Isolated reports describe erythematous rashes occurring shortly after taking aztreonam or, rarely, imipenem. This could be caused by a non-immune mechanism, but Saxon et al suggested that cross reactivity and allergic reactions to imipenem could occur in patients known to be allergic to penicillin as determined by IgE antibody titre.3 Recently, an immediate hypersensitivity reaction has been described after a first exposure to aztreonam in a patient allergic to penicillin, and we suggest that in our patient the reaction could have been mediated by IgE antibodies.4
centration normalised, but she remained in poor condition, receiving only parenteral nourishment. Owing to progressive osteolysis and severe bone pain oral clodronic acid was restarted (2400 mg/day). After seven days she suddenly developed repeated grand mal attacks; her calcium concentration was 1 72 mmol/l. Intravenous calcium, diazepam, and phenobarbitone controlled the tetany, but she remained severely hypocalcaemic (lowest calcium concentration 1 48 mmol/1) despite daily infusions with calcium. The multiple myeloma progressed rapidly and she died. Necropsy was not done. Blood samples taken in the hypercalcaemic phase preceding the first course of clodronic acid showed an almost completely suppressed parathyroid function (parathyroid hormone concentration 1 ng/l), a marginally low 1 ,25-dihydroxycholecalciferol concentration (21 pmol/l), and a normal calcitonin concentration (0-09 Rg/l). At the time of severe hypocalcaemia her parathyroid hormone concentration increased to 179 ng/l, her 1 ,25-dihydroxycholecalciferol concentration returned to normal (41 pmol/l), and her calcitonin concentration was unaltered; her magnesium concentration was low (0 40 mmol/l) and phosphate concentration high (2 63 mmol/l). Activity of alkaline phosphatase was raised (1059 IU/1), but her osteocalcin concentration was low (2-1 tg/l). Our patient developed severe hypocalcaemia and hypomagnesaemia shortly after starting treatment with clodronic acid and remained hypocalcaemic despite an adequate increase in parathyroid function. Diphosphonates inhibit osteoclastic bone resorption and consequently skeletal calcium mobilisation.4 Mild asymptomatic hypocalcaemia is often observed after treatment with diphosphonates, but it is usually compensated for by a secondary hyperparathyroidism.2 Only one case of symptomatic hypocalcaemia induced by diphosphonate seems to have been reported. This was in a patient who developed finger tip paraesthesia (corrected calcium concentration 197 mmol/1) after a single intravenous dose of aminohydroxypropylidene diphosphonate for hypercalcaemia caused by a malignancy.' Aminoglycosides often induce renal tubular damage and renal loss of calcium and magnesium, resulting in hypocalcaemia and hypomagnesaemia.3 Hypomagnesaemia is known to inhibit peripheral effects of parathyroid hormone and to suppress parathyroid function.5 In our patient starting aminoglycoside was followed by an increased creatinine concentration, indicating damage to the renal tubules. Furthermore, hypomagnesaemia, probably induced by aminoglycosides and insufficient dietary intake, was observed.
1 Adkinson NF, Saxon A, Spence MR, Swabb EA. Crossallergenicity and immunogenicity of aztreonam. Rev Infect Dis 1985;7(suppl 4):S613-21. 2 Saxon A, Hassner A, Swabb EA, Wheeler B, Adkinson NF Jr. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin-allergic subjects. J Infect Dis 1984;149: 16. 3 Saxon A, Adelman DC, Patel A, et al. Imipenem cross-reactivity with penicillin in humans. J Allergy Clin Immunol 1988;82: 213-7. 4 Alvarez JS, Del Castillo JAS, Garcia IS, Ortiz MJA. Immediate hypersensitivity to aztreonam. Lancet 1990;335:1094.
Severe hypoglycaemia after treatment with diphosphonate and aminoglycoside Drs ULRIK PEDERSEN-BJERGAARD and JOHN MYHRE (Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark) write: Diphosphonates and aminoglycosides can induce transient biochemical hypocalcaemia by two different mechanisms.'3 We report on a patient with multiple myeloma who developed persisting severe hypocalcaemia after treatment with clodronic acid and netilmicin. A 62 year old woman with multiple myeloma presented with multiple osteolytic lesions and severe hypercalcaemia (calcium concentration 4-3 mmol/l). The figure shows her corrected calcium concentration, course of treatment, and major events. The initial episode of hypercalcaemia was controlled with volume repletion, corticosteroids, and infusions of plicamycin (1250 [tg/day for four days).. Recurring hypercalcaemia was treated with oral clodronic acid 2400 mg/day. This treatment was discontinued after 13 days owing to marginal hypocalcaemia (2 19 mmol/l). A few weeks later she developed severe enterobacter septicaemia, which was treated for 15 days with netilmicin (0-200 mg/day) and cefuroxime. Her creatinine concentration increased to a maximum of 305 [tmol/l and calcium concentration fell to 168 mmol/l without any hypocalcaemic symptoms. During recovery her calcium con-
35.
