Worse after antibiotics: Precipitating endotoxin release?

Clinical Scenario:

A middle-aged female patient presents to the emergency department stating she was diagnosed with a urinary tract infection (UTI) several days ago, but does not feel like her symptoms are improving with the ciprofloxacin and subsequent bactrim given.  She is currently complaining of nausea, vomiting, chills, back pain, and dysuria.  In triage, her vitals are normal (no fever, not tachycardic, normotensive).  On exam, she seems uncomfortable, but is fully alert and orientated and giving you her entire history.  You order a urinalysis with reflex culture, some fluids, and ceftriaxone to be given.

After 2 liters of fluid and the antibiotics, the nurse comes to tell you the patient is now not alert nor orientated, and hypotensive with systolic in the 70s.  She has no rash or wheezing and you don't think that is necessarily anaphylaxis. You look at her labs and see a white blood count of 22.  Her lactate returns at 16.  You pressure bag 3 more liters of NS into her, and on recheck her lactate has risen to 18!  She is intubated for airway protection and you find that her arterial pH is 6.52, with her bicarbonate on her basic metabolic panel below the detectable level (less than 5).  CT abdomen/pelvis without contrast (given creatinine greater than 10) revealed bilateral peri-nephric stranding, suggestive of pyelonephritis without a stone.

Clinical Question:

After she is transferred up the MICU, you wonder what had happened.  How did this woman, who came in talking to you, suddenly deteriorate so quickly?

Since most urinary tract infections in women are caused by E. coli, could it be that the treatment with antibiotics caused a lysis of gram negative cells and release a bolus of endotoxins into the circulatory system that caused circulatory collapse?

Literature review:

The idea of antibiotic therapy used in a rational manner can precipitate adverse reactions.  For example, the Jarisch-Herxheimer reaction with the treatment of syphilis with penicillin causes transient worsening of symptoms as the spirochetes are lysed.  With the high mortality and morbidity of sepsis, researches have been examining if certain antibiotics can precipitate circulatory collapse due to lysis of bacteria.

The lipopolysaccharide (LPS) found in gram negative bacteria cell walls has been implicated as mediating an inflammatory response from the body in gram negative sepsis.  LPS triggered inflammation weakens mitochondrial oxidative phosphorylation (which correlates well with high ScVO2 found in some septic patients).  The LPS also triggers a release of TNF-alpha and other cytokines such as IL-6 from macrophages contributing to septic shock from decreased myocardial contractile force and decreased systemic vascular resistance, which leads subsequently to hypotension.  Experimental models where TNF-alpha have been injected into animals have resulted in hypotension, metabolic acidosis, acute tubular necrosis, and ultimately death.

While endotoxins are constantly released into the blood stream during bacteria infection, causing patients to feel sick and become febrile, the administration of antibiotics has been shown to precipitate a large release of endotoxins due to lysis of bacteria.  Compared to bound endotoxin, free endotoxin may have up to 50 fold increase in activity. 

Not all antibiotics release endotoxins equally.  Certain beta-lactam antibiotics appear to liberate a greater amount of endotoxin compared to other antibiotics.  The mechanism of action is theorized to be the interaction of beta-lactam antibiotics with the penicillin-binding proteins (PBP) found in bacteria cell walls.  The inhibition of PBP3 specifically seems to cause a decrease in septum formation in dividing cells, causing long filaments to form.  This increase in biomass with subsequent lysis is theorized to be the cause large increase in endotoxin associated with antibiotics that bind specifically to PBP3.  In contrast, antibiotics that bind to PBP2 seem to form more spheroid cells with rapid lysis, leading to decreased endotoxin release.

Periti and colleagues found that aztreonam, piperacillin, ceftazidime, and cefuroxime seem to have high affinities to PBP3.  With increasing concentrations of these antibiotics, they start saturating other PBP sites, causing less filament formations, suggesting that the larger release of endotoxins associated with these antibiotics may be reduced with higher doses of antibiotics.  Ceftriaxone and cefepime appear to have equal affinities for many of the PBPs causing more spheroid cells and less endotoxin release.  Carbapenems such as imipenem and meropenem showed greatest affinity for PBP2.  Many studies have compared imipenem and ceftazidime, generally demonstrating higher release of endotoxin with ceftazidime therapy.  A study by Arditi and colleagues found that ceftriaxone induced a larger endotoxin release and subsequent TNF-alpha release when compared to imipenem, correlating with the theory that imipenem primarily with PBP2 while ceftriaxone has more equal affinity over all binding sites.  Goscinski and colleagues found that in E. coli treated with cefuroxime, there was higher release of endotoxin after the second dose, supporting the theory of filament formation with subsequent lysis.  They also found that the addition of tobramycin reduced the amount of endotoxin released.

