Infection (2015) 43:125–126 DOI 10.1007/s15010-014-0692-3
CORRESPONDENCE
Fatal lactic acidosis associated with linezolid therapy M. Djibre´ • T. Pham • M. Denis • V. Pras Landre M. Fartoukh
•
Received: 29 September 2014 / Accepted: 10 October 2014 / Published online: 19 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
To the Editor Linezolid is frequently used to treat infections related to a variety of Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Lactic acidosis associated with Linezolid therapy has been already reported, mostly with prolonged use, but this complication is a rare cause of death. We report herein a life-threatening lactic acidosis after 15 days of linezolid exposure. A 70-year-old man was admitted to the intensive care unit (ICU) of our hospital for a severe metabolic acidosis in December 2013. He had a past medical history of tobacco use, alcoholic liver cirrhosis, hypertension, coronary disease, iliac angioplasty stenting, and rheumatoid arthritis treated with steroids. Three months before ICU admission, he suffered a severe aortic stenosis-related acute pulmonary edema, and underwent a surgical valve replacement in November 2013. Cardiac surgery was complicated by the occurrence of atrial fibrillation, gastroduodenal bleeding ulcer, and ischemic colitis requiring a left colectomy. The patient was
M. Djibre´ (&) T. Pham M. Fartoukh AP-HP, Hoˆpital Tenon, Service de Re´animation me´dicochirurgicale, 75970 Paris, France e-mail: [email protected] T. Pham M. Fartoukh Sorbonne Universite´s, UPMC Univ Paris 06, Paris, France M. Denis AP-HP, Hoˆpital Tenon, Service de Maladies Infectieuses et Tropicales, 75970 Paris, France V. Pras Landre AP-HP, Centre Re´gional de Pharmacovigilance, Hoˆpital Saint Antoine, 75012 Paris, France
febrile during the postoperative period. A sternal wound sample yielded Enterococcus faecium and Enterobacter aerogenes, whereas Staphylococcus hominis and Staphylococcus haemolyticus were recovered in blood cultures. A trans-esophageal echocardiography ruled out endocarditis. Vancomycin and imipenem were administered for 8 days. Five days after antibiotics discontinuation, the patient had chills and became febrile up to 40 °C. A thoraco-abdominal CT scan showed ascites, of which culture remained negative. Vancomycin and imipenem were again administered for 20 further days for suspected sternal infection. On December 6, 2013, the patient was referred to the infectious disease ward of our hospital for persistent sepsis. There was a small dehiscence on the abdominal wound on physical examination, from which multidrug-resistant Enterobacter cloacae were isolated, while a blood culture was positive for normally susceptible Klebsiella pneumoniae. Laboratory tests showed hyperleukocytosis at 29.8 9 109 cell/L (N 4–10 9 109/L) with 24.4 9 109 polymorphonuclear neutrophils (N 1.5–7 9 109/L), hemoglobin 7.9 g/dL (N 12–18 g/dL), and platelet count 162 9 109 cell/L (N 150–400 9 109/L). Serum creatinine was 175 lmol/l (N 60–120 lmol/l), bicarbonate 16 mmol/ L (N 23–31 mmol/L) and anionic gap 17 mmol/L (N 7–17 mmol/l). Prothrombin time was 23 % (N 70–120 %), and serum bilirubin 24 lmol/l (N \ 17). Repeated trans-esophageal echocardiography and CT scan ruled out endocarditis as well as any intrathoracic or abdominal abscess. A thoracic F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET) suggested a sternal manubrium osteitis. Vancomycin was switched to intravenous linezolid on December 11, and rifampicin and ofloxacin were added on December 20, while imipenem was administered for treating Enterobacter cloacae and Klebsiella pneumoniae. Ongoing co-medications since
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126 Table 1 Time course of laboratory tests results (reference range) Parameter
D-5
D0 Start of linezolid
D ? 9 D ? 15 ICU admission
D ? 16
pH
–
–
–
6.89
7.21
Serum bicarbonate (23–31 mmol/l)
16
19
14
8
7
Serum lactate (\2 mmol/l)
–
–
–
23
19
PaCO2 (mm Hg)
–
–
–
25
23
PaO2 (mm Hg)
–
–
–
117
128
ALT (7–31 UI/l)
88
44
7
20
916
AST (0–31 UI/l)
221
33
22
117
3,663
ALP (30–120 UI/l)
157
166
109
118
133
GGT (9–36 UI/l)
138
182
97
73
67
Tot Bili (\17 lmol/l)
24
29
26
114
134
PTI (70–120 %)
23
57
49
–
20
Serum creatinine (60–120 lmol/l)
