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
Submitted by Steven Hung (@DocHungER), PGY-2
Faculty reviewed by Richard Griffey