NLM NIDDK Livertox Database

Livertox

DRUG RECORD

 

TETRACYCLINE AND OXYTETRACYCLINE

 

Tetracycline and oxytetracycline are indicated for therapy of mild to moderate infections due to susceptible organisms. High doses of several forms of tetracycline given intravenously have been associated with acute fatty liver that can be severe and result in liver failure and death. Oral tetracycline and oxytetracycline use has been rarely and not very convincingly linked to acute hepatic injury.

 

Background

Oxytetracycline is the natural product of Streptococcus rimosus and tetracycline a semisynthetic derivative of chlortetracycline. These agents have similar indications and are most frequently used for upper respiratory and skin and soft tissue infections. Chronic therapy with tetracycline is effective in ameliorating acne, but because of their better absorption and tissue penetration, minocycline and doxycycline have largely replaced tetracycline for this indication. Tetracycline and oxytetracycline are also active against infections with several rickettsial, spirochetal, chlamydial and mycoplasmas infections and are often used for therapy of non-specific urethritis and several Rickettsia diseases, such as Rocky Mountain spotted fever and Lyme disease. Both tetracycline and oxytetracycline are available in multiple generic forms as capsules or tablets of 250 and 500 mg and generally recommended in doses of 250-500 mg three to four times daily for 7 to 30 days. Chronic therapy is typical for therapy of acne. Pediatric formulations as oral suspension are also available. Parenteral tetracycline is no longer used. Tetracycline was FDA-approved in 1957 and currently 2 million prescriptions are filled yearly.

 

Hepatotoxicity

High doses of intravenous tetracycline can induce fatty liver disease and may result in severe hepatic dysfunction, acute liver failure and death. This syndrome is more common among pregnant women, largely during the last trimester or early post-partum period. However, instances of acute fatty liver attributed to intravenous tetracycline have been reported in non-pregnant women and in men and even in children. The injury is characterized by onset of weakness, fever, fatigue, nausea and abdominal pain after 3 to 10 days of therapy. Laboratory tests show minimal to moderate elevations in serum aminotransferase and alkaline phosphatase levels with mild jaundice, but presence of hyperammonemia and coagulopathy. Pancreatitis, renal dysfunction and lactic acidosis are also common, although not always specifically sought. The syndrome may be reversible if tetracycline is stopped promptly, but the syndrome is usually recognized late and can progress to multiorgan failure and death despite stopping the agent. This syndrome also occurs with high doses of intravenous doxycycline and minocycline. This syndrome is rarely seen currently as tetracycline is no longer available in parenteral form and the use of intravenous tetracyclines has been superseded by availability of safer, better tolerated and more effective broad-spectrum antibiotics.

Oral tetracycline has been associated with rare instances of acute liver injury but the association with tetracycline use as opposed to other agents being taken has not always been very well shown. Despite frequency of its use, oral tetracycline remains a very rare cause of liver injury. In contrast, cases of doxycycline and minocycline-induced liver disease are well described. Rare instances of acute fatty liver have been attributed to oral tetracycline particularly when given to pregnant women in high doses. Currently, tetracycline is considered to be inadvisable in pregnant women, particularly during the last trimester.

 

Mechanism of Injury

The hepatic injury from intravenous forms of tetracycline was likely due to mitochondrial injury due to inhibition of mitochondrial protein synthesis although another possibility is that tetracycline interferes with fat metabolism in hepatocytes. The injury is less idiosyncratic than direct, varying in frequency and severity based upon pharmacokinetics and host metabolic factors (age, pregnancy, drug-accumulation, and other factors affecting mitochondrial function). The rare idiosyncratic forms of liver injury from tetracycline are of unknown cause, but are likely to be immunoallergic.

 

Outcome and Management

Acute fatty liver due to tetracycline has a high fatality rate and is best managed with intensive care and attention to multiorgan support. Lactic acidosis should be treated with intravenous glucose (20% infusions) and bicarbonate. Idiosyncratic acute liver injury from tetracycline is rare and usually resolves rapidly once the agent is withdrawn. An instance of chronic cholestasis with vanishing bile duct syndrome has been reported, although the patient had received several medications that might have accounted for the hepatic injury.