2-5-~ ~ / E 2 0-
~ ~ ~ ~
E .' 1 5 Diagnosis
~ ~ ~ ~ ~~~~~~~Nra rnge
Sternum and rib fractures
Septicaemia
tClodronate
CZ
0
20 30 oh10
Grand mal
Death
Clodronate affacks
40
50
60
70
80
90
io
T
These side effects of aminoglycoside probably compromised the normal homoeostatic response to the diphosphonate-induced hypocalcaemia by inhibiting peripheral effects of parathyroid hormone. Because diphosphonates can induce hypocalcaemia care should be taken when administering them simultaneously with aminoglycosides or to patients with impaired parathyroid function. Calcium and magnesium concentrations should be monitored closely in these patients. It is important to notice that renal loss of calcium and magnesium can continue for many weeks after aminoglycosides are stopped and that the effect of diphosphonates can also persist for weeks. 1 Jodrell DI, Iveson TJ, Smith IE. Symptomatic hypocalcaemia after treatment with high dose aminohydroxypropylidene diphosphonate. Lancet 1987;i:622. 2 Papapoulos SE, Harinck HIJ, Bijvoet OLM, Gleed JH, Fraher LJ, O'Riordan JLH. Effects of decreasing serum calcium on circulating parathyroid hormone and vitamin D metabolites in normocalcaemic and hypercalcaemic patients treated with APD. BoneMiner 1986;1:69-78. 3 Keating MJ, Sethi MR, Bodey GP, Samaan NA. Hypocalcemia with hypoparathyroidism and renal tubular dysfunction associated with aminoglycoside therapy. Cancer 1977;39: 1410-4. 4 Fleisch H. Bisphosphonates: history and experimental basis. Bone 1987;8(suppl 1):S23-8. 5 Rude RK, Oldham SB, Singer FR. Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. ClGn Endocrinol 1976;5:209-24.
Another quirk of quinine Drs C C HARLAND and L G MILLARD (University Hospital, Nottingham NG7 2UH) write: A 78 year old man with ischaemic heart disease was admitted to hospital with breathlessness, weight loss, a generalised eruption, and splinter haemorrhages, which had developed over two months. He had received isosorbide dinitrate, digoxin, spironolactone, and aminophylline for two years and quinine bisulphate for three months to treat night cramps. Only quinine was discontinued on his admission to hospital. Two distinct rashes were examined by biopsy: a papulonecrotic eruption with a photosensitive distribution and a maculopapular eruption on the trunk and limbs. Histological examination of the maculopapular eruption showed a perivascular lymphocytic infiltrate; cutaneous necrosis associated with an intense angiocentric infiltrate of pleomorphic T cell lymphocytes was present in the papulonecrotic lesion. The cutaneous signs, including splinter haemorrhages, regressed two weeks after quinine was withdrawn but the maculopapular eruption recurred 24 hours after he was inadvertently prescribed a single dose of quinine bisulphate three weeks after his admission. Again, this cleared on withholding quinine. He died two months later as a result of cardiac failure secondary to ischaemic heart disease. There was no evidence of lymphoreticular disease, vasculitis, or endocarditis on necropsy. Therefore, we believe that his cutaneous symptoms were likely to have been the result of an atypical lymphocytic vasculitis induced by quinine. Photosensitivity is a well known side effect of quinine,' and cutaneous neutrophilic vasculitis has been reported after its use.2 The combination of splinter haemorrhages and a maculopapular and photosensitive papulonecrotic eruption due to a quinine induced lymphocytic vasculitis has not been reported previously. It is important that doctors are aware that such cutaneous manifestations of treatment with quinine may be benign, so that unnecessary investigations for an underlying vasculitis or lymphoid malignancy are avoided. 1 Ferguson J, Addo HA, Johnson BE, Frain-Bell W. Quinine induced photosensitivity: clinical and experimental studies.
Brj Dermnatol 1987;117:631-40.
