Question 30

You are looking after a 54 year old man post cadaveric liver transplantation with impaired graft function and failure to progress. A large subhepatic bile collection was drained percutaneously on day 7 when he was started on piperacillin-tazobactam. Culture of the drain fluid reveals heavy growth of Enterococcus spp.

What activity does piperacillin have against Enterococcus spp?
The Provisional report is that the Enterococcus is resistant to Vancomycin. List 3 antibiotics would you consider in this situation.
What are the main toxicities of each of the antibiotics you have listed in your answer to b)?
Which antibiotic would you select, and why?

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College Answer

a) Piperacillin:

Piperacillin activity is similar to penicillin, and less than that of ampicillin. Enterococci are relatively penicillin resistant; E. faecium is more resistant than E. faecalis. Most VRE have high-level resistance to β-lactams (and aminoglycosides).

b) Antibiotics:

The main options would be:

teicoplanin
linezolid
tigecycline
daptomycin
ceftaroline (E.faecalis not faecium)

c) Main toxicities of each of the antibiotics:

Teicoplanin: relatively little toxicity, less than vancomycin; thrombocytopenia, anaemia, renal or hepatic dysfunction
Linezolid: mitochondrial toxin, hence thrombocytopenia, anaemia, peripheral or ocular neuropathy, lactic acidosis, serotonin syndrome
Tigecycline: nausea & vomiting; teratogenic; catabolic, FDA reports increased risk of death in HAP or VAP compared to alternative treatments
Daptomycin: myopathy
Ceftaroline: no significant toxicity

d) Antibiotic:

A reasoned answer is required. Linezolid may be preferred over teicoplanin due to its greater efficacy and better tissue penetration (it is poorly protein bound, so volume of distribution approximates to total body water). No dosage reduction is necessary in renal or hepatic failure. Van A resistance is common in Australia, so many VRE are teicoplanin resistant. Tigecycline and daptomycin generally regarded as third line drugs. Ceftaroline new to practice and limited experience to date.

Discussion

VRE seems to be a topic favoured by the CICM examiners.

This bunch of cocci were previously known as Group D streptococci. They are not particularly pathogenic, but their intrinsic resistance to antibiotics makes them interesting to the intensivist.

a) Enterococci have intrinsic resistance to β-lactam antibiotics due to the low affinity of their penicillin-binding proteins for penicillin. Interestingly, piperacillin has approximately the same activity as benzylpenicillin against these enterococci; ticarcillin and cephalosporins have about four times less activity, and are thus essentially useless.

b) Antibiotic choices and their toxicities

Antibiotic	Toxicity
Teicoplanin	Thrombocytopenia Rarely, red man syndrome Rarely, nephrotoxicity
Linezolid	Thrombocytopenia Lactic acidosis (inhibition of mitochondrial protein synthesis) Serotonin syndrome Peripheral neuropathy Optic neuropathy
Daptomycin	Myopathy, with raised CK Nephrotoxicity
Tigecycline	Nausea and vomiting were the most commonly reported side effects, and organ toxicity seems to be mild. The college answer mentions a certain FDA warning about using tigecycline in hospital-acquired pneumonia, especially VAP. This is based on a mortality difference of 1%; but it was an increase from 3.0% to 4.0%, which is a 25% increase in relative risk of death.
Ceftaroline	Little is known about the toxicity of ceftaroline, because infectious diseases physicians reserve it for the most dire of circumstances, and thus nobody has had much of a chance to use it. The studies say that it "demonstrated a safety profile similar to that of comparator drugs". A notable weirdness is the sudden emergence of a positive Coombs test during treatment, which did not evolve into haemolytic anaemia.

As to this specific biliary sepsis patient? Their collection is VRE infected, and one needs a drug with good tissue penetration. The college have chosen linezolid.

References

Hollenbeck, Brian L., and Louis B. Rice. "Intrinsic and acquired resistance mechanisms in enterococcus." Virulence 3.5 (2012): 421-433.

Kaye, Donald. "Enterococci: biologic and epidemiologic characteristics and in vitro susceptibility." Archives of Internal Medicine 142.11 (1982): 2006-2009.

Wilson, A. P. R. "Comparative safety of teicoplanin and vancomycin."International journal of antimicrobial agents 10.2 (1998): 143-152.

Lawrence, Kenneth R., May Adra, and P. Ken Gillman. "Serotonin toxicity associated with the use of linezolid: a review of postmarketing data." Clinical infectious diseases 42.11 (2006): 1578-1583.

Attassi, Kinan, et al. "Thrombocytopenia associated with linezolid therapy."Clinical infectious diseases 34.5 (2002): 695-698.

Bressler, Adam M., et al. "Peripheral neuropathy associated with prolonged use of linezolid." The Lancet infectious diseases 4.8 (2004): 528-531.

Rucker, Janet C., et al. "Linezolid-associated toxic optic neuropathy."Neurology 66.4 (2006): 595-598.

Vinh, Donald C., and Ethan Rubinstein. "Linezolid: a review of safety and tolerability." Journal of Infection 59 (2009): S59-S74.

Arbeit, Robert D., et al. "The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections." Clinical Infectious Diseases38.12 (2004): 1673-1681.

Raja, Aarti, et al. "Daptomycin." Nature Reviews Drug Discovery 2.12 (2003): 943-944.

Stein, Gary E., and William A. Craig. "Tigecycline: a critical analysis." Clinical infectious diseases 43.4 (2006): 518-524.

Stein, Gary E., and Timothy Babinchak. "Tigecycline: an update." Diagnostic microbiology and infectious disease 75.4 (2013): 331-336.

Saravolatz, Louis D., Gary E. Stein, and Leonard B. Johnson. "Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus." Clinical infectious diseases 52.9 (2011): 1156-1163.

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