175
129
115
161
136
Platelet count (150–400 9 109/ l)
162
195
155
49
76
PaCO2 partial pressure of arterial carbon dioxide, PaO2 partial pressure of arterial oxygen, ALT alanine aminotransferase, AST aspartate aminotransferase, ALP alkaline phosphatase, Tot Bili total bilirubin, GGT gamma-glutamyltransferase, PTI prothrombin time index, D: day, D0 refers to the day on which linezolid was started, D ? 15 refers to the day of admission to the ICU
December 11 included furosemide, amiodarone, esomeprazole, prednisone, aspirin, bromazepam, nefopam, bisoprolol and calcium heparin. On December 24, the patient started vomiting. He became drowsy and dyspneic and was admitted to our ICU on December 26. Glasgow Coma Scale was 8 of 15, blood pressure 117/47 mm Hg, heart rate 96 beats/min and temperature 33.4 °C. Physical examination revealed conjunctival jaundice, abundant ascites and lower limbs edema. There were no signs of poor peripheral perfusion. Laboratory tests on ICU admission showed severe lactic acidosis with pH 6.89, carbon dioxide partial pressure 24 mm Hg and lactate 23 mmol/l (Table 1). The patient was mechanically ventilated and received renal replacement therapy. Microbiological investigation (ascites, pleural effusion, blood, urinary and respiratory tract specimens) were negative. Empiric antimicrobial therapy associated vancomycin, imipenem and amikacin. Coloscopic and gastroscopic examinations were normal, except for a mild acute gastritis. The patient rapidly developed shock, atrioventricular block, and multiple organ failure, and died on December 27. A post-mortem examination confirmed liver cirrhosis and gastritis, but failed to identify any source of sepsis.
123
We report here a case of severe and fatal lactic acidosis after a 15-day linezolid exposure. A direct causal relationship of linezolid exposure in the occurrence of lactic acidosis may be assumed for the following reasons: (1) there were no other usual causes of lactic acidosis, such as septic shock or liver failure, as confirmed by complete microbiological investigation and post-mortem examination. Moreover, there was no history of use of metformin, nucleoside analogue or other drugs known to cause lactate acidosis; (2) lactic acidosis has already been described after linezolid exposure; [1] (3) exposure duration to linezolid is compatible since several cases have been published, with time ranging from 4 h after a single infusion to 120 days [2, 3]. The incidence of lactic acidosis complicating linezolid exposure is unknown. Only a few cases have been published in the literature. Linezolid inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit. Thus, lactic acidosis is thought to occur by a mechanism of mitochondrial toxicity [3]. In our patient, liver cirrhosis may have contributed to lactic acidosis, although there was no indication of acute liver failure at time of occurrence of severe lactic acidosis (Table 1). The severity of linezolid-induced lactic acidosis varies from asymptomatic form with only biological abnormalities, to life-threatening events and occasionally death [2–4]. Physicians should be aware of the possible occurrence of lactic acidosis related to linezolid exposure, as this complication may be a life-threatening metabolic emergency and requires discontinuation of the drug. This severe adverse effect should be suspected in patients treated with this drug and developing nausea and vomiting, tachycardia, altered mental status, asthenia, malaise, loss of vision, muscle weakness, and tachypnea [5]. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
References 1. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med. 2003;348:86–7. 2. Contou D, Fichet J, Grimaldi D, et al. Early life-threatening lactic acidosis following a single infusion of linezolid. Int J Antimicrob Agents. 2011;38:84–5. 3. De Vriese AS, Coster RV, Smet J, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis. 2006;42:1111–7. 4. Boutoille D, Grossi O, Depatureaux A, et al. Fatal lactic acidosis after prolonged linezolid exposure for treatment of multidrugresistant tuberculosis. Eur J Intern Med. 2009;20:e134–5. 5. Wiener M, Guo Y, Patel G, et al. Lactic acidosis after treatment with linezolid. Infection. 2007;35:278–81.