Days Serum calcium concentration, treatment, and major events in patient with multiple myeloma BMJ
VOLUME 302
2 FEBRIUARY 1991
2 Rockl H, Stollman K. Vasculitis allergica cutis caused by quinine with the clinical picture of purpura with thrombopenia.
MunchenerMedizinische Wochenschrift 1968;110:2549-53.
295
centration normalised, but she remained in poor condition, receiving only parenteral nourishment. Owing to progressive osteolysis and severe bone pain oral clodronic acid was restarted (2400 mg/day). After seven days she suddenly developed repeated grand mal attacks; her calcium concentration was 1 72 mmol/l. Intravenous calcium, diazepam, and phenobarbitone controlled the tetany, but she remained severely hypocalcaemic (lowest calcium concentration 1 48 mmol/1) despite daily infusions with calcium. The multiple myeloma progressed rapidly and she died. Necropsy was not done. Blood samples taken in the hypercalcaemic phase preceding the first course of clodronic acid showed an almost completely suppressed parathyroid function (parathyroid hormone concentration 1 ng/l), a marginally low 1 ,25-dihydroxycholecalciferol concentration (21 pmol/l), and a normal calcitonin concentration (0-09 Rg/l). At the time of severe hypocalcaemia her parathyroid hormone concentration increased to 179 ng/l, her 1 ,25-dihydroxycholecalciferol concentration returned to normal (41 pmol/l), and her calcitonin concentration was unaltered; her magnesium concentration was low (0 40 mmol/l) and phosphate concentration high (2 63 mmol/l). Activity of alkaline phosphatase was raised (1059 IU/1), but her osteocalcin concentration was low (2-1 tg/l). Our patient developed severe hypocalcaemia and hypomagnesaemia shortly after starting treatment with clodronic acid and remained hypocalcaemic despite an adequate increase in parathyroid function. Diphosphonates inhibit osteoclastic bone resorption and consequently skeletal calcium mobilisation.4 Mild asymptomatic hypocalcaemia is often observed after treatment with diphosphonates, but it is usually compensated for by a secondary hyperparathyroidism.2 Only one case of symptomatic hypocalcaemia induced by diphosphonate seems to have been reported. This was in a patient who developed finger tip paraesthesia (corrected calcium concentration 197 mmol/1) after a single intravenous dose of aminohydroxypropylidene diphosphonate for hypercalcaemia caused by a malignancy.' Aminoglycosides often induce renal tubular damage and renal loss of calcium and magnesium, resulting in hypocalcaemia and hypomagnesaemia.3 Hypomagnesaemia is known to inhibit peripheral effects of parathyroid hormone and to suppress parathyroid function.5 In our patient starting aminoglycoside was followed by an increased creatinine concentration, indicating damage to the renal tubules. Furthermore, hypomagnesaemia, probably induced by aminoglycosides and insufficient dietary intake, was observed.
1 Adkinson NF, Saxon A, Spence MR, Swabb EA. Crossallergenicity and immunogenicity of aztreonam. Rev Infect Dis 1985;7(suppl 4):S613-21. 2 Saxon A, Hassner A, Swabb EA, Wheeler B, Adkinson NF Jr. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin-allergic subjects. J Infect Dis 1984;149: 16. 3 Saxon A, Adelman DC, Patel A, et al. Imipenem cross-reactivity with penicillin in humans. J Allergy Clin Immunol 1988;82: 213-7. 4 Alvarez JS, Del Castillo JAS, Garcia IS, Ortiz MJA. Immediate hypersensitivity to aztreonam. Lancet 1990;335:1094.
Severe hypoglycaemia after treatment with diphosphonate and aminoglycoside Drs ULRIK PEDERSEN-BJERGAARD and JOHN MYHRE (Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark) write: Diphosphonates and aminoglycosides can induce transient biochemical hypocalcaemia by two different mechanisms.'3 We report on a patient with multiple myeloma who developed persisting severe hypocalcaemia after treatment with clodronic acid and netilmicin. A 62 year old woman with multiple myeloma presented with multiple osteolytic lesions and severe hypercalcaemia (calcium concentration 4-3 mmol/l). The figure shows her corrected calcium concentration, course of treatment, and major events. The initial episode of hypercalcaemia was controlled with volume repletion, corticosteroids, and infusions of plicamycin (1250 [tg/day for four days).. Recurring hypercalcaemia was treated with oral clodronic acid 2400 mg/day. This treatment was discontinued after 13 days owing to marginal hypocalcaemia (2 19 mmol/l). A few weeks later she developed severe enterobacter septicaemia, which was treated for 15 days with netilmicin (0-200 mg/day) and cefuroxime. Her creatinine concentration increased to a maximum of 305 [tmol/l and calcium concentration fell to 168 mmol/l without any hypocalcaemic symptoms. During recovery her calcium con-
35.
