Should I choose a bactericidal over bacteriostatic antibiotic in the treatment of my patient with pneumonia complicated by bacteremia?

You don’t have too!  Although “bacteriostatic” antibiotics have traditionally been regarded as inferior to “bactericidal” antibiotics in the treatment of serious infections, a 2018 “myth busting” systemic literature review1 concluded that bacteriostatic antibiotics are just as effective against a variety of infections, including pneumonia, non-endocarditis bacteremia, skin and soft tissue infections and genital infections; no conclusion can be made in regards to endocarditis or bacterial meningitis, however, due insufficient clinical evidence.1-3

Interestingly, most of the studies included in the same systemic review showed that bacteriostatic antibiotics were more effective compared to bactericidal antibiotics.1 So, for most infections in hospitalized patients, including those with non-endocarditis bacteremia, the choice of antibiotic among those that demonstrate in vitro susceptibility should not be based on their “cidal” vs “static” label.

Such conclusion should not be too surprising since the definition of bacteriostatic vs bactericidal is based on arbitrary in vitro constructs and not validated by any available in vivo data. In addition, static antibiotics may kill bacteria as rapidly as cidal antibiotics in vitro at higher antibiotic concentrations.3

Another supportive evidence is a 2019 study finding similar efficacy of sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteremia compared to continued IV antibiotic therapy despite frequent use of bacteriostatic oral antibiotics (eg, linezolid, clindamycin and doxycycline). 4

 

References

  1. Wald-Dickler N, Holtom P, Spellberg B. Busting the myth of “static vs cidal”: as systemic literature review. Clin Infect Dis 2018;66:1470-4. https://academic.oup.com/cid/article/66/9/1470/4774989
  2. Steigbigel RT, Steigbigel NH. Static vs cidal antibiotics. Clin Infect Dis 2019;68:351-2. https://academic.oup.com/cid/article-abstract/68/2/351/5067395
  3. Wald-Dickler N, Holtom P, Spellberg B. Static vs cidal antibiotics; reply to Steigbigel and Steigbigel. Clin Infect Dis 2019;68:352-3. https://academic.oup.com/cid/article-abstract/68/2/352/5067396?redirectedFrom=fulltext
  4. Jorgensen SCJ, Lagnf AH, Bhatia S, et al. Sequential intravenous-to-oral outpatient antbiotic therapy for MRSA bacteraemia: one step closer.  J Antimicrob Chemother 2019;74:489-98.  https://www.ncbi.nlm.nih.gov/pubmed/30418557

 

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Should I choose a bactericidal over bacteriostatic antibiotic in the treatment of my patient with pneumonia complicated by bacteremia?

Can native valve infective endocarditis be associated with hemolytic anemia?

Yes, but it’s rare!  Hemolytic anemia (HA) in the setting of infective endocarditis (IE) has only been described in a few case reports (1-3).  Although diseased valves may cause shearing stress that fragments RBCs, similar to that associated with mechanical heart valves, an autoimmune hemolytic process has also been implicated. 

A 2018 case report describes a patient with hypertrophic obstructive cardiomyopathy (HOCM) with left ventricular outflow tract (LVOT) obstruction who had HA secondary to subacute IE due to Actinomyces israelii (1).   The anemia completely resolved after treating the IE (1). The cause was most likely mechanical shearing (schistocytes or fragmented RBCs present on peripheral smear) by the diseased valves; autoimmune hemolysis was considered unlikely in this case due to consistently negative Coombs tests and failure to respond to corticosteroids (1). 

An autoimmune mechanism was invoked by a 1999 report reviewing 6 cases of HA associated with IE (3).  All patients had fragmented erythrocytes, but several also demonstrated an immune-mediated mechanism for their HA, supported by the presence of spherocytes, splenomegaly, and + Coombs test (2,3).  The production of anti-erythrocyte antibodies, modification of antigenicity of erythrocyte antigens, or unmasking of antigens in IE may play a role (1,3). Additional evidence in support of an immune-mediated mechanism of HA in IE has been provided by an experimental study demonstrating significantly shorter RBC half-life in rabbits with intact spleen compared to that of splenectomized animals (4).

