Learning about fungi is hard enough even for infectious disease fellows (Narrator: especially for infectious disease fellows). By the time you learn how to differentiate the yeasts from the molds, the fungi kingdom decides to throw you a curve ball: Enter the shape shifters into the game of fungi learning – the dimorphic fungi.
The Dimorphic fungi shape shift depending on the weather (literally). They exist as molds in the great outdoors (environmental temperatures) and yeasts in the great indoors (inside our bodies at body temperatures). Clinically, this also means you will see the yeast forms in a histopathology review of a tissue sample, and our friends in the microbiology lab can re-create the environmental factors to grow them out as mold forms in culture. So essentially, they also shape shift between the microbiology lab and the pathology department. (They are sneaky Fung(uy)i…)
Some of the clinically relevant dimorphic fungi have a predilection for geographical location (endemic mycoses), and therefore are very popular in board exams to the dismay (or joy, after this review series?) of medical trainees.
#ClimateChangeIsReal isn’t just pertinent in the political arena, but also for these endemic fungi. The grave consequences of climate change might change and expand the geographical distribution(1,2) of these fungi and therefore result in more catch-up learning on our end. This is almost akin to learning the constant re-classification and re-naming of the fungi kingdom (thanks, no thanks taxonomists…)
In this review series, I will go over the endemic fungi in a ‘high yield’ approach that will hopefully be pertinent for both shelf exams/boards and clinical practice.
I’ve also purposefully made it a two-pager/per fungi review (or 1 pager if you print it double-sided, #SaveTheTrees). We will be providing PDF links with every Fungi review. This will be an easy reference for a pocketbook, handouts to print to teach your medical students or if you want to flex your knowledge of endemic fungi during rounds (All win-win-win situations!)
The profile of each shape shifter will be released every Friday in the spirit of #FungalFriday. The dimorphic fungi that will be covered during the #ShapeShifterSeries include:
Our First Shape shifter in the series to be released this coming #FungalFriday will be Histoplasmosis, aka the Ohio valley disease/Cave disease. What does Ohio or caves for the matter have to do with this Fungus? Find out more this coming Friday!
Fatima Al Dhaheri, MBBS The Fung(uy)i squad
References: 1. The Lancet Infectious Diseases. Climate change: the role of the infectious disease community. Lancet Infect Dis. 2017;17:1219. 2. Greer A, Ng V, Fisman D. Climate change and infectious diseases in North America: the road ahead. CMAJ. 2008;178:715–722.
[This post was written by Ahmed Abdul Azim, a senior infectious disease fellow at Beth Israel Deaconess Medical Center]
During the fall and winter season, you are likely to see a few cases of viral meningitis. Even though viral encephalitis is less common, it is important to try to differentiate these clinical entities as a clinician, since they carry different prognoses. (The bulk of this review is adapted from Mandell, Douglas and Bennett’s principles and practice of infectious diseases)1
Cerebral spinal fluid analysis
Before we go any further, let’s briefly review cerebral spinal fluid findings on lumbar puncture for different syndromes:
Important points to consider: · Bacterial meningitis: 10% of cases have a lymphocyte predominant CSF cell analysis · WNV encephalitis: over a 1/3 of patients with WNV encephalitis had neutrophil predominant CSF pleocytosis · Enteroviruses: CSF analysis done early in illness course may yield neutrophil predominant pleocytosis in 2/3 of cases – generally will convert to lymphocytic predominant if repeated in 12-24 hours.
Take home point: always interpret CSF within the clinical context in front of you!