2-5-~ ~ / E 2 0-
~ ~ ~ ~
E .' 1 5 Diagnosis
~ ~ ~ ~ ~~~~~~~Nra rnge
Sternum and rib fractures
Septicaemia
tClodronate
CZ
0
20 30 oh10
Grand mal
Death
Clodronate affacks
40
50
60
70
80
90
io
T
These side effects of aminoglycoside probably compromised the normal homoeostatic response to the diphosphonate-induced hypocalcaemia by inhibiting peripheral effects of parathyroid hormone. Because diphosphonates can induce hypocalcaemia care should be taken when administering them simultaneously with aminoglycosides or to patients with impaired parathyroid function. Calcium and magnesium concentrations should be monitored closely in these patients. It is important to notice that renal loss of calcium and magnesium can continue for many weeks after aminoglycosides are stopped and that the effect of diphosphonates can also persist for weeks. 1 Jodrell DI, Iveson TJ, Smith IE. Symptomatic hypocalcaemia after treatment with high dose aminohydroxypropylidene diphosphonate. Lancet 1987;i:622. 2 Papapoulos SE, Harinck HIJ, Bijvoet OLM, Gleed JH, Fraher LJ, O'Riordan JLH. Effects of decreasing serum calcium on circulating parathyroid hormone and vitamin D metabolites in normocalcaemic and hypercalcaemic patients treated with APD. BoneMiner 1986;1:69-78. 3 Keating MJ, Sethi MR, Bodey GP, Samaan NA. Hypocalcemia with hypoparathyroidism and renal tubular dysfunction associated with aminoglycoside therapy. Cancer 1977;39: 1410-4. 4 Fleisch H. Bisphosphonates: history and experimental basis. Bone 1987;8(suppl 1):S23-8. 5 Rude RK, Oldham SB, Singer FR. Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. ClGn Endocrinol 1976;5:209-24.
Another quirk of quinine Drs C C HARLAND and L G MILLARD (University Hospital, Nottingham NG7 2UH) write: A 78 year old man with ischaemic heart disease was admitted to hospital with breathlessness, weight loss, a generalised eruption, and splinter haemorrhages, which had developed over two months. He had received isosorbide dinitrate, digoxin, spironolactone, and aminophylline for two years and quinine bisulphate for three months to treat night cramps. Only quinine was discontinued on his admission to hospital. Two distinct rashes were examined by biopsy: a papulonecrotic eruption with a photosensitive distribution and a maculopapular eruption on the trunk and limbs. Histological examination of the maculopapular eruption showed a perivascular lymphocytic infiltrate; cutaneous necrosis associated with an intense angiocentric infiltrate of pleomorphic T cell lymphocytes was present in the papulonecrotic lesion. The cutaneous signs, including splinter haemorrhages, regressed two weeks after quinine was withdrawn but the maculopapular eruption recurred 24 hours after he was inadvertently prescribed a single dose of quinine bisulphate three weeks after his admission. Again, this cleared on withholding quinine. He died two months later as a result of cardiac failure secondary to ischaemic heart disease. There was no evidence of lymphoreticular disease, vasculitis, or endocarditis on necropsy. Therefore, we believe that his cutaneous symptoms were likely to have been the result of an atypical lymphocytic vasculitis induced by quinine. Photosensitivity is a well known side effect of quinine,' and cutaneous neutrophilic vasculitis has been reported after its use.2 The combination of splinter haemorrhages and a maculopapular and photosensitive papulonecrotic eruption due to a quinine induced lymphocytic vasculitis has not been reported previously. It is important that doctors are aware that such cutaneous manifestations of treatment with quinine may be benign, so that unnecessary investigations for an underlying vasculitis or lymphoid malignancy are avoided. 1 Ferguson J, Addo HA, Johnson BE, Frain-Bell W. Quinine induced photosensitivity: clinical and experimental studies.
Brj Dermnatol 1987;117:631-40.
Days Serum calcium concentration, treatment, and major events in patient with multiple myeloma BMJ
VOLUME 302
2 FEBRIUARY 1991
2 Rockl H, Stollman K. Vasculitis allergica cutis caused by quinine with the clinical picture of purpura with thrombopenia.
MunchenerMedizinische Wochenschrift 1968;110:2549-53.
295
