523
DIAGN MICROBIOLINFECTDIS 1992;15:523-526
CASE REPORTS
High Pentamidine Levels Associated with Hypoglycemia and Azotemia in a Patient with Pneumocystis carinii Pneumonia Ronald Comtois, Jo61 Pouliot, Andr6 Gervais, Bernard Vinet, and Claude Lemieux
We report on a patient who presented with a Pneumocystis carinii pneumonia. Intravenous pentamidine (4 mg/kg/day) was given for 14 days without the occurrence of adverse effects. During this treatment, the mean (+-SD) serum pentamidine trough concentration was 94 + 16 ng/ml. Three days later, the patient was admitted because of fever, and pentamidine (4 mg/kg/day) was again started. Fasting hypoglycemia
and azotemia then occurred; the mean serum trough pentamidine level was 190 +- 10 ng/ml during this week of treatment. We conclude that the occurrence of hypoglycemia and azotemia during pentamidine therapy may not be idiosyncrasic, but seemed associated in our patient with high levels of serum pentamidine.
INTRODUCTION
samples obtained during both treatments with pentamidine allowed assessment of pancreatic ~ cell function in light of measured serum pentamidine levels.
Hypoglycemia has been reported in 6%-35% of patients receiving pentamidine (Waskin et al., 1988), whereas hyperglycemia has been observed less commonly (Goa and Campoli-Richards, 1987). Bouchard et al. (1982) had suggested that pentamidine induces a direct cytolytic effect on 13 cells leading to insulin release and hypoglycemia. However, no published clinical study suggests a relationship between pentamidine levels and adverse effects. We report herein a case of a patient with Pneumocystis carinii pneumonia w h o developed a sudden hypoglycemia during the second treatment with pentamidine. Retrospective analysis of blood and urine From the Departments of Medicine (R.C., J.P., A.G.), Biochemistry (B.V.), and Microbiology(C.L.), Notre-Dame Hospital, University of Montreal, Montreal, Canada. Address reprint requests to Dr. R. Comtois, Notre-Dame Hospital, 1560Sherbrooke east, Montreal, Quebec H2L 4M1, Canada. Received 5 August 1991; accepted 19 November 1991. ©1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
MATERIALS A N D M E T H O D S Complete blood and platelet counts and serum chemistry (including glucose, insulin, electrolytes, creatinine, calcium, amylase, liver enzymes, and pentamidine) were monitored twice weekly during pentamidine therapy. Chest roentgenogram, clearance of creatinine, and 24-hr urinary cortisol and amylase were monitored at baseline and at the end of each treatment. Capillary blood glucose was monitored four times daily during the period of treatment. Serum insulin was measured by radioimmunoassay (Bio-Mega, Canada, Montreal) and was expressed as glucose-insulin ratio in order to document more adequately the relative insulin levels (Fajan and Floyd, 1976). Serum pentamidine was measured by high-performance liquid chromatography, as de-
524
scribed previously (Min-Hwa et al., 1986), with the following modifications: pentamidine was extracted by passage onto a C-18 extraction cartridge after protein precipitation with 100% acetonitrile. Impurities were removed by washing the cartridge with 100% methanol and pentamidine was recovered with lmL of 65% methanol in 0.35 M heptanesulfonic acid, pH 3.0. The analysis was performed on a PKB-100 Supelco column eluted with 60% methanol in 0.025 M heptanesulfonic acid, pH 3.0. Detection was by fluorescence. The sensitivity of the assay was 15 ng/ml. The coefficients of variation ranged from 3.6% to 8.3% depending on whether the concentration of pentamidine was, respectively, high (600 + 22 ng/ml) or low (49.5 + 4.0 ng/ml). Blood samples for pentamidine determination were taken immediately before the next dose administration; they thus represent trough levels. Serum specimens were kept at - 20°C. At this temperature, pentamidine was stable in serum for at least 2 months.
