

13. Huovinen P, Toivanen P. Trimethoprim resistance in Finland after fiveyears’ use of plain trimethoprim. Br Med J 1980; i: 72-74.

14. Hughes DTD, Bye A, Hodder P. Levels of trimethoprim and sulphamethoxa-zole in blood and sputum in relation to treatment of chest infections. In:Advances in Antimicrobial and Antineoplastic Chemotherapy, vol I. NewYork: University Park Press, 1971: 1105-06.

15. Liebenow W, Prikryl J. Structural relationships of new 2,4-diamino-5-benzylpyrimidines. J Antimicrob Chemother 1979; 5: suppl. B, 15-18.

bacterial dihydrofolate reductase. These combinationshave been tried mainly in urinary infection; few workers,if any, have compared the combination with trimethoprimalone. It is hard to see any likely advantage of tetroxo-prim over trimethoprim, either singly or in combi-

nations, since tetroxoprim is only about a fifth as potentas trimethoprim,16,17 and any postulated advantage fortetroxoprim seems slight. The toxicity of rifampicinmust also limit the usefulness of rifampicin-trimetho-prim combinations.Which agents should be prescribed now? For the

treatment and prevention of urinary-tract infections, thearguments for favouring trimethoprim alone are per-suasive. Until trial evidence accumulates, a reasonabledosage for acute infections in adults is 200 mg twice

daily for 5 days and for prophylaxis 100 mg daily. Asyrup formulation is awaited. For the treatment of manyother infections clinical trials are required. When a com-bination drug is under consideration the prescriber willhave to assess the slight potential benefit of the ad-ditional sulphonamide against its toxicity and cost. Theoccasional fatalities associated with co-trimoxazole ther-

apy include agranulocytosis18 and renal failure19—side-effects typical of sulphonamides. It is regrettable that noadequate trials comparing trimethoprim with trimetho-prim/sulphonamide combinations had been publishedwhen co-trimoxazole was introduced. Since the two res-

pective components of both co-trimoxazole and co-tri-mazine are not necessarily used together, it is question-able whether each combination merits an approvedpharmaceutical name. The procedure for such approvalrequires examination.

SEVERE HYPOKALÆMIA

ROUTINE requests for biochemical profiles of patientsadmitted to hospital are a mixed blessing. The satisfac-tion of a smart diagnosis of, say, hypercalcxmia or para-proteinaemia has been replaced by the dilemma of decid-ing whether symptomless often elderly patients with

hyperparathyroidism or myeloma require treatment,but, despite the increasing load on laboratory facilities,most of the requests are justified. For instance, everyoneknows that hypokalxmia may cause sudden cardiacdeath which should be avoidable, hence the demand forplasma electrolyte determinations, but just how commonis dangerous hypokalæmia and who is likely to have it?

Capitalising on their biochemistry department’s com-puterised record system, Lawson and his colleaguesl inGlasgow have analysed the electrolyte concentrations of58 000 patients in hospital. In three years they found 3patients with plasma potassium concentrations below 2mmol/1 and a further 472 patients with concentrationsbetween 2 and 2 4 mmol/1—an overall incidence of 1 ‘.As might be expected, mortality was much greater 111

16. Wiedermann B. Activity of tetroxopnm and sulphadiazine alone and in com-bination on Gram-negative bacteria. J Antimicrob Chemother 1979, 5suppl. B, 45-47.

17. Bywater MJ, Holt HA, Reeves DS. Activity m vitro of tetroxoprim-sulpha-diazine. J Antimicrob Chemother 1979; 5: suppl. B, 51-60.

18. Inman WHW. Studies of fatal marrow depression with special referencephenylbutazone and oxyphenbutazone, Br Med J 1977; i: 1500-05.