Other antibiotics seem to release less endotoxin by various methods.  Polymyxin actually has a binding effect to endotoxins, inhibiting the biological activity of endotoxins.  Some antibiotics lead to the loss of viability in bacteria without lysis and release of endotoxins, such as quinolones.  Gentamicin, tobramycin, and amikacin have even been shown to neutralize the effects of endotoxins.

While studies have clearly shown a link between antibiotics and the release of endotoxins and the effect of endotoxins and cytokines in precipitating an inflammatory response as well as septic shock, it has remained to be seen if this correlates with clinical outcome.  There have been few prospective human studies into the administration of different antibiotics in the treatment of gram negative sepsis.  One pertinent randomized study by Prins and colleagues of urosepsis patients treated with imipenem compared to ceftazidime found a more rapid defervescence with the administration of imipenem.  Endotoxin and cytokine release also increased after administration of ceftazidime compared to no increase in the imipenem group.  However in other physiological measures and mortality, there were no differences between the two study groups.  Another study by Byl and colleagues examined again the difference between imipenem and ceftazidime in human septic patients.  While both antibiotics did appear to induce endotoxin release and increase cytokine production in a small number of patients, there did not seem to be a difference in the two groups.  Both studies found that the endotoxin rise only appreciably happened to a fraction of their study population that were septic. 

In a review by Holzheimer, he found that clinical significance of antibiotic-induced endotoxin release has only been documented in a few clinical disorders such as meningitis and urosepsis.  In a prospective study by Mignon and colleagues in septic patients in an ICU, there was no significant increase in endotoxin levels after initiation of empiric antibiotic therapy however there was clinical deterioration in 42% of patients 4 hours after antibiotic administration, which correlated with higher endotoxin levels when compared to stable septic patients.  Maskin and colleagues randomized 24 gram-negative septic patients between imipenem and ceftazidime.  All patients showed high levels of LPS, TNF-alpha, and IL-6 compared to controls.  TNF-alpha concentrations were higher in patients treated with ceftazidime compared to imipenem, however LPS and other cytokine production was not significantly different.  Many of these studies were limited by small sample sizes as well as sepsis caused by a wide variety of bacteria.

Severe sepsis is a difficult disease to deal with in the emergency department due to the uncertainty of source combined with the multiple comorbidities of the patient.  It requires fluid resuscitation as well as the quick administration of antibiotics.  While it seems that some antibiotics may precipitate circulatory collapse due to release of endotoxins and subsequent increased production of cytokines in a small subset of patients, there have been no large, randomized studies demonstrating a mortality difference in regard to selection of a specific antibiotic.

Take home points:

-Certain antibiotics cause a greater release of endotoxins and cytokines compared to others, possibly correlated with circulatory collapse

-No large, prospective studies have demonstrated an advantage to selecting certain class of antibiotics over another

  

References:

1. Arditi M, Kabat William, Yogev R. Anitibiotic-Induced Bacterial Killing Stimulates Tumor Necrosis Factor-alpha release in whole blood. J Infect Dis 1993;167:240-4.

2. Byl B, Clevenbergh P, Kentos A, Jacobs F, Marchant A, Vincent JL, Thys JP. Ceftazidime and Imipenem-Induced Endotoxin Release. Eur J Clin Microbiol Infect Dis 2001;20:804-807.

3. Goscinski G, Tano E, Lowdin E, Sjolin J. Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: higher release after the second dose. Journal of Antimicrobial Chemotherapy. 2007;60(2):328-333.

4. Holzheimer RG. Antibiotic Induced Endotoxin Release and Clinical Sepsis: a Review. Journal of Chemotherapy 2001;13:159-172.

5. Kirikae T, Nakano M, Morrison DC. Antibiotic-Induced Endotoxin Release from Bacteria and Its Clinical Significance. Microbiol Immuno 1997;41(4)285-294.

6. Lepper PM, Held TK, Schneider EM, Bolke E, Gerlach H, Trautmann M. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Medicine 2002;28:824-833.

7. Maskin B, Fontan PA, Spinedi EG, Gammella D, Badolati A. Evaluation of endotoxin release and cytokine production induced by antibiotics in patients with Gram-negative nosocomial pneumonia. Critical Care Medicine. 2002;30(2):349-354.

8. Mignon F, Piagnerelli M, Van Nuffelen M, Vincent JL. Effect of empiric antibiotic treatment on plasma endotoxin activity in septic patients.

9. Periti P, Mazzei T. New criteria for selecting the proper antimicrobial chemotherapy for severe sepsis and septic shock. International Journal of Antimicrobial Agents. 1999;12(2):97-105.

10. Prins JM, van Agtmael MA, Kuijper EJ, van Deventer SJ, Speelman P. Antibiotic-induced endotoxin release in patients with Gram-negative urosepsis: a double-blind study comparing imipenem and ceftazidime. J Infect Dis 1995. 172:886–891

Submitted by Steven Hung (@DocHungER), PGY-2

Faculty reviewed by Richard Griffey