CASE REPORT
A 45-year-old man, known to have antibodies to human immunodeficiency virus (HIV) since 1986, presented in November 1989 with a 3-day history of nonproductive cough and fever. He had no previous personal or family history of glucose intolerance, ethanol abuse, or pancreatitis. Serum electrolytes were within normal range with glucose 5.5 mmol/L (normal, 3.9-6.1 mmol/L), blood urea 4.3 mmolYL (normal, 2.5-7.9 mmol/L), and creatinine 87 ~mol/L (normal, 72-179 ~mol/L). Liver enzyme levels were normal as was the urine analysis. Lactate dehydrogenase was elevated, 327 U/L (normal, 115-225 U/L). Alveolar infiltrates of the lung bases were noted on the chest radiograph. Bronchoalveolar lavage was positive for P. carinii, and therapy with intravenous trimethoprimsulfamethoxazole (20 mg and 100 mg/kg/day, respectively) was started. Despite initial improvement, the fever remained >38°C after 5 days, and the treatment was then changed to intravenous pentamidine (4 mg/kg/day). After 2 days of pentamidine therapy, the patient felt normal and, after 14 days of treatment, he was discharged. As shown in Figure 1, no adverse reactions were observed during the first course except for an asymptomatic slight elevation of serum amylase, which decreased after pentamidine cessation. Three days later, the patient was admitted because of 24-hr of fever at 39°C. No pulmonary infiltrates were noted on the chest radiograph. Three days later, the bronchoalveolar lavage was positive for P. carinii, and therapy with intravenous pentamidine (4 mg/kg/day) was started because the pa-
R. Comtois et al.
tient looked seriously ill, the lactate dehydrogenase levels increased from 165 (day 15) to 291 U/L (day 18), and we did not find any other cause for the high fever. The fever resolved in 10 days. As illustrated in Figure 1, however, the patient developed a gradual impairment in renal function and an acute hypoglycemia 5 days after the start of this 3-week pentamidine course. When the renal insufficiency was noticed (day 25), intravenous physiologic saline at 100 ml/hr was used for 18 hr, and thereafter the pentamidine was given every other day in order to correct two potential causes: dehydration and pentamidine intoxication. Subsequently, the creatinine levels gradually normalized. The fasting hypoglycemia occurred on day 25 at 08:00 hr, whereas the patient did not take his supper the day before. He presented with sweating, palpitation, and trembling with a relief of these symptoms by ingestion of 180 ml of sweetened juice. This hypoglycemic episode was associated with the lowest serum glucose-insulin ratio (2.3 mmol/L/108 pmol/L: 21 x 106) documented in the patient. The blood glucose was well controlled w h e n the patient followed until the end of pentamidine treatment a normal diet with three meals and three snacks and w h e n the pentamidine dosage interval was lengthened. Thereafter, the basal blood glucose levels gradually increased with an increment of the glucose-insulin ratio [7.1 mmol/L/64 pmolYL (111 x 106) on day 42] even though the pentamidine dosage was decreased and the P. carinii pneumonia seemed well controlled without the use of intravenous glucose administration. The serum amylase levels increased during each therapy with pentamidine, as shown in Figure 1. After the second treatment (day 42), however, the serum amylase remained elevated at 231 U/L (normal, 15-120 U/L) as well as amylase urinary levels at 30.3 U/hr (normal, 2-19 U/hr). The serum pentamidine trough concentration during the last week of the first therapy was 92 ng/ml (day 12) and 95 ng/ml (day 15). During the second therapy, w h e n the fasting hypoglycemia and renal impairment occurred, the pentamidine trough levels were 190 ng/ml (day 25) and 205 ng/ml (day 28). From day 27, pentamidine was given intravenously every 48 hr, which resulted in a decrease in pentamidine levels (55 ng/ml on day 42). Simultaneously, we observed an improvement in renal function and, also, no hypoglycemic episode recurred. Two months later, the patient felt well except for mild upper abdominal pain unrelated to meals. A 75-g glucose tolerance test was administered: the serum basal glucose was 5.6 mmol/L; a peak level of 10.1 mmolYL was observed at 60 rain and, at 120 min, the serum glucose was 8.7 mmol/L. The test
Pentamidine Levels in a Pneumocystis carinii Patient
525
"I z_ _J
I~K)
v LU
Z uJ
3
./£
I
I
I..-
|
I~L~Z~E23..~,,I I
i
i
I
I
PENTAMIDINE(240 rag/dayot therapy) I I I I I 2001
14~0
I Z[ E
o
E u.l Z
Z
~ m
l,-
< I-.Z W
{~"
4O
n-
i.~' 1st AOMISSIOW
I S
I 10
|-.. ,5
, t 2O 2rid AOMI$~OI¢
2IlL
,a
3O
;$
i 40
,
TIME (days) F I G U R E 1_ Plasma glucose-insulin, amylase, pentamidine, and creatinine
concentrations during Pneumocystis carinii pneumonia.