 

References

1. Toom S, Xu Y. Hemolytic anemia due to native valve subacute endocarditis with Actinomyces israellii infection. Clin Case Rep 2018;6: 376-79. https://onlinelibrary.wiley.com/doi/epdf/10.1002/ccr3.1333 

2. Hsu CM, Lee PI, Chen JM, et al. Fatal Fusarium endocarditis complicated by hemolytic anemia and thrombocytopenia in an infant. Pediatr Infect Dis 1994;13:1146-48. https://www.ncbi.nlm.nih.gov/pubmed/7892087 

3. Huang HL, Lin FC, Hung KC, et al. Hemolytic anemia in native valve infective endocarditis. Jpn Circ J 1999;63:400-403. https://www.ncbi.nlm.nih.gov/pubmed/10943622 

4. Joyce RA, Sand MA. Mechanism of anaemia in experimental bacterial endocarditis. Scand J Haematol 1975;15:306-11. https://www.ncbi.nlm.nih.gov/pubmed/1198067 

 

Contributed by Scott Goodwin, Medical Student, Harvard Medical School, Boston, MA. 

 

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Can native valve infective endocarditis be associated with hemolytic anemia?

How can I tell if my febrile patient who uses IV drugs had cotton fever?

Although IV drug use (IVDU) is associated with febrile illness of numerous etiologies (eg, soft tissue infections, pneumonia, bacteremia, endocarditis), certain features of a febrile illness may be helpful in considering cotton fever (CF) as the cause.1-3

First, onset of fever—often associated with chills, shortness of breath, nausea, vomiting, headache, abdominal pain and myalgias—in CF is usually manifest within 10-30 minutes of drug injection. Second, infectious disease workup, including blood cultures and chest radiograph, are unrevealing despite clinical signs of systemic inflammatory response syndrome (SIRS), such as leukocytosis, tachypnea and tachycardia. Third, symptoms and clinical signs of inflammation usually resolve or improve within 6-12 h of onset (less commonly up to 24-48 h). Nevertheless, CF remains a diagnosis of exclusion.

As for the cause of CF, the most widely-held theory revolves around the endotoxin of Pentoea agglomerans (formerly Enterobacter agglomerans), a gram-negative rod that colonizes cotton plants. Since cotton is often used as a filter during injection of illicit substances, any endotoxin present in the cotton is also injected resulting in abrupt onset of a febrile illness. Of note, the toxin is water soluble and heating (often part of the preparation of the drug) enhances its toxic effect.3

References

  1. Zerr AM, Ku K, Kara A. Cotton Fever: a condition self-diagnosed by IV drug users. JABFM 2016;29: 276-279.PDF
  2. Xie Y, Pope BA, Hunter AJ. Cotton fever: does the patient know best? J Gen Intern Med 31:442-4. PDF
  3. Torka P, Gill S. Cotton fever: an evanescent process mimicking sepsis in an intravenous drug abuser. J Emerg Med 2013;44:e385-e387. PDF
How can I tell if my febrile patient who uses IV drugs had cotton fever?

Should Aerococcus urinae growth from the urine of my elderly patient be considered a pathogen?

Although for many years Aerococcus urinae was considered a urinary contaminant, increasingly it is recognized as an emerging pathogen capable of causing not only urinary tract infection (UTI) but also secondary bacteremia and endocarditis, among others.1   

The proportion of patients with aerococcal bacteriuria with symptoms suggestive of UTI ranges from 55-98%.1 So A. urinae can no longer be assumed to be a contaminant, particularly in the presence of symptoms suggestive of UTI.

A. urinae UTI often affects the elderly (median age 79 y) and those with pre-existing urinary tract pathologies, such as prostatic hyperplasia, urethral stricture, renal calculi, and prior urinary tract surgery.2,3 Many patients also have underlying comorbidities such as diabetes, heart disease, dementia, and chronic renal failure.3

One clue to the presence of A. urinae in the urine is its particularly pungent odor reminiscent of that of patients with trimethylaminuria (fish odor syndrome).4

Once you decide you should treat A. urinae, keep in mind that it is NOT predictably susceptible to trimethoprim-sulfamethoxazole, fluoroquinolones, or fosfomycin!  Instead, consider penicillin, ampicillin, cephalosporin, or nitrofurantoin to which most strains are susceptible.5,6.