CSF to serum glucose ratio of < 0.4 is suggestive of bacterial meningitis
Traumatic LP may cause elevated CSF protein: for every 1000 RBC/mm3, subtract 1 mg/dL protein
Traumatic LP may cause elevated CSF WBC: for every 500-1000 RBC/mm3, subtract 1 WBC/mm3
RBC Adjustment for WBC in CSF = Actual WBC in CSF – (WBC in blood x RBC in CSF/RBC in blood)
Viral meningitis versus encephalitis
Both syndromes often present with a triad of2: (1) FEVER (2) HEADACHE and (3) ALTERED MENTAL STATUS However, the trick is to explore the history and signs further. Epidemiological clues include:
prevalence of disease in the local area
animal and insect exposure
underlying immune status
Patients with viral encephalitis: tend to have diffuse cerebral cortex involvement with abnormal cerebral function – Symptoms: altered mental status, motor/sensory deficits, altered behavior and/or personality changes, speech and/or movement disorders
Patients with viral meningitis: DO NOT have diffuse cerebral cortex involvement → cerebral function IS INTACT – Symptoms: headache, lethargy, neck stiffness/pain
Patients with meningoencephalitis: tend to have a combination of meningitis and encephalitis symptoms
Regardless, if a patient has symptoms and/or signs of meningitis or encephalitis, a lumbar puncture can be helpful.
Viral Meningitis – Common Pathogens
Overall, most cases of aspectic meningitis syndromes are caused by viruses
1. Enteroviruses (e.g. Coxsackie, echovirus, other non-polio enteroviruses) – by far the most common cause of viral meningitis/aseptic meningitis3
Summer/fall seasons (less commonly in the winter)
abrupt onset fever
Think of enterovirus viral meningitis in patients when rash and/or diarrhea is present
CSF analysis done early in illness course may yield neutrophil predominant pleocytosis in 2/3 of cases – generally will convert to lymphocytic predominant if repeated in 12-24 hours4.
Take home point: always interpret CSF within the clinical context in front of you!
2. Herpes virus simplex viral meningitis – usually caused by HSV-2 >> HSV-18
Only accounts for 0.5-3% of viral meningitis/aseptic meningitis cases9
Typically mild symptoms
80% with HSV-2 genital lesions/ulcers up to 1 week prior to presenting with viral meningitis
Patients with a clinical picture consistent with aseptic meningitis and have HSV isolated in CSF will end up having HSV-2 in 95% of cases. This is a self-limited illness3
3. West Nile Virus – more likely to cause an encephalitis syndrome. Yet, may present with aseptic meningitis or asymmetrical flaccid paralysis10
Viral Encephalitis – Common Pathogens
A cause is identified in approximately 36-63% of cases10,11
Causes of encephalitis (Most common to least common in US study of patients that met criteria for encephalitis)12:
Varicella zoster virus (VZV): 14%
West Nile virus (WNV): 11%
*In a study of HIV uninfected patients, viruses caused up to 38% of cases, followed by bacterial pathogens at 33%, Lyme disease at 7%, and fungi at 7%. Syphilis was identified as the culprit in 5% of cases, and mycobacterial infections at 5%, while prion disease was responsible for 3% of cases of encephalitis11
1. HSV encephalitis: most common cause of encephalitis in the US (1/250,000 population annually). HSV-1 accounts for greater than 90% of HSV encephalitis in adults13. Fewer than 6% of CSF PCR cases had a “normal” neurological exam14.