was interpreted as normal. The clearance of creatinine was 2.14 mlYs (compared with 0.98 ml/s on day 42) and the 24ohr urinary cortisol was 117 mmol/day (compared with 77 mmol/day on day 42; normal, 55-200 nmol/day). The serum amylase and lipase were 242 U/L and 335 U/L respectively (normal, 0-190 U/L). The ultrasonography of the pancreas was normal.
DISCUSSION Dysglycemia is a prominent side effect of pentamidine, but the pathophysiology of these changes is unclear. Waskin et al. (1988) reported that hypoglycemia was more likely to occur in patients who received therapy of longer duration or in repeated courses, with an increasing dosage of pentamidine, and in those who experienced azotemia during treatment. According to our case report, these risk factors could be related to high serum pentamidine levels. In agreement with Bouchard et al. (1982), our patient was hypoglycemic, at least in part, because of release of insulin, and then hyperglycemic because of insulin deficiency. The proposed mechanism of hypoglycemia is a progressive cytotoxicity of pancreatic
islet cells (Boillot and Velt, 1985). During the hypoglycemic episode, our patient showed a glucoseinsulin ratio of 21 x 10 6, which is far less than 44 x 106 (or an insulin-glucose ratio >0.3 in conventional units), a level highly suggestive of hyperinsulinisrn, according to Fajan and Floyd (1976). In vitro studies of pancreatic islet cells indicate that pentamidine is selectively cytotoxic to [3 cells of the pancreas. However, other contributing factors may play a role in the occurrence of hypoglycemia associated with pentamidine therapy. Thus, low caloric intake may be, as in our patient, a risk factor. In addition, azotemia itself may predispose patients to hypoglycemia by contributing to decreased gluconeogenesis (Fisher et al., 1986). Since
DIAGN MICROBIOLINFECTDIS 1992;15:523-526
CASE REPORTS
High Pentamidine Levels Associated with Hypoglycemia and Azotemia in a Patient with Pneumocystis carinii Pneumonia Ronald Comtois, Jo61 Pouliot, Andr6 Gervais, Bernard Vinet, and Claude Lemieux
We report on a patient who presented with a Pneumocystis carinii pneumonia. Intravenous pentamidine (4 mg/kg/day) was given for 14 days without the occurrence of adverse effects. During this treatment, the mean (+-SD) serum pentamidine trough concentration was 94 + 16 ng/ml. Three days later, the patient was admitted because of fever, and pentamidine (4 mg/kg/day) was again started. Fasting hypoglycemia
and azotemia then occurred; the mean serum trough pentamidine level was 190 +- 10 ng/ml during this week of treatment. We conclude that the occurrence of hypoglycemia and azotemia during pentamidine therapy may not be idiosyncrasic, but seemed associated in our patient with high levels of serum pentamidine.
INTRODUCTION
samples obtained during both treatments with pentamidine allowed assessment of pancreatic ~ cell function in light of measured serum pentamidine levels.
