Infectious Disease

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
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

Pediatrics: Refusal to use arm

Clinical Scenario:
A 5 week old infant presented to the Emergency Department (ED) with refusal to move right arm for the past 3 days. No significant past medical history; the pregnancy was uncomplicated, and born via Cesarian-section due to failure to descend at full term at 40 weeks.  The patient has otherwise been feeding well and moving all of his other extremities. No history of trauma or fever. The arm and shoulder have no erythema, no swelling, however the patient screams in pain whenever you move the arm. 

X-rays of the right shoulder and entire right arm were unremarkable. Laboratory tests demonstrated a slightly elevated white blood cell count (WBC), however the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were both elevated.  You admit the patient for further work up.  The following day (actually a few hours later since was a late admission) the patient underwent a sedated MRI, which revealed humeral osteomyelitis with associated septic arthritis.

Clinical Question:
What are common causes of osteomyelitis/septic arthritis in a newborn?  What is the best tests/imaging to diagnose it?

Literature review:
Osteomyelitis can cause significant morbidity and mortality in a neonate/infant and can be difficult to diagnose.  In one small study, Wong and colleagues found that only 10 of the 30 babies studied demonstrated any systemic signs of infection, such as fever.  This study also found that more than half of the infants affected were born pre-term, and 70% of the patients with osteomyelitis had extended contact with the healthcare system (eg prolonged stay in the hospital).

A review by Montgomery and colleagues found that Staphylococcus aureus (S. aureus), to be the most common cause of osteomyelitis, with cases of Methicillin resistant S. aureus rising nationally.  In infants and children specifically, other common bacteria causing osteomyelitis are Group B Streptococcus, Ecsherichia coli, Kingella kingae usually spread hematogenously.

In a review of septic arthritis with concomitant adjacent osteomyelitis, such as this particular case, it was found that the shoulder was the most likely of all the joints (elbows, hips, knees, ankle) to be infected, as it was in this patient.  S. aureus again was the most common organism to cause a simultaneous osteomyelitis with associated septic arthritis.

In osteomyelitis, the WBC is often not a sensitive marker. One study in the journal of Pediatrics found that only 35% of children with osteomyelitis had an elevated WBC.  In contrast, ESR and CRP elevations were more sensitive, at 92% and 98% respectively.  Combined together, ESR and CRP offered the greatest sensitivity in detecting osteomyelitis.  After initiation of treatment, the ESR usually normalized within 24 days and the CRP in 10 days.

The recommended imaging modality for acute osteoarticular infections is magnetic resonance imaging (MRI) with contrast given the superior imaging it provides of bone as well as the soft tissues when compared to other imaging modalities.  In follow up after treatment, positron emission tomography (PET) or commuted tomography appears to be better imaging modalities. 

Take home points:
-Osteomyelitis/septic arthritis needs a high degree of suspicion for diagnosis given paucity of other symptoms such as fever.
-WBC can be normal, ESR and CRP together are more sensitive.
-Patients can have no other symptoms besides from joint pain.
-Preferred imaging is MRI with contrast.

1. Montgomery NI, Rosenfeld S. Pediatric Osteoarticular Infection Update. J. Pediatr Orthop. 2014.
2. Unkila-Kallio L, Kallio MJ, Eskola J, Peltola H. Serum C-reactive protein, erythrocyte sedimentation rate, and white blood cell count in acute hematogenous osteomyelitis of children. Pediatrics. 1994;93(1):59
3. Wong M, Isaacs D, Howman-Giles R, Uren R. Clinical and diagnostic features of osteomyelitis occurring in the first three months of life. Pediatr Infect Dis J. 1995;14(12):1047-53

Submitted by Steven Hung (@DocHungER), PGY-2
Faculty reviewed by Joan Noelker

Antibiotics for Mandible Fractures?