> 96% have CSF pleocytosis14,15,16
Protein is elevated; glucose is normal 95% of the time14,15,16
MRI > CT, revealing changes of temporal lobes in ~89% of cases confirmed by CSF PCR15
CSF PCR is highly sensitive and specific, with an excellent positive and negative predictive value17
If HSV encephalitis is suspected and PCR is negative, repeat HSV PCR testing in 3-5 days
HSV PCR remains positive up to 7 days in 98% of cases after onset of symptoms
Treatment: IV acyclovir is the treatment of choice; call your nearest ID colleague for help
Mortality in acyclovir-treated patients stratified by age group18:
11% in < 2 year olds
22% in 22-59 year olds
62% in > 60 year olds (initial level of consciousness strongly predicted mortality16)
2. West Nile Virus encephalitis: transmitted via a mosquito (vector) bite, currently the most common cause of epidemic viral encephalitis nationally19
Most are asymptomatic (80%); macular rash in up to 50% of cases20
<1% develop neuroinvasive disease, of which 60% develop encephalitis21
High risk patients for neuroinvasive disease: solid organ transplant patients22
Cranial neuropathies, mostly facial palsy: 20%
Lower motor neuron type lesion: areflexia, hypotonia, preserved sensation
Tremors are not uncommon either
CSF analysis: pleocytosis (>60% of cases lymphocytic predominant), elevated protein and normal glucose13
WNV encephalitis will likely have neuroimaging findings; that is not the case with WNV meningitis
MRI much more sensitive than CT. Most common abnormalities seen involving basal ganglia, brain stem and thalamus1
CSF diagnosis: WNV-specific IgM in CSF23
No established therapy for neuroinvasive disease. Case reports of improvement with IVIG for neuroinvasive disease1
Mortality: 12% in severe neuroinvasive disease. Residual neurological changes such as parkinsonism not uncommon
Approximately 30% of patients reported fatigue symptoms 6 months to 5 years after infection onset24
Viral Meningoencephalitis – Clinical Approach
So you are the house officer encountering a patient with 1-2 weeks of progressively worsening fevers, headaches and severe behavioral changes or depressed mental status: what do you do next?
As a standard work up for likely encephalitis in the United States, CSF studies should include1:
CSF opening pressure
Cell count and differential
Protein and glucose (paired with serum glucose)
Gram stain and bacterial cultures
Initial viral studies to include:
WNV IgM serology (if seasonally appropriate);
CSF viral cultures
Imaging in encephalitis: Magnetic resonance imaging (MRI) of the brain is more sensitive than computed tomography (CT)15. Unless contraindicated, all patients with encephalitis should undergo MR imaging.
Temporal lobe and limbic changes → HSV, HHV-619
Hemorrhagic strokes and demyelinating lesions → VZV vasculopathy25
Subependymal enhancement → CMV ventriculitis25
Predominant demyelination → PML (JC virus)
1. Mandell, Douglas and Bennett’s principles and practice of infectious diseases (8th ed. 2015 / Philadelphia, PA : Elsevier) 2. Whitley RJ, and Gnann JW: Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002; 359: pp. 507-513 3. Connolly KJ, and Hammer SM: The acute aseptic meningitis syndrome. Infect Dis Clin North Am 1990; 4: pp. 599-622 4. Gomez B, Mintegi S, Rubio MC, et al: Clinical and analytical characteristics and short-term evolution of enteroviral meningitis in young infants presenting with fever without source. Pediatr Emerg Care 2012; 28: pp. 518-523 5. Rotbart HA: Diagnosis of enteroviral meningitis with the polymerase chain reaction. J Pediatr 1990; 117: pp. 85-89 6. Sawyer MH, Holland D, and Aintablian N: Diagnosis of enteroviral central nervous system infection by polymerase chain reaction during a large community outbreak. Pediatr Infect Dis J 1994; 13: pp. 177-182 7. Ahmed A, Brito F, Goto C, et al: Clinical utility of polymerase chain reaction for diagnosis of enteroviral meningitis in infancy. J Pediatr 1997; 131: pp. 393-397 8. Shalabi M, and Whitley RJ: Recurrent benign lymphocytic meningitis. Clin Infect Dis 2006; 43: pp. 1194-1197 9. Corey L, and Spear PG: Infections with herpes simplex viruses (2). N Engl J Med 1986; 314: pp. 749-757 10. Kupila L, Vuorinen T, Vainionpaa R, et al: Etiology of aseptic meningitis and encephalitis in an adult population. Neurology 2006; 66: pp. 75-80 11. Tan K, Patel S, Gandhi N, et al: Burden of neuroinfectious diseases on the neurology service in a tertiary care center. Neurology 2008; 71: pp. 1160-1166 12. Glaser CA, Gilliam S, Schnurr D, et al: In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998-2000. Clin Infect Dis 2003; 36: pp. 731-742 13. Tyler KL: Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s. Herpes 