Hypoglycemia has been reported in 6%-35% of patients receiving pentamidine (Waskin et al., 1988), whereas hyperglycemia has been observed less commonly (Goa and Campoli-Richards, 1987). Bouchard et al. (1982) had suggested that pentamidine induces a direct cytolytic effect on 13 cells leading to insulin release and hypoglycemia. However, no published clinical study suggests a relationship between pentamidine levels and adverse effects. We report herein a case of a patient with Pneumocystis carinii pneumonia w h o developed a sudden hypoglycemia during the second treatment with pentamidine. Retrospective analysis of blood and urine From the Departments of Medicine (R.C., J.P., A.G.), Biochemistry (B.V.), and Microbiology(C.L.), Notre-Dame Hospital, University of Montreal, Montreal, Canada. Address reprint requests to Dr. R. Comtois, Notre-Dame Hospital, 1560Sherbrooke east, Montreal, Quebec H2L 4M1, Canada. Received 5 August 1991; accepted 19 November 1991. ©1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
MATERIALS A N D M E T H O D S Complete blood and platelet counts and serum chemistry (including glucose, insulin, electrolytes, creatinine, calcium, amylase, liver enzymes, and pentamidine) were monitored twice weekly during pentamidine therapy. Chest roentgenogram, clearance of creatinine, and 24-hr urinary cortisol and amylase were monitored at baseline and at the end of each treatment. Capillary blood glucose was monitored four times daily during the period of treatment. Serum insulin was measured by radioimmunoassay (Bio-Mega, Canada, Montreal) and was expressed as glucose-insulin ratio in order to document more adequately the relative insulin levels (Fajan and Floyd, 1976). Serum pentamidine was measured by high-performance liquid chromatography, as de-
524
scribed previously (Min-Hwa et al., 1986), with the following modifications: pentamidine was extracted by passage onto a C-18 extraction cartridge after protein precipitation with 100% acetonitrile. Impurities were removed by washing the cartridge with 100% methanol and pentamidine was recovered with lmL of 65% methanol in 0.35 M heptanesulfonic acid, pH 3.0. The analysis was performed on a PKB-100 Supelco column eluted with 60% methanol in 0.025 M heptanesulfonic acid, pH 3.0. Detection was by fluorescence. The sensitivity of the assay was 15 ng/ml. The coefficients of variation ranged from 3.6% to 8.3% depending on whether the concentration of pentamidine was, respectively, high (600 + 22 ng/ml) or low (49.5 + 4.0 ng/ml). Blood samples for pentamidine determination were taken immediately before the next dose administration; they thus represent trough levels. Serum specimens were kept at - 20°C. At this temperature, pentamidine was stable in serum for at least 2 months.
CASE REPORT
A 45-year-old man, known to have antibodies to human immunodeficiency virus (HIV) since 1986, presented in November 1989 with a 3-day history of nonproductive cough and fever. He had no previous personal or family history of glucose intolerance, ethanol abuse, or pancreatitis. Serum electrolytes were within normal range with glucose 5.5 mmol/L (normal, 3.9-6.1 mmol/L), blood urea 4.3 mmolYL (normal, 2.5-7.9 mmol/L), and creatinine 87 ~mol/L (normal, 72-179 ~mol/L). Liver enzyme levels were normal as was the urine analysis. Lactate dehydrogenase was elevated, 327 U/L (normal, 115-225 U/L). Alveolar infiltrates of the lung bases were noted on the chest radiograph. Bronchoalveolar lavage was positive for P. carinii, and therapy with intravenous trimethoprimsulfamethoxazole (20 mg and 100 mg/kg/day, respectively) was started. Despite initial improvement, the fever remained >38°C after 5 days, and the treatment was then changed to intravenous pentamidine (4 mg/kg/day). After 2 days of pentamidine therapy, the patient felt normal and, after 14 days of treatment, he was discharged. As shown in Figure 1, no adverse reactions were observed during the first course except for an asymptomatic slight elevation of serum amylase, which decreased after pentamidine cessation. Three days later, the patient was admitted because of 24-hr of fever at 39°C. No pulmonary infiltrates were noted on the chest radiograph. Three days later, the bronchoalveolar lavage was positive for P. carinii, and therapy with intravenous pentamidine (4 mg/kg/day) was started because the pa-
