Use of Serum Drug Concentration Monitoring During the Treatment of Severe Rifampicin and Ethambutol Poisoning: A Case Report

doi:10.21203/rs.3.rs-952481/v1

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Case Report

Use of Serum Drug Concentration Monitoring During the Treatment of Severe Rifampicin and Ethambutol Poisoning: A Case Report

https://doi.org/10.21203/rs.3.rs-952481/v1

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Background: Despite rifampicin and ethambutol being widely used to treat patients with tuberculosis, reports of potentially lethal overdoses of these drugs are rare. The toxic effects of rifampicin become apparent at doses of 9–12 g, and become potentially fatal at doses over 14 g.

Case presentation: We describe a case of severe rifampicin (18 g) and ethambutol (25 g) poisoning that was successfully managed using hemoperfusion (HP) and hemodiafiltration (HDF) in conjunction with serum blood drug concentration monitoring. A 57-year-old female was rushed to the emergency room of Shenzhen Third People's Hospital (China) 4 hours after she ingested 120 tablets of rifampicin (18 g) and 100 tablets of ethambutol (25 g). After emergency symptom treatment, she was transferred to a ward where she presented in an irritable state, with orange–red skin and mucus membrane discoloration and slight yellowing of the sclera. The patient’s serum levels of rifampicin (177.2 mg/L), desacetylrifampicin (194.40 mg/L), and ethambutol (13.44 mg/L) were determined. After three cycles of HP and HDF, her serum drug levels had declined to within a normal range, and the color of her skin and mucosa gradually returned to normal. She was discharged from the hospital after a 4-day stay. Ten days after discharge, her follow-up bloodwork indicated normal liver and kidney functioning.

Conclusions: HDF and HP are effective at clearing toxic levels of rifampicin. Serum drug concentration monitoring helps accurately guide drug poisoning treatment.

Infectious Diseases

Serum drug concentration monitoring

rifampicin

ethambutol

poisoning

treatment.

Rifampicin and ethambutol are widely used in the treatment of tuberculosis. The normal oral dose of rifampicin is 0.45–0.6 g/day, with toxic effects presenting if 9–12-g doses are administered; fatalities may occur at doses in excess of 14 g [1, 2]. However, reports of rifampicin and ethambutol poisoning are rare. The few published case reports have shown that acute rifampicin poisoning often results in tonic-clonic seizures, altered sensorium, renal and hepatic dysfunction, severe metabolic acidosis, and red man syndrome (red color associated with the skin, mucous membranes, urine, feces, sweat, and tears) [3]. Overdoses of ethambutol may be associated with neuropathy [4]. There are no effective antidotes for rifampicin and ethambutol poisoning, but supportive measures include gastric lavage, metabolic acidosis correction, diuresis, hemodiafiltration (HDF), and hemoperfusion (HP) [5]. However, few reports have documented the utility of serum drug concentration monitoring. We report a patient who consumed a lethal dose of rifampicin and ethambutol, and underwent treatment that involved effect serum drug concentration monitoring.

A 57-year-old woman was admitted to Shenzhen (China) Third People's Hospital on May 24, 2021, 4 hours after she had taken large doses of rifampicin and ethambutol. The patient had a history of diabetes, but no prior history of mental illness.

One month before admission, she underwent chest radiography due to the presence of a persistent cough and shortness of breath; the X-ray showed right pleural effusion. The patient was diagnosed with tuberculous pleurisy following detection of Mycobacterium tuberculosis in her pleural effusion. Isoniazid, rifampicin, ethambutol, and pyrazinamide were prescribed as her anti-tuberculosis treatment. During the treatment period, the patient's husband abandoned her to the care of her family. Moreover, the patient's pregnant daughter was worried about the possible spread of tuberculosis, and rarely cared for the patient. The patient felt abandoned by her relatives and determined to commit suicide. Four hours before her admission, the patient consumed 120 rifampicin tablets (18 g) and 100 ethambutol tablets (25 g). She was rushed to our emergency room for treatment.

Upon admission, the patient’s body temperature was 36.3℃, her pulse was 115 bpm, and her blood pressure was 175/86 mmHg. She was conscious, irritable, had orange–red discoloration of the skin and mucous membranes, and demonstrated slight yellow discoloration of the sclera; she did not demonstrate pain during percussion of the areas around her liver and kidneys. A biochemical examination showed a total bilirubin level of 30.2 µmol/L and a blood potassium level of 2.5 mmol/L. After gastric lavage, fluid replacement, and other symptomatic treatments, she was transferred to the ward.

After transferring to the ward, a serum drug concentration screen was conducted for rifampicin (177.2 mg/L), desacetylrifampicin (DRFP, 194.40 mg/L), and ethambutol (13.44 mg/L). Further blood work revealed her white blood cell count (12.31 × 10⁹/L), D-dimer concentration (1.79 µg/mL), total bilirubin level (48.6 µmol/L), unconjugated bilirubin level (47.7 µmol/L), lactic acid concentration (5.9 mmol/L), and serum potassium level (2.93 mmol/L). The laboratory results, combined with her medical history, resulted in a diagnosis of rifampicin and ethambutol poisoning, tuberculous pleurisy, hypertension, and hypokalemia.