2004; 11: pp. 57A-64A 14. Raschilas F, Wolff M, Delatour F, et al: Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35: pp. 254-26 15. Domingues RB, Tsanaclis AM, Pannuti CS, et al: Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis 1997; 25: pp. 86-91 16. Whitley RJ, Alford CA, Hirsch MS, et al: Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 314: pp. 144-149 17. Lakeman FD, and Whitley RJ: Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1995; 171: pp. 857-86 18. Whitley RJ, Alford CA, Hirsch MS, et al: Factors indicative of outcome in a comparative trial of acyclovir and vidarabine for biopsy-proven herpes simplex encephalitis. Infection 1987; 15: pp. S3-S8 19. Kramer LD, Li J, and Shi PY: West Nile virus. Lancet Neurol 2007; 6: pp. 171-181 20. Watson JT, Pertel PE, Jones RC, et al: Clinical characteristics and functional outcomes of West Nile Fever. Ann Intern Med 2004; 141: pp. 360-365 21. Sejvar JJ, Haddad MB, Tierney BC, et al: Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003; 290: pp. 511-515 22. Jean CM, Honarmand S, Louie JK, et al: Risk factors for West Nile virus neuroinvasive disease, California, 2005. Emerg Infect Dis 2007; 13: pp. 1918-1920 23. Shi PY, and Wong SJ: Serologic diagnosis of West Nile virus infection. Expert Rev Mol Diagn 2003; 3: pp. 733-741 24. Garcia MN, Hause AM, Walker CM, et al: Evaluation of prolonged fatigue post-West Nile virus infection and association of fatigue with elevated antiviral and proinflammatory cytokines. Viral Immunol 2014; 27: pp. 327-333 25. Gilden DH, Mahalingam R, Cohrs RJ, et al: Herpesvirus infections of the nervous system. Nat Clin Pract Neurol 2007; 3: pp. 82-94
The ATS and IDSA recently released the much-anticipated update to the community-acquired pneumonia (CAP) guidelines. The previous version was published back in 2007 and the new guidelines have included some major changes. Here is a rundown of all those changes that you need to know.
1. Health care associated pneumonia (HCAP) no longer exists
HCAP was an entity created with the 2007 CAP guidelines. It encompassed non-hospital acquired pneumonia in patients who had recent contact with the healthcare system. The recommendation was to treat HCAP with empiric broad-spectrum antibiotic therapy against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PsA). With this strategy however, we were over-treating a lot of people. This study found that while 30% of all patients hospitalized for CAP received empiric anti-MRSA treatment, only 0.7% of all patients had MRSA pneumonia.
In the new guidelines, HCAP no longer exists. Instead, the guidelines emphasize assessment of risk factors for pathogens such as MRSA and PsA.
2.Treatment is now based on severity of the pneumonia rather than the location of the admitted patient
Prior guidelines differentiated antibiotic recommendations based on patient triage to the floor or the intensive care unit. In the new guidelines, treatment recommendations are based on the severity of the pneumonia, based on a list of criteria:
3.Only obtain blood cultures in severe CAP or if risk factors for MRSA and/or PsA are present
The new guidelines focus on cost-effective use of diagnostic tests. Outpatient setting: recommend against any diagnostic testing (except for a chest X-ray) Inpatient non-severe pneumonia: recommend blood cultures and sputum gram stain/culture ONLY if risk factors for MRSA and/or PsA are present Inpatient severe pneumonia: recommend blood cultures, sputum gram stain/culture, Streptococcus pneumoniae urine antigen, and Legionella urine antigen and PCR/culture *Legionella diagnostic tests are also recommended in times of an outbreak
These recommendations are based on literature demonstrating that:
Overall prevalence of true positive blood cultures is 1-9% in patients with CAP3-6
The majority of true positive blood cultures occur in patients with severe CAP6,7
Blood culture results change clinical management in <2% of patients with CAP3,4,6
The rate of blood culture contaminants is similar to the rate of true blood culture positives, resulting in unnecessary antibiotics and extended lengths of stay in the hospital3,4,6
4. Procalcitonin should NOT be used in the diagnosis of CAP
Procalcitonin is not a reliable marker for diagnosis of bacterial infections; it has roughly 65-75% sensitivity for detecting bacterial pneumonia8. Consequently, the risk of not treating bacterial CAP due to a low procalcitonin level can lead to poor outcomes. Although there is data to support use of procalcitonin in determining the duration of antibiotics in CAP9,10, the guidelines recommend use only in situations where duration exceeds the recommended 5-7 days.