19. Richmond JM, Whitworth JA, Fairley KF, Kincaid-Smith P. Co-trimoxazolenephrotoxicity. Lancet 1979; i: 493-93.

1. Lawson DH, Henry DA, Lowe JM, Gray JMB, Morgan HG. Severe hypoka-lemia in hospitalized patients. Arch Intern Med 1979; 139: 978-80

Page 2: SEVERE HYPOKALÆMIA

521

this group (30%) than in normokalasmic patientsmatched for age and sex (8%). Interestingly, cardiovas-cular disease was under-represented in the hypokalaemicgroup whereas a primary diagnosis of malignant diseasewas frequent. Acute myeloid leukaemia was especiallylikely (22 times more than expected), an associationwhich is well recognised.2-5 The cause for this is obscure,but the kidney seems unable to conserve potassium.Lysozyme, released in large quantities by abnormalcellular proliferation and destruction, was once thoughtto damage the proximal tubule2·6 but several cases havebeen reported with normal serum lysozyme levels5,7 andlysozymuria may be a result of renal tubular dysfunc-tion.8 Another possibility may be the frequent and pro-longed use of antibiotics in these patients. Carbenicillin9and massive doses of penicillin 10 are anions which can-not be reabsorbed in the distal nephron; the electricalnegativity of the tubular lumen rises and potassium se-cretion increases, causing hypokalxmia. However, someof these patients with hypokalaemia have a positivepotassium balance" indicating a probable intracellulartransfer of potassium.Lawson et al. then analysed the group with profound

hypokalaemia (<2 mmol/1). Although drug therapy wasthe principal cause (33%), only 4 patients out of 64 hadbeen admitted with diuretic-induced hypokal&aelig;mia de-spite the fact that 11 % of patients admitted to medicalwards are on diuretics. Other drugs incriminated wereinsulin during rehydration of diabetic ketoacidosis, clin-damycin (causing severe pseudomembranous colitis),and carbenoxolone-a frequently overlooked cause ofelectrolyte imbalance. Intravenous fluid therapy with in-adequate potassium supplements was particularly com-mon (17%).One curious fact was the excess of women with hypo-

kal&aelig;mia (70%). Statistically this was unlikely to havearisen by chance and neither age nor the type of diseasewas to blame. Errors in recording the data were

excluded and difficulty in blood sampling was an im-probable cause. Laxative abuse could be partly respon-sible : as the Glasgow workers point out, this is commonin women, -and they tend to be secretive about it. Thesex difference was also noted in geriatric patients bysome Danish workers12 who wondered whether elderlymen consume more potassium than women. Perhapsolder women are more likely to have had diuretics at

2. Osserman EF, Lawlor DP. Serum and urinary lysozyme (muramidase) inmonocytic and myelomonocytic leukemia. J Exp Med 1966; 124: 921-52.

3. Pickering TG, Catovsky D. Hypokalaemia and raised lysozyme levels inacute myeloid leukaemia. Quart J Med 1973; 42: 677-82.

4. Hocker P, Reizenstein P. Calcium and potassium disturbances in acute leuk-aemia. Blut 1974; 29: 398-406.

5. Mir MA, Brabin B, Tang OT, Leyland MJ, Delamore IW. Hypokalemia inacute myeloid leukemia. Ann Intern Med 1975; 82: 54-57.

6. Muggia FM, Heinemann HO, Osserman EF. Hypokalemia in cases of mono-cytic leukemia with lysozymuria. J Clin Invest 1967; 46: 1098.

7. Ledoux F, Bergerat J-P, Vetter J-M, Lang JM, Oberling F. Long-termhypokalemia in acute myeloid leukemia. Arch Intern Med 1978; 138:1287-90.

8. Prockrop DJ, Davidson WD. A study of urinary and serum lysozyme in pa-tients with renal disease. N Eng J Med 1964; 270: 269-74.

9. Stapleton FB, Nelson B, Vats TS, Linshaw MA. Hypokalemia associatedwith antibiotic treatment. Am J Dis Child 1976; 130: 1104-08.