The patient was treated with HP, HDF, and intravenous infusion of glutathione and adenosine methionine. Daily samples were collected to monitor changes in her routine bloodwork parameters, coagulation function, and liver and kidney function (Table 1, Figure 1). Her serum drug concentrations were measured at multiple points after HP and HDF. After three cycles (27 hours) of HP and HDF, the serum drug concentrations had decreased to within a normal range (Table 2). Furthermore, the patient’s vital signs stabilized, her spirit and appetite recovered, the color of her skin and mucosa returned to normal, the yellow discoloration of her sclera resolved, and her bilirubin and lactic acid levels decreased. As her renal function and blood coagulation functions had normalized, she was discharged after 4 days. Ten days after discharge, her routine bloodwork and liver and kidney function re-examinations were completely normal (Table 1).

Table 1

Laboratory results in every timepoints.
Characteristic	Timepoints from poisoning
Characteristic	4 hours	11 hours	27 hours	51 hours	75 hours	14 days
Leukocyte (×10⁹/L)	7.16	12.31	8.93	6.37	4.83	7.40
D-dimmer (µg/ml)		1.79			1.31
Lactate (mmol/L)	2.37	5.9	1.8	1.6	1.6
Liver function
Total bilirubin (µmol/L)	30.2	48.6	54.1	11.4	4.3	8.8
Conjugated bilirubin (µmol/L)		0	4.4	3.2	2.5	2.6
Unconjugated bilirubin (µmol/L)		47.7	44.5	8.2	1.8	6.2
ALT (U/L)	21.9	19.1	32.9	39	67	16.4
AST (U/L)	30.6	33.3	27.9	41	80	30.6
GGT (U/L)	31.8	31	28.5	23	26
ALP (U/L)		97	103	104	94
Renal function
Urea nitrogen (mmol/L)	3.95	3.33	0.82	1.76	1.56	4.05
Serum creatinine (µmol/L)	38.0	<13.3	22.1	44	50	50.1
GFR (ml/min)				107.6	103.17
Electrolyte
Potassium (mmol/L)	2.5	2.93	4.07	3.85	3.05
Sodium (mmol/L)	139	145.7	141.5	137	137
Chlorine (mmol/L)	107	102.2	108	102.2	99.5
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Glutamyl transpeptidase; ALP: Alkaline phosphatase; GFR: Glomerular filtration rate

Table 2

The medicine concentration in different timepoints.
Timepoints after poisoning	Samples	Medicine concentration
Timepoints after poisoning	Samples	Rifampicin (mg/L)	Ethambutol (mg/L)	Deacetylrifampicin (mg/L)
11 hours (before HP/HDF)	Serum	177.2	13.44	194.4
13 hours (2 hours after HP)	Serum	103.5	7.29	104.5
17 hours (4 hours after HDF)	Serum	55.33	5.63	69.5
29 hours	Serum	19.8	3.57	30.9
41 hours	Serum	6.32	2.24	4.37
53 hours	Serum	2.45	1.37	1.21
65 hours	Serum	0.32	1.08	0.07
77 hours	Serum	0.1	0.64	0.03
101 hours	Serum	0.06	0.46	Undetected

This case describes the successful treatment of a patient who had consumed lethal doses of rifampicin and ethambutol. The treatment involved HP and HDF in conjunction with serum drug concentration monitoring. HP and HDF were effective at clearing the rifampicin and ethambutol from her blood. The monitoring of serum drug concentrations directly and sensitively reflected the changing drug concentrations in circulation and guided the formulation and adjustment of the treatment.

Toxic doses of rifampicin can lead to metabolic acidosis, convulsions, thrombocytopenia, cholestatic jaundice, oliguric renal failure, and red man syndrome [3]. The present patient consumed 18 g of rifampicin and developed characteristic orange-red discoloration of the skin and mucosal membranes, yellow discoloration of the sclera, progressive increases in bilirubin levels within a short period, and increased blood lactic acid levels. Although emergency measures (e.g., gastric lavage and rehydration) were taken early in the patient’s treatment, the rifampicin blood concentration remained grossly elevated and the bilirubin concentration was twice its normal level. After 16–18 hours of blood purification, the rifampicin serum drug concentration had decreased to a safe level, but the patient’s bilirubin level continued rising. Thus, the serum drug concentration not only reflected the severity of the drug poisoning, but also reflected the drug’s clearance in real time.