 

References

  1. Rasmussen M. Aerococcus: an increasingly acknowledged human pathogen. Clin Microbiol Infect 2016;22:22-27. https://www.ncbi.nlm.nih.gov/pubmed/26454061
  2. Tathireddy H, Settypalli S, Farrell JJ. A rare case of aerococcus urinae infective endocarditis. J Community Hosp Intern Med Perspectives 2017; 7:126-129. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473194/
  3. Higgins A, Garg T. Aerococcus urinae: An emerging cause of urinary tract infection in older adults with multimordidity and urologic cancer. Urology Case Reports 2017;24-25. https://www.ncbi.nlm.nih.gov/pubmed/28435789
  4. Lenherr N, Berndt A, Ritz N, et al. Aerococcus urinae: a possible reason for malodorus urine in otherwise healthy children. Eur J Pediatr. 2014;173:1115-7 https://www.ncbi.nlm.nih.gov/pubmed/24913181
  5. Christensen JJ, Nielsen XC. Aerococcus urinae. Antimicrobe @ http://www.antimicrobe.orgb75.asp , accessed June 14, 2018.
  6. Dimitriadi D, Charitidou C, Pittaras T, et al. A case of urinary tract infection caused by Aerococcus urinae. J Bacteriol Mycol 2016; 2: 00041. https://pdfs.semanticscholar.org/a1cf/048d8444ce054ca9a332f7c2b4a218325ff6.pdf

 

Should Aerococcus urinae growth from the urine of my elderly patient be considered a pathogen?

My patient with pyelonephritis has positive blood cultures for E. coli? Should I order repeat blood cultures to make sure the bacteremia is clearing?

Although a common practice, follow-up blood cultures (FUBCs) may not be necessary in otherwise clinically stable or improving patients with aerobic gram-negative bacteremia. This is probably due to the often-transient nature of gram-negative bloodstream infections  and less propensity of these organisms to cause intravascular infections (eg, endocarditis) compared to gram-positives. 1

A 2017 study addressing the value of FUBCs in gram-negative bacteremia found that repeat positive blood cultures were uncommon with positive results not associated with mortality or higher ICU admissions. 1 Specifically, 17 FUBCs had to be drawn to yield 1 positive result.  Although the numbers of positive FUBCs were too low for in-depth analysis, it was concluded that FUBCs added little value in the management of gram-negative bacteremias.

In contrast, FUBCs are recommended in the following situations: 1-3

  • Staphylocccus aureus bacteremia given the propensity of this organism to cause intravascular (eg, endocarditis) and metastatic infections.
  • Presumed or documented endocarditis or intravascular device infections (eg, intravenous catheters and pacemakers) to document timely clearance of bacteremia
  • Infections involving organisms that may be difficult to clear such as fungemia or multi-drug resistant pathogens.

As with many things in medicine, clinical context is important before ordering tests and blood cultures are no different. The urge to order FUBCs should also be balanced with the possibility of having to deal with  contaminants. 

References

  1. Canzoneri CN, Akhavan BJ, Tosur Z et al. Follow-up blood cultures in gram-negative bacteremia: Are they needed? Clin Infect Dis 2017;65:1776-9. https://www.ncbi.nlm.nih.gov/pubmed/29020307
  2. Tabriz MS, Riederer K, Baran J, et al. Repeating blood cultures during hospital stay: Practice pattern at a teaching hospital and a proposal for guidelines. Clin Microbiol Infect 2004;10:624-27. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1469-0691.2004.00893.x
  3. Mylotte JM, Tayara A. Blood cultures: Clinical aspects and controversies. Eur J Clin Microbiol Infect Dis 200;19:157-63. https://www.ncbi.nlm.nih.gov/pubmed/10795587

 

 

My patient with pyelonephritis has positive blood cultures for E. coli? Should I order repeat blood cultures to make sure the bacteremia is clearing?

Do most patients with mycotic aneurysms have endocarditis?

No! In fact, the great majority of patients who develop mycotic aneurysm (MAs) in the postantibiotic era have no evidence of endocarditis1-3.

MAs are thought to be related to microbial arteritis due to blood stream infection of any source with implantation of circulating pathogen (usually bacterial) in atherosclerotic, diseased, or traumatized aortic intima. Plus, MAs may develop due to an adjacent infectious process (eg, vertebral osteomyelitis), either through direct extension or via lymphatic vessels, pathogen seeding of vasa vasorum, or infection of a pre-existing aneurysm1,2.  All these factors may occur in the absence of endocarditis.

Many of your patients may be at risk of MA such as those with advanced age or history of diagnostic or therapeutic arterial catheterization, illicit intravascular drug use, hemodialysis and depressed host immunity1-3..  Staphylococcus aureus, Salmonella sp, S. epidermidis and Streptococcus sp are common culprits in descending order1-3.

So think of MA in your patient with recent blood stream infection,  particularly due to S. aureus or Salmonella sp, in the setting of persistent signs of infection  with or without evidence of endocarditis.