Clinical Scenario:

You’re working a busy Saturday overnight, and the traumas are rolling in. You’ve just finished packaging up your patient with an abdominal GSW for the OR, and they’re bringing back a new patient before the stretcher is even flipped over. He’s a 25 year-old male, presenting to the ED after being in an altercation with some friends of friends. He was hit in the face during the fistfight. He is complaining of left-sided jaw pain and facial swelling. He is able to open his jaw to a reasonable degree, but uncomfortably. There is no apparent intra-oral injury. CT max/face shows multiple minimally-displaced fractures of the left mandibular ramus and paramental region.

Luckily for you the ENT consult resident is still in the department from seeing your last patient with a complicated ear lac. She evaluates the patient with her senior and looks over the images. The patient will need surgical repair, but is OK for discharge with close pre-op follow-up next week. They recommend mouthwash, nasal spray, analgesia, and antibiotics.

Clinical question:

When are prophylactic antibiotics indicated in mandibular fractures, and how effective are they are preventing infection?

3D CT recon of minimally-displaced mandible fractures. Image from MD Consult.

Literature review:

The use of antibiotics for mandible fractures has been common practice for some time, based on the assumption that such fractures are at high risk of infection due to contamination with oral flora. However, like many dogmatic practices, it appears the initial evidence upon which the “standard practice” is based is sorely lacking [1]. 

A recent systematic review of 31 studies including a total of 5,437 patients published in the Journal of Oral and Maxillofacial Surgery in 2011 found that the overall evidence to support the use of prophylactic antibiotics in mandible fractures is of poor quality [1]. Only 9 of the included studies were RCTs, including 974 patients. The study author laments numerous methodological shortcomings of these RCTs – all had relatively small cohort sizes, none included power calculations, 7/9 RCTs did not describe randomization method, none reported allocation concealment, only one study reported an intention-to-treat analysis, and none reported NNT figures. 

The author found it impossible to perform any quantitative analysis due to heterogeny of study design and poor quality of included studies. For example: only 10/31 studies included information on time from injury to operative management, 13/31 studies did not describe the type of antibiotic used, half of studies did not describe route of administration of duration of course, and 23/31 studies did not report dose of antibiotic used! Significant heterogeny was also found between the types of fractures included, the types of surgical repairs performed, and the types of antibiotic used.

Five of the 9 included RCTs concluded that antibiotics were effective in preventing infection. However, the rates of infections varied widely between included studies – from 4.5-62% in untreated groups and 1.9-29% in treated groups, limiting applicability of those conclusions.

The study author reports that there may be some signal indicating antibiotics are superior to nothing in terms of preventing infection, but concludes:

“Even then, we are not sure which antibiotic to use, we do not know best route of administration, we are not confident about duration of course, and we have very limited information about the optimal dosage. Even worse, we do not have the slightest idea about how many patients we need to treat with prophylactic antibiotics to prevent a complication, and there is no clue about how much this costs the health care spectrum. Therefore, even in this very optimistic scenario, the available evidence is not sufficient to support a standard protocol for the use of prophylactic antibiotics in the treatment of mandible fracture.”

Recommendations for post-operative antibiotics have also become more conservative in recent years. A study group in Switzerland conducted an RCT comparing 24hrs of post-op IV antibiotics only vs post-op IV antibiotics followed by a 5-day PO antibiotic course [2]. It was designed as a pilot study and only included 59 patients, but they found no significant differences in incidence of infection between the two groups.

Another recent retrospective review of 197 patients who underwent operative repair of mandible fracture, published by a group at St. Louis University, found that advanced patient age was the only statistically significant difference in infected and uninfected groups [3]. Injury severity score, fracture type, duration of antibiotic course, and antibiotic type did not differ significantly between the two groups. One primary limitation of this study is the low rate of the primary outcome (only 9 post-op infections occurred).


- There is insufficient evidence to strongly support or discourage the routine use of prophylactic antibiotics in closed mandible fractures.

- Signal from some studies indicating possible benefit of antibiotics warrants further investigation in the form of a well-designed, adequately-powered, placebo-controlled RCT.