CORRESPONDENCE
Fatal lactic acidosis associated with linezolid therapy M. Djibre´ • T. Pham • M. Denis • V. Pras Landre M. Fartoukh
•
Received: 29 September 2014 / Accepted: 10 October 2014 / Published online: 19 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
To the Editor Linezolid is frequently used to treat infections related to a variety of Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Lactic acidosis associated with Linezolid therapy has been already reported, mostly with prolonged use, but this complication is a rare cause of death. We report herein a life-threatening lactic acidosis after 15 days of linezolid exposure. A 70-year-old man was admitted to the intensive care unit (ICU) of our hospital for a severe metabolic acidosis in December 2013. He had a past medical history of tobacco use, alcoholic liver cirrhosis, hypertension, coronary disease, iliac angioplasty stenting, and rheumatoid arthritis treated with steroids. Three months before ICU admission, he suffered a severe aortic stenosis-related acute pulmonary edema, and underwent a surgical valve replacement in November 2013. Cardiac surgery was complicated by the occurrence of atrial fibrillation, gastroduodenal bleeding ulcer, and ischemic colitis requiring a left colectomy. The patient was
M. Djibre´ (&) T. Pham M. Fartoukh AP-HP, Hoˆpital Tenon, Service de Re´animation me´dicochirurgicale, 75970 Paris, France e-mail: [email protected] T. Pham M. Fartoukh Sorbonne Universite´s, UPMC Univ Paris 06, Paris, France M. Denis AP-HP, Hoˆpital Tenon, Service de Maladies Infectieuses et Tropicales, 75970 Paris, France V. Pras Landre AP-HP, Centre Re´gional de Pharmacovigilance, Hoˆpital Saint Antoine, 75012 Paris, France
febrile during the postoperative period. A sternal wound sample yielded Enterococcus faecium and Enterobacter aerogenes, whereas Staphylococcus hominis and Staphylococcus haemolyticus were recovered in blood cultures. A trans-esophageal echocardiography ruled out endocarditis. Vancomycin and imipenem were administered for 8 days. Five days after antibiotics discontinuation, the patient had chills and became febrile up to 40 °C. A thoraco-abdominal CT scan showed ascites, of which culture remained negative. Vancomycin and imipenem were again administered for 20 further days for suspected sternal infection. On December 6, 2013, the patient was referred to the infectious disease ward of our hospital for persistent sepsis. There was a small dehiscence on the abdominal wound on physical examination, from which multidrug-resistant Enterobacter cloacae were isolated, while a blood culture was positive for normally susceptible Klebsiella pneumoniae. Laboratory tests showed hyperleukocytosis at 29.8 9 109 cell/L (N 4–10 9 109/L) with 24.4 9 109 polymorphonuclear neutrophils (N 1.5–7 9 109/L), hemoglobin 7.9 g/dL (N 12–18 g/dL), and platelet count 162 9 109 cell/L (N 150–400 9 109/L). Serum creatinine was 175 lmol/l (N 60–120 lmol/l), bicarbonate 16 mmol/ L (N 23–31 mmol/L) and anionic gap 17 mmol/L (N 7–17 mmol/l). Prothrombin time was 23 % (N 70–120 %), and serum bilirubin 24 lmol/l (N \ 17). Repeated trans-esophageal echocardiography and CT scan ruled out endocarditis as well as any intrathoracic or abdominal abscess. A thoracic F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET) suggested a sternal manubrium osteitis. Vancomycin was switched to intravenous linezolid on December 11, and rifampicin and ofloxacin were added on December 20, while imipenem was administered for treating Enterobacter cloacae and Klebsiella pneumoniae. Ongoing co-medications since