R. Comtois et al.
tient looked seriously ill, the lactate dehydrogenase levels increased from 165 (day 15) to 291 U/L (day 18), and we did not find any other cause for the high fever. The fever resolved in 10 days. As illustrated in Figure 1, however, the patient developed a gradual impairment in renal function and an acute hypoglycemia 5 days after the start of this 3-week pentamidine course. When the renal insufficiency was noticed (day 25), intravenous physiologic saline at 100 ml/hr was used for 18 hr, and thereafter the pentamidine was given every other day in order to correct two potential causes: dehydration and pentamidine intoxication. Subsequently, the creatinine levels gradually normalized. The fasting hypoglycemia occurred on day 25 at 08:00 hr, whereas the patient did not take his supper the day before. He presented with sweating, palpitation, and trembling with a relief of these symptoms by ingestion of 180 ml of sweetened juice. This hypoglycemic episode was associated with the lowest serum glucose-insulin ratio (2.3 mmol/L/108 pmol/L: 21 x 106) documented in the patient. The blood glucose was well controlled w h e n the patient followed until the end of pentamidine treatment a normal diet with three meals and three snacks and w h e n the pentamidine dosage interval was lengthened. Thereafter, the basal blood glucose levels gradually increased with an increment of the glucose-insulin ratio [7.1 mmol/L/64 pmolYL (111 x 106) on day 42] even though the pentamidine dosage was decreased and the P. carinii pneumonia seemed well controlled without the use of intravenous glucose administration. The serum amylase levels increased during each therapy with pentamidine, as shown in Figure 1. After the second treatment (day 42), however, the serum amylase remained elevated at 231 U/L (normal, 15-120 U/L) as well as amylase urinary levels at 30.3 U/hr (normal, 2-19 U/hr). The serum pentamidine trough concentration during the last week of the first therapy was 92 ng/ml (day 12) and 95 ng/ml (day 15). During the second therapy, w h e n the fasting hypoglycemia and renal impairment occurred, the pentamidine trough levels were 190 ng/ml (day 25) and 205 ng/ml (day 28). From day 27, pentamidine was given intravenously every 48 hr, which resulted in a decrease in pentamidine levels (55 ng/ml on day 42). Simultaneously, we observed an improvement in renal function and, also, no hypoglycemic episode recurred. Two months later, the patient felt well except for mild upper abdominal pain unrelated to meals. A 75-g glucose tolerance test was administered: the serum basal glucose was 5.6 mmol/L; a peak level of 10.1 mmolYL was observed at 60 rain and, at 120 min, the serum glucose was 8.7 mmol/L. The test
Pentamidine Levels in a Pneumocystis carinii Patient
525
"I z_ _J
I~K)
v LU
Z uJ
3
./£
I
I
I..-
|
I~L~Z~E23..~,,I I
i
i
I
I
PENTAMIDINE(240 rag/dayot therapy) I I I I I 2001
14~0
I Z[ E
o
E u.l Z
Z
~ m
l,-
< I-.Z W
{~"
4O
n-
i.~' 1st AOMISSIOW
I S
I 10
|-.. ,5
, t 2O 2rid AOMI$~OI¢
2IlL
,a
3O
;$
i 40
,
TIME (days) F I G U R E 1_ Plasma glucose-insulin, amylase, pentamidine, and creatinine
concentrations during Pneumocystis carinii pneumonia.
was interpreted as normal. The clearance of creatinine was 2.14 mlYs (compared with 0.98 ml/s on day 42) and the 24ohr urinary cortisol was 117 mmol/day (compared with 77 mmol/day on day 42; normal, 55-200 nmol/day). The serum amylase and lipase were 242 U/L and 335 U/L respectively (normal, 0-190 U/L). The ultrasonography of the pancreas was normal.
DISCUSSION Dysglycemia is a prominent side effect of pentamidine, but the pathophysiology of these changes is unclear. Waskin et al. (1988) reported that hypoglycemia was more likely to occur in patients who received therapy of longer duration or in repeated courses, with an increasing dosage of pentamidine, and in those who experienced azotemia during treatment. According to our case report, these risk factors could be related to high serum pentamidine levels. In agreement with Bouchard et al. (1982), our patient was hypoglycemic, at least in part, because of release of insulin, and then hyperglycemic because of insulin deficiency. The proposed mechanism of hypoglycemia is a progressive cytotoxicity of pancreatic
islet cells (Boillot and Velt, 1985). During the hypoglycemic episode, our patient showed a glucoseinsulin ratio of 21 x 10 6, which is far less than 44 x 106 (or an insulin-glucose ratio >0.3 in conventional units), a level highly suggestive of hyperinsulinisrn, according to Fajan and Floyd (1976). In vitro studies of pancreatic islet cells indicate that pentamidine is selectively cytotoxic to [3 cells of the pancreas. However, other contributing factors may play a role in the occurrence of hypoglycemia associated with pentamidine therapy. Thus, low caloric intake may be, as in our patient, a risk factor. In addition, azotemia itself may predispose patients to hypoglycemia by contributing to decreased gluconeogenesis (Fisher et al., 1986). Since