At present, there are different views on the timing of blood purification after poisoning. Some advocate performing HP based on the clinical situation, especially when the patient's condition continues to deteriorate after intensive supportive treatment [6]. Others advocate performing HP immediately. The former method may delay the best treatment. Hence, injuries to the liver, kidney, and other organs may occur before HP, resulting in injuries that may be difficult to reverse. The latter treatment method lacks objective evidence for developing and adjusting the treatment scheme. Serum drug concentration monitoring can directly and sensitively reflect the drug concentration in circulation and its clearance, allowing further interventions to be employed before severe functional organ damage occurs. This approach is conducive to controlling the starting and ending points of blood purification, and helps guide adjustments to the treatment plan. Thus, serum drug concentration monitoring helps to protect organ function, reduces organ damage, prevents or minimizes sequelae, and reduces patient medical expenses.

Rifampicin is highly bound to plasma proteins, and the maximum serum concentration of the free drug, as well as its area under the drug concentration–time curve, accounts for only 10–20% of the total drug concentration [7]. In our patient, 2 hours of HP resulted in the rifampicin plasma concentration decreasing from 177.2 mg/L to 103.5 mg/L, a decrease of 41.6%. This result confirmed that HP is an effective method for removing macromolecular substances that are easily bound to proteins, consistent with previous reports [8]. Rifampicin is generally believed to not be significantly cleared by HDF due to the molecule’s large molecular weight, tissue distribution, and high protein binding (80%) [3]. The median HDF clearance rate is reportedly only 40 mL/min, which is not significant [9]. However, in our case, HDF filtration was performed after HP, further reducing the rifampicin plasma concentration from 103.5 mg/L to 55.327 mg/L (a further decrease of 46.5%). This good clearance seems inconsistent with the reported poor efficacy of rifampicin clearance by HDF.

To explore the cause of the efficacy of rifampicin clearance using HDF, we also observed the clearance of DRFP [10, 11], a deacetylated metabolite of rifampicin. The concentration of DRFP in our patient, before blood purification, was higher than that of rifampicin at that time. However, the concentration of DRFP decreased to 104.5 mg/L after 2 hours of HP and to 69.5mg/L after 4 hours of HDF treatment, confirming that HP and HDF have significant effects on the clearance of DRFP. The bioavailability of rifampicin is reported to increase in a nonlinear manner, probably due to the saturation of the first-pass metabolism in the liver [12, 13]. Boeree et al. [8] evaluated the use of high-dose rifampicin and found that rifampicin exposure increased almost 10-fold as the dose was increased from 10 to 35 mg/kg. This phenomenon may be due to saturation of the biliary and hepatic excretion pathways [14, 15].

Our patient’s serum rifampicin concentration had significantly increased within 18 hours after admission, and the concentration of DRFP was higher than that of rifampicin. We speculate that the rifampicin deacetylation and biliary excretion mechanisms were both saturated. HP and HDF cleared large amounts of DRFP, promoting rifampicin deacetylation. Therefore, under normal circumstances, the clearance of rifampicin by dialysis is inefficient, but when toxic doses of rifampicin are taken, the effect of HDF is significant.

The effect of HDF on ethambutol clearance remains controversial. Previous studies have reported that ethambutol is 20–30% protein bound, facilitating effective HDF clearance [6, 16]. However, on study also reported that HDF clearance of ethambutol is insufficient [8]. Our patient orally consumed 25 g of ethambutol, and after 6 hours of blood purification (2 hours of HP and 4 hours of HDF), the blood concentration had decreased from 13.44 mg/L to 5.63 mg/L (a decrease of 58.1%), confirming its effective clearance. After 2 hours of HP, the serum drug concentration had decreased from 13.44 mg/L to 7.29 mg/L (a decrease of 45.76%). After 4 hours of HDF, the serum drug concentration had decreased from 7.29 mg/L to 5.63 mg/L (a further decrease of 22.77%). We speculated that the HDF clearance rate is lower than that of HP, and is mainly related to the elimination of a large proportion of the drug before HDF was employed.

In summary, we reported a case involving the consumption of toxic doses of rifampicin and ethambutol and demonstrated both HDF and HP demonstrated good clearance effects in high-dose rifampicin poisoning. Moreover, serum drug concentration monitoring can accurately guide drug poisoning treatment plans.

HP, hemoperfusion; HDF, hemodiafiltration; DRFP, desacetylrifampicin.

Ethics approval and consent to participate

This study was approved by the Ethical Committee of the Shenzhen Third People's Hospital, and each participating patient provided written informed consent; and the patient’s informed consent for publication of the case was obtained.

Consent for publication

The patient’s guardian signed the written consent to publish the medical data and images.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

This research supported by Shenzhen Fund for Guangdong Provincial High- level Clinical Key Specialties (No. SZGSP: 010).

Author Contributions

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Acknowledgements

We would like to thank the patient for his participation in this study.

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Use of Serum Drug Concentration Monitoring During the Treatment of Severe Rifampicin and Ethambutol Poisoning: A Case Report

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