Chiefs’ Inquiry Corner – 2/14/22

February 14, 2022

Chief residents of the NYU Langone Internal Medicine Residency give quick-and-easy, evidence-based answers to interesting questions posed by house staff, both in their clinics and on the wards.

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 Linezolid is a synthetic antibiotic that belongs to the oxazolidinone class and has broad bactericidal activity against gram positive organisms (e.g., enterococci and staphylococci, as well as most streptococci) in addition to moderate activity against Mycobacterium tuberculosis. Its mechanism of action involves inhibition of the formation of the ribosomal 70s unit, which subsequently blocks bacterial protein synthesis. Its use is typically reserved for severe infections involving multidrug resistant pathogens, such as methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococcal infections.  Linezolid therapy has been associated with mild and transient elevations in serum transaminase and alkaline phosphatase levels in anywhere from 1-10% of patients, although the precise mechanisms of these enzyme elevations have not been elucidated and there is still the distinct possibility that it has more to do with the underlying condition than actual hepatic injury caused by linezolid. More frequently, linezolid has been associated with lactic acidosis that is generally seen after 1-8 weeks of therapy and is sometimes associated with evidence of hepatic injury and jaundice. This is thought to be a result of injury to and dysfunction of hepatic mitochondria (theorized to be due to inhibition of mitochondrial ribosomal function that parallels the known effect on bacterial ribosomal function), with subsequent microvesicular steatosis and resultant disturbances in hepatic function; this may or may not be accompanied by jaundice and/or serum transaminase and alkaline phosphatase elevations. Mitochondrial damage by linezolid also underlies the other serious side effects associated with this medication including peripheral and optic neuropathy, pancreatitis, serotonin syndrome, and nephrotoxicity.  Risk factors for developing lactic acidosis from linezolid include higher doses, prolonged courses of therapy, and concomitant chronic liver or renal disease. The lactic acidosis, even if severe, often resolves quickly with discontinuation of the antibiotic, although it should be noted that rarely, this lactic acidosis may be fatal. Optic and peripheral neuropathy due to linezolid resolve more slowly with discontinuation of the drug, and can be permanent.

References: Linezolid-Liver Toxicity
   The antibiotic vancomycin can cause two types of hypersensitivity reactions: anaphylaxis, and an anaphylactoid reaction known as ‘red man syndrome.’  Clinically, red man syndrome presents as pruritis and an erythematous rash that involves the face, neck, and upper torso. Hypotension and angioedema can occur, although less frequently. Patients commonly report diffuse burning and itching, or a generalized sense of discomfort. Some may even experience dizziness, agitation, headache, chills, fever, and perioral paresthesias. In severe cases, chest pain and dyspnea can occur. Signs of red man syndrome can appear as early as 4-10 minutes after initiation of infusion of vancomycin, or can begin soon after the infusion is complete. It is often associated with rapid (<1 hour) infusion of the first dose of vancomycin, and thus most hospital protocols require vancomycin to be infused over 60 minutes at a minimum.  Initially, red man syndrome was thought to result from impurities in vancomycin preparations (leading to the less-than-flattering nickname of ‘Mississippi mud’). However, reports of the syndrome persisted even after improvements were made to the drug’s purity. It is now known that vancomycin causes degranulation of mast cells and basophils, resulting in IgE-independent histamine release. The extent of histamine release is thought to be related at least partly to the amount and rate of the vancomycin infusion. Interestingly, antibiotics such as ciprofloxacin, amphotericinB, and rifampin are also capable of causing direct degranulation of mast cells and basophils, implicating them as possible additional causes of red man syndrome and increasing the risk of this reaction if administered together or with vancomycin. Opioid analgesics, muscle relaxants, and contrast dye can all also stimulate histamine release and can further increase the risk of red man syndrome in patients also receiving vancomycin. If a patient experiences red man syndrome, the vancomycin infusion should be discontinued immediately and the patient should be given diphenhydramine 50mg intravenously or orally. Once the rash and itching resolve, the infusion can be resumed at a lower rate and/or with reduced dosage.

References: Red man syndrome
Stool cultures are frequently ordered indiscriminately in patients presenting with acute diarrhea. However, this is both inefficient and costly; results are positive in an estimated 1.6-5.6% of cases, and cost anywhere from $900-$1200 per positive stool culture.  Nonetheless, there are no established guidelines on which patients require a stool culture. Generally, it is reasonable to send this test of patients with grossly bloody stool, severe dehydration, signs of inflammatory disease, symptoms lasting more than several days, or a history of immunosuppression. Studies have shown that obtaining stool cultures in patients only whose stools test positive for leukocytes first as a screening test decreases the cost to $150 per positive culture. Similarly, obtaining cultures only in patients with grossly bloody stools increases the yield for positive culture results to >30%. In the hospital setting, stool cultures have limited utility if obtained for patients whose diarrhea started at least three days after admission (obtaining C. diff studies may be more useful) but are still useful if there is a known nosocomial outbreak, if the patient has a history of immunosuppression, or if the patient is >65 years old and has a significant comorbidity (such as severe or end-stage liver, renal, or pulmonary disease, or inflammatory bowel disease).

References: Acute Diarrhea in Adults