1) Kyzas PA. Use of antibiotics in the treatment of mandible fractures: a systematic review. Journal of Oral and Maxillofacial Surgery 2011;69(4):827-32.
2) Schaller B, Soong PL, Zix J, Iizuka T, Lieger O. The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomized, double-blind, placebo-controlled pilot clinical study. Part 2: mandibular fractures in 59 patients. Br J Oral Maxillofac Surg 2013;51:803-7.
3) Hindawi YH, Oakley GM, Kinsella CR, Cray JJ, Lindsay K, Scifres AM. Antibiotic duration and postoperative infection rates in mandibular fractures. Journal of Craniofacial Surgery 2011;22(4):1375-7.

Submitted by Aurora Lybeck, PGY-3.
Edited by C. Sam Smith, PGY-3.

Faculty reviewed by Chris Brooks. 

Sour Milk: Antibiotic Coverage For a Breast Abscess

Clinical scenario:  

Your patient is a middle-aged female who was brought in from home for altered mental status.  As EMS is moving her over to the stretcher, they say: "this lady has some kind of infection on her breast ... I saw it when I went to do her EKG".  The patient is febrile to 39.3, tachycardic in the 120’s, but maintaining a blood pressure of 150’s/80’s.  She has a large, right- sided breast abscess with some spontaneous drainage.  Clearly, this patient has severe sepsis and she needs IVF, antibiotics, and source control.

Clinical Question:  

What is the most appropriate antibiotic choice for coverage of a breast abscess?  Obviously, the patient needs an I&D, but in the meantime, what typically is growing in there?  Should anaerobic coverage be routine?

The Literature:
There are several articles that address culture results from breast abscesses in the era of community acquired MRSA.  Here are two:
One article [1]  reports the culture results of 189 drained  breast abscesses from both lactating (LA) and non-lactating (NL) women at a single center from 2003-2006. In both cases, Staph aureus was the most commonly isolated organism (67.7% from LA, 30.5% from NL, and 42.6% of all cultures overall)  The majority of these S. aureus  isolates were MSSA not MRSA (39 vs. 3.7%).  Importantly, the second most commonly isolated class of bacteria were mixed anaerobes (13.7% overall), followed by anaerobic cocci (6.3% overall).  The authors, therefore strongly suggested that anaerobic coverage be a component of all initially empiric coverage for breast abscesses.
A second article [2] similarly tracked the culture results of 46 drained breast abscesses in a community setting. Staphylococcus aureus was  again the most common aerobic organism, present in 12 cultures (32%).  In contrast to the previous article,  58% of the S. aureus  isolates  were MRSA. The remaining positive cultures yielded Coag-negative Staph (16%), diphtheroids (16%), and Pseudomonas aeruginosa (8%).    This study was severely limited for estimating the prevalence of infection with anaerobic bacteria, as only 8/46 abscesses had swabs sent for anaerobic culture. Of these 2/8 (25%) grew anaerobes.


In addition to arranging for I&D, cover for at least Staph aureus (MRSA if you suspect it) and Anaerobes when treating breast abscesses.  

- If the person is sick and septic like our clinical scenario, cover broadly for MRSA, anaerobes and pseudomonas as well.  Possible options include:
               Inpatient - Vancomycin & Zosyn OR Vancomycin & Unasyn.
               Outpatient - Augmentin (if nursing) OR Bactrim/Flagyl if MRSA suspected. 

[1] Dabbas, N., Chand, M., Pallett, A., Royle, G. T., & Sainsbury, R. (2010). Have the Organisms that Cause Breast Abscess Changed With Time?––Implications for Appropriate Antibiotic Usage in Primary and Secondary Care. The breast journal, 16(4), 412-415.
[2] Moazzez, A., Kelso, R. L., Towfigh, S., Sohn, H., Berne, T. V., & Mason, R. J. (2007). Breast abscess bacteriologic features in the era of community-acquired methicillin-resistant Staphylococcus aureus epidemics. Archives of Surgery, 142(9), 881-884.

Contributed by Maia Dorsett, PGY-3
Faculty Reviewed by Stephen Liang