Final Fun Fact: Did you know that the term “mycotic aneurysm” is a misnomer, having been first introduced by Sir William Osler to describe aneurysms of the aortic arch in a patient with (you guessed it) bacterial not fungal endocarditis?

References:

  1. Gomes MN, Choyke PL, Wallace RB. Infected aortic aneurysms: A changing entity. Ann Surg 1992;215:435-42. https://www.ncbi.nlm.nih.gov/pubmed/1616380
  2. Muller BT, Wegener OR, Grabitz K, et al. Mycotic aneurysms of the thoracic and abdominal aorta and iliac arteries: Experience with anatomic and extra-anatomic repair in 33 cases. J Vasc Surg 2001;33:106-13. https://www.ncbi.nlm.nih.gov/pubmed/11137930
  3. Mukherjee JT, Nautiyal A, Labib SB. Mycotic aneurysms of the ascending aorta. Tex Heart Inst J 2012;39:692-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461658/
Do most patients with mycotic aneurysms have endocarditis?

Where should I expect to hear radiation of mitral regurgitation in my patient with endocarditis?

 

Mitral regurgitation (MR) murmur can radiate to several places on the chest wall as well as the spine and….ready for this…. the top of the head!

Classically, MR is thought to have 4 patterns of radiation1,2

  1. Axilla and the inferior angle of the left scapula (typical)
  2. Left sternal border, base of the heart and into the neck
  3. Cervical and lumbar spine (down to sacrum)
  4. Right of the sternum (associated with a “giant left atrium”)

Less well-known and perhaps most intriguing is the radiation of MR to the top of the head. Original reports involved patients who often had ruptured chordae tendineae due to subacute bacterial endocarditis and/or rheumatic heart disease2.

It was posited that “the flail portion of the mitral valve folds back into the left atrial cavity forming a hood which deflects the regurgitant stream against the atrial wall”.  In the setting of a flail anterior leaflet, if the jet stream is sufficiently high energy and comes in contact with the spine, the murmur may be transmitted by bone conduction to the top of the skull2

I suggest you explain to your patient what you are doing before you auscultate the top of their heads!

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References

  1. Chatterjee K. Physical examination. In Topol EJ, ed. Textbook of cardiovascular medicine, 2007, pp 193-224. Lippincott, Williams &Wilkins. Philadelphia. https://books.google.com/books?id=35zSLWyEWbcC&pg=PA219&lpg=PA219&dq=top+of+the+head+mitral+regurgitation+murmur&source=bl&ots=56Erim4eNM&sig=82TrOiU52ojmhVBMG7G2jMULxVo&hl=en&sa=X&ved=0ahUKEwit8_WnmorVAhVGyj4KHcwUC_8Q6AEIRzAF#v=onepage&q=top%20of%20the%20head%20mitral%20regurgitation%20murmur&f=false
  2. Merendino KA, Hessel EA. The “murmur on top of the head” in acquired mitral insufficiency: Pathological and clinical significance. JAMA 1967;199:892-896. http://jamanetwork.com/journals/jama/article-abstract/663746
Where should I expect to hear radiation of mitral regurgitation in my patient with endocarditis?

Why is there a predilection for the tricuspid valve (TV) infection among injection drug users (IDUs) with infective endocarditis (IE)?

Although right-sided IE accounts for only 9% of IE cases among non IDUs, in IDUs it accounts for over three-quarters of IE cases1.  

Several potential mechanisms have been posited to explain susceptibility of TV to infection in IDUs, including endothelial damage due to repeated inoculation of small bacterial loads, specific substances (eg talc) injected with drugs,  cocaine-induced vasospasm and thrombus formation, and drug-induced pulmonary hypertension associated with increased pressure gradients and turbulence.  In addition, facilitation of bacterial adhesion due to the deposition of immune complexes (eg antibody vs antigens in injected drugs) on the TV and coating of the injected particulate matter with bacterial adherence matrix molecules on valve surfaces may also play an important role1,2.

Add to these potential factors a higher risk nasal and cutaneous colonization with Staphylococcus aureus (a common cause of IE) among IDUs, and we have a perfect storm!

References

  1. Frontera JA, Gradon JD. Right-sided endocarditis in injection drug users: review of proposed mechanisms of pathogenesis. Clin Infect Dis 2000;30:374-9.
  2. Chahood J, Yakan AS, Saad H, et al. Right-sided infective endocarditis and pulmonary infiltrates: An update. Cardiol Rev 2016;24:230-37.
Why is there a predilection for the tricuspid valve (TV) infection among injection drug users (IDUs) with infective endocarditis (IE)?