References

References to tetracycline and oxytetracycline-induce liver injury are provided in the introductory overview section on the tetracyclines.

 

Drug Class: Tetracyclines

Other drugs within this class: Demeclocycline, Doxycycline, Minocycline

 

 

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Case 1. Liver failure from intravenous tetracycline.
[Modified from Robinson MJ, Rywlin AM. Tetracycline-associated fatty liver in the male. Report of an autopsied case. Am J Dig Dis 1970; 15: 857-62. PubMed Citation]

A 72 year old man treated for cystitis and diverticulitis with 10 days of iv tetracycline developed lactic acidosis and multi-organ failure. The patient had no previous history of liver disease or risk factors for hepatitis. When initially admitted to the hospital, he had fever, abdominal pain, leukocytosis and an abnormal urinalysis, but liver tests were normal (Table). He was treated with hydration and iv tetracycline in doses of 3 gm daily. His fever improved slowly but by day 4, liver tests were mildly abnormal and they had worsened by day 8. Colistin was added on day 6, and chloramphenicol was substituted for tetracycline on day 10. The following day, he developed progressive restlessness, stupor and respiratory failure. He had renal failure and severe acidosis and he died within hours of attempting resuscitation and dialysis. Autopsy showed an enlarged fatty liver with minimal inflammation and no obvious hepatocellular necrosis. Fat was also identified in renal tubular cells. There was marked ascites and hemorrhagic pancreatitis.

 

Key Points

 

Medication:	Tetracycline (3 g iv daily for 10 days)
Pattern:	Hepatocellular
Severity:	5+ (Death from hepatic failure and lactic acidosis)
Latency:	4 Days
Recovery:	Fatal
Other medications:	Colistin and chloramphenicol (after onset of liver injury)

 

Laboratory Values

 

Days After Starting	Days After Stopping	ALT (U/L)	Alk P (U/L)	Bilirubin (mg/dL)	Other
0		32	8	0.3	Started iv tetracycline
4		190	10	2.4	BUN 39 mg/dL
8		530	11.5	2.2	Colistin added im q 12 hr
10		Tetracycline stopped; chloramphenicol started.
11	1	1550	15	6.8	BUN 105; CO2 11 mEq/L
Increasing stupor and respiratory failure, hemodialysis and resuscitative measures failed.
Normal Values		<40	<13

 

* King Armstrong units

 

Comment

Acute fatty liver caused by tetracycline was initially thought to occur only in pregnant women during the last trimester, but was subsequently reported to occur at other times during pregnancy, after delivery, in non-pregnant women, in men and even in children. The syndrome typically occurs after 3 to 10 days of relatively high doses of im or iv tetracycline. The case above is typical in demonstrating that the precipitous onset of symptoms is a late phenomenon and has a grim prognosis; symptoms are preceded by several days of worsening liver injury, although laboratory tests may be only mildly or moderately abnormal. Acute fatty liver is accompanied by minimal hepatic inflammation and liver cell necrosis and is a syndrome of mark mitochondrial failure, early appearance of hepatic synthetic dysfunction and lack of ATP to drive normal metabolism. The injury is not confined to the liver and renal failure and pancreatitis are common. As in this case, the immediate cause of death is typically multiorgan failure due to lactic acidosis or pancreatitis.

 

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REPRESENTATIVE TRADE NAMES
Oxytetracycline – Terramycin®, Urobiotic®
Tetracycline – Sumycin®

DRUG CLASS
Anti-Infective Agents

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH
Terramycin® (oxytetracycline hydrochloride) Product Labeling, Pfizer Labs.
Tetracycline (tetracycline hydrochloride) Product Labeling, Barr Laboratories.

 

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Oxytetracycline Hydrochloride	2058-46-0	C22-H24-N2-O9.Cl-H
Tetracycline Hydrochloride	64-75-5	C22-H24-N2-O8.Cl-H

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1. Recent References on Tetracycline and Oxytetracycline

2. Trials on Tetracycline and Oxytetracycline

3. TOXLINE Citations on Tetracycline and Oxytetracycline

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