10. Carroll K, Long F, Smith RBW. Complications in a patient with subacutebacterial endocarditis with particular reference to massive penicillin ther-apy. Med J Aust 1969; ii: 1296-98.

11. Muggia FM, Heinemann HO, Farmangi M, Osserman EF. Lysozymuria andrenal tubular dysfunction in monocytic and myelomonocytic leukemia.Am J Med 1969; 47: 351-66.

12. Krakauer R, Lauritzen M. Diuretic therapy and hypokalaemia in geriatricout-patients. Dan Med Bull 1978; 25: 126-29.

home for hypertension, obesity, or oedema-treatmentwhich escapes notice when they are admitted to hospital.Balance studies should show whether these women areindeed potassium depleted or, alternatively, prone tomajor redistribution of potassium due to abnormalitiesin cell membranes.

Although hypokalaemia may be suggested by symp-toms of muscular weakness, paralytic ileus, or polyuria,the condition is often symptomless and correct diagnosisrests on a high index of suspicion. Dietary inadequaciesapart, potassium depletion occurs when there is exces-sive loss from the gastrointestinal tract or the kidneys.The diseases and drugs known to be associated withhypokalaemia have been extensively reviewed.13 Diure-tics were an infrequent cause of severe hypokalaemia inthe Glasgow study, which will please those who feel thatpotassium supplements do more harm than good,14 buthypokalaemia remains unpredictable and patients receiv-ing diuretics, especially those taking digitalis, shouldhave their plasma potassium measured regularly.

SEPTIC&AElig;MIA IN DIALYSIS PATIENTS

THE world hasmodialysis population rose from a merehandful in 1966 to over 10 000 in 1971 and almost65 000 in 1976’. By 1977 over 60 000 patients had beentreated in Europe alone.2 Nsouli and co-workers3 at thePeter Bent Brigham Hospital, Boston, have reviewed theincidence of septicaemia in the 1014 patients withchronic renal failure (CRF) and 147 with acute renalfailure (ARF) whom they have treated over the past 12years. Their report comes as a reminder that serious in-fection is a major complication. The incidence of sep-ticsemia was much the same in CRF and ARF&mdash;9.5%and 10.9%-but the infecting organisms and the out-come differed strikingly in the two groups. In ARF, in-fection with gram-negative organisms predominated andover half the patients died. In CRF the mortality wasonly 19% and most of the bactersemias were staphylo-coccal, stemming from access-site infection; the one-third which were gram-negative accounted for all butone of the fatal episodes. Gram-negative septicaemia didnot normally originate from the vascular access site; thelungs and gastrointestinal tract were the commonestsources and accounted for the great majority of infec-tions in patients with ARF. This is not surprising sincea high proportion of patients who are dialysed for ARFhave recently undergone either surgery or severe

trauma; they may have bowel or peritoneal sepsis, chestinfection sometimes aggravated by tracheostomy andventilation, and indwelling urethral catheters. What issurprising is that the genitourinary tract was not impli-cated as the source of the septicaemia in any of the ARFpatients in the Boston series. There was no evidence,either, that septicaemia was attributable to contamin-

13. Nardone DA, McDonald WJ, Girard DE. Mechanisms in hypokalemia: clini-cal correlation. Medicine 1978; 57: 435-45.

14. Burchell HB. Dilemmas in potassium therapy. Circulation 1973; 47:1144-46.

1. Manis T, Friedman EA. Dialytic therapy for irreversible uremia. N Engl JMed 1979; 301: 1260-65.

2. Wing AJ, et al. Combined report on regular dialysis and transplantation inEurope, viii, 1977. Proc Europ Dialysis Transplant Assoc 1978; 15: 3-77.

3. Nsouli KA, Lazarus JM, Schoenbaum SC, Gottlieb MN, Lowrie EG, ShocairM. Bacteremic infection in hemodialysis. Arch Intern Med 1979; 139:1255-58.