123
M. Djibre´ et al.
126 Table 1 Time course of laboratory tests results (reference range) Parameter
D-5
D0 Start of linezolid
D ? 9 D ? 15 ICU admission
D ? 16
pH
–
–
–
6.89
7.21
Serum bicarbonate (23–31 mmol/l)
16
19
14
8
7
Serum lactate (\2 mmol/l)
–
–
–
23
19
PaCO2 (mm Hg)
–
–
–
25
23
PaO2 (mm Hg)
–
–
–
117
128
ALT (7–31 UI/l)
88
44
7
20
916
AST (0–31 UI/l)
221
33
22
117
3,663
ALP (30–120 UI/l)
157
166
109
118
133
GGT (9–36 UI/l)
138
182
97
73
67
Tot Bili (\17 lmol/l)
24
29
26
114
134
PTI (70–120 %)
23
57
49
–
20
Serum creatinine (60–120 lmol/l)
175
129
115
161
136
Platelet count (150–400 9 109/ l)
162
195
155
49
76
PaCO2 partial pressure of arterial carbon dioxide, PaO2 partial pressure of arterial oxygen, ALT alanine aminotransferase, AST aspartate aminotransferase, ALP alkaline phosphatase, Tot Bili total bilirubin, GGT gamma-glutamyltransferase, PTI prothrombin time index, D: day, D0 refers to the day on which linezolid was started, D ? 15 refers to the day of admission to the ICU
December 11 included furosemide, amiodarone, esomeprazole, prednisone, aspirin, bromazepam, nefopam, bisoprolol and calcium heparin. On December 24, the patient started vomiting. He became drowsy and dyspneic and was admitted to our ICU on December 26. Glasgow Coma Scale was 8 of 15, blood pressure 117/47 mm Hg, heart rate 96 beats/min and temperature 33.4 °C. Physical examination revealed conjunctival jaundice, abundant ascites and lower limbs edema. There were no signs of poor peripheral perfusion. Laboratory tests on ICU admission showed severe lactic acidosis with pH 6.89, carbon dioxide partial pressure 24 mm Hg and lactate 23 mmol/l (Table 1). The patient was mechanically ventilated and received renal replacement therapy. Microbiological investigation (ascites, pleural effusion, blood, urinary and respiratory tract specimens) were negative. Empiric antimicrobial therapy associated vancomycin, imipenem and amikacin. Coloscopic and gastroscopic examinations were normal, except for a mild acute gastritis. The patient rapidly developed shock, atrioventricular block, and multiple organ failure, and died on December 27. A post-mortem examination confirmed liver cirrhosis and gastritis, but failed to identify any source of sepsis.
123
We report here a case of severe and fatal lactic acidosis after a 15-day linezolid exposure. A direct causal relationship of linezolid exposure in the occurrence of lactic acidosis may be assumed for the following reasons: (1) there were no other usual causes of lactic acidosis, such as septic shock or liver failure, as confirmed by complete microbiological investigation and post-mortem examination. Moreover, there was no history of use of metformin, nucleoside analogue or other drugs known to cause lactate acidosis; (2) lactic acidosis has already been described after linezolid exposure; [1] (3) exposure duration to linezolid is compatible since several cases have been published, with time ranging from 4 h after a single infusion to 120 days [2, 3]. The incidence of lactic acidosis complicating linezolid exposure is unknown. Only a few cases have been published in the literature. Linezolid inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit. Thus, lactic acidosis is thought to occur by a mechanism of mitochondrial toxicity [3]. In our patient, liver cirrhosis may have contributed to lactic acidosis, although there was no indication of acute liver failure at time of occurrence of severe lactic acidosis (Table 1). The severity of linezolid-induced lactic acidosis varies from asymptomatic form with only biological abnormalities, to life-threatening events and occasionally death [2–4]. Physicians should be aware of the possible occurrence of lactic acidosis related to linezolid exposure, as this complication may be a life-threatening metabolic emergency and requires discontinuation of the drug. This severe adverse effect should be suspected in patients treated with this drug and developing nausea and vomiting, tachycardia, altered mental status, asthenia, malaise, loss of vision, muscle weakness, and tachypnea [5]. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
References 1. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med. 2003;348:86–7. 2. Contou D, Fichet J, Grimaldi D, et al. Early life-threatening lactic acidosis following a single infusion of linezolid. Int J Antimicrob Agents. 2011;38:84–5. 3. De Vriese AS, Coster RV, Smet J, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis. 2006;42:1111–7. 4. Boutoille D, Grossi O, Depatureaux A, et al. Fatal lactic acidosis after prolonged linezolid exposure for treatment of multidrugresistant tuberculosis. Eur J Intern Med. 2009;20:e134–5. 5. Wiener M, Guo Y, Patel G, et al. Lactic acidosis after treatment with linezolid. Infection. 2007;35:278–81.