The argument from the guideline authors is that there is more literature in support for PSI in accurately predicting mortality rather than the CURB-65 score11-14. However, PSI incorporates data that may not be available in all circumstances, and certainly will not be available to the outpatient clinician who is trying to decide whether to admit a patient or not (such as pH, which can only be obtained from an arterial blood gas). So, although PSI may be recommended for use in the emergency department, the CURB-65 will likely remain in use, especially due to its efficiency in the outpatient setting.
6.Algorithm for CAP antibiotic treatment The meat of the guidelines is the treatment regimens – and there are quite a few changes.
1) Macrolides are no longer recommended as first line therapy in uncomplicated outpatient CAP unless the local streptococcal resistance to azithromycin is <25% (this study shows that most parts of the U.S. have resistance rates >25%).
2) Amoxicillin and doxycycline take the place of macrolides as first line treatment in uncomplicated outpatient CAP.
You may be thinking – “wait, amoxicillin doesn’t even cover atypical pathogens (i.e. Mycoplasma pneumoniae and Legionella pneumophila)!” This is true. But studies have shown that in otherwise-healthy patients, there was no difference in outcomes among those who received amoxicillin vs. an antibiotic that treats atypical organisms16. Exactly why that is remains unclear, but could be because healthy individuals clear the infection on their own or because the majority of these pneumonias are actually due to a virus, so they would improve with or without any antibiotics 5.
3) In hospitalized patients:
Non-severe CAP – only treat empirically for MRSA and/or PsA if the organism has been isolated from the patient’s respiratory tract in the past
Severe CAP – treat empirically for MRSA and/or PsA if the patient has any risk factors for MRSA and/or PsA respiratory infection
7.Treat anaerobes only in cases with suspected or proven lung abscess and/or empyema
Empiric treatment of anaerobes in aspiration pneumonia remains controversial, but the new guidelines recommend only treating anaerobes if there is suspicion for or a proven lung abscess and/or empyema.
8.Continue antibiotics for at least 48 hours in patients who are diagnosed with influenza pneumonia
This recommendation is based off the data that influenza infection predisposes to subsequent bacterial superinfections17 and a patient could have both a viral and a bacterial pneumonia at the same time. The guidelines state that if there is significant clinical improvement in 48 hours and no evidence to suggest a superimposed bacterial pneumonia, antibiotics can be discontinued at that time.
9. Duration of antibiotics is based on clinical improvement (but should be a minimum of 5 days)
Gone are the days of prespecified number of days for antibiotic duration. Instead, monitor the patient for signs of clinical improvement.
If cultures are not growing MRSA and/or PsA, can stop empiric treatment for MRSA and/or PsA.
If clinically improving, stop antibiotics following 48 hours of clinical improvement after a minimum of 5 days. Clinical improvement is determined by resolution of vital sign abnormalities, ability to eat/improved appetite, and normal mentation.
10. Do not use corticosteroids as adjunctive treatment and do not obtain routine follow up chest X-rays
These were not necessarily strategies that I employed prior to the publication of these guidelines, and corticosteroid use in CAP is controversial, but at this time, there is no strong data to support either of these adjunctive management strategies in patients with CAP.
1. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Resp Crit Care Med. 2019; 200(7):e45-e67. 2. Self WH, Wunderink RG, Williams DJ, et al. Staphylococcus aureus Community-acquired Pneumonia: Prevalence, Clinical Characteristics, and Outcomes. Clin Infect Dis. 2016; 63(3):300-309. 3. Chalasani NP, Valdecanas MA, Gopal AK, McGowan JE Jr, and Jurado RL. Clinical utility of blood cultures in adult patients with community-acquired pneumonia without defined underlying risks. Chest. 1995; 108(4):932-936. 4. Corbo J, Friedman B, Bijur P, and Gallagher EJ. Limited usefulness of initial blood cultures in community acquired pneumonia. Emerg Med J. 2004; 21(4):446-448. 5. Jain S, Self WH, Wunderink RG, et al. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. New Eng J Med. 2015. 373:415-427. 6. Lee JH and Kim YH. Predictive factors of true bacteremia and the clinical utility of blood cultures as a prognostic tool in patients with community-onset pneumonia. Medicine (Baltimore). 2016; 95(41):e5058. 7. Waterer GW and Wunderink RG. The influence of the severity of community-acquired pneumonia on the usefulness of blood cultures. Respir Med. 2001; 95(1):78-82. 8. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a Marker of Etiology in Adults Hospitalized With Community-Acquired Pneumonia. Clin Infect Dis. 2017;65(2):183-190. 9. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017; 10:CD007498. 10. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107. 11. Aujesky D, Auble TE, Yealy DM, et al. Prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia. Am J Med. 2005; 118(4):384-392. 12. Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vandervoort MK, and Feagan BG. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin. JAMA. 2000; 283(6):749-755. 13. Carratala J, Fernandez-Sabe N, Ortega L, et al. Outpatient care compared with hospitalization for community-acquired pneumonia: a randomized trial in low-risk patients. Ann Intern Med. 2005;142(3):165-172. 14. Renaud B, Coma E, Labarere J, et al. Routine use of the Pneumonia Severity Index for guiding the site-of-treatment decision of patients with pneumonia in the emergency department: a multicenter, prospective, observational, controlled cohort study. Clin Infect Dis. 2007;441(1):41-49. 15. Blondeau JM and Theriault N. Application of the Formula for Rational Antimicrobial Therapy (FRAT) to Community-Acquired Pneumonia. J Infect Dis Ther. 2017;5:313. 16. Postma DW, van Werkhoven CH, van Elden LJR, et al. Antibiotic Treatment Strategies for Community-acquired Pneumonia in Adults. New Eng J Med. 2015;372:1312-1323. 17. Metersky ML, Masterton RG, Lode H, File TM Jr, and Babinchak T. Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza. Int J Infect Dis. 2012;16(5):e321-331.
This post is the last in a three-part series covering the management of beta-lactam allergies. Part 1 explained the enormous impact that penicillin allergies have on patient outcomes, while Part 2 discussed the different types of allergic reactions and the potential (or lack thereof) for beta-lactam allergy cross reactivity. This last post will cover the methods used to assess beta-lactam allergies. Let’s jump right in!
There are a variety of strategies that can be used to assess a patient’s beta-lactam allergy, each having their own place in the allergy assessment algorithm. The following will be detailed in this post:
Far and away the most important step in assessing a
patient’s beta-lactam allergy is a detailed patient interview. An allergy
evaluation is recommended by many of the top health organizations in the
country, including the Center for Disease Control and Prevention (CDC),
National Quality Forum, Infectious Diseases Society of America (IDSA), American
Board of Internal Medicine (ABIM), and the American Academy of Allergy, Asthma
& Immunology (AAAAI).1 Just a minute or two of questioning the
patient can yield an entirely different story than the allergy history in the
medical chart. Some common questions I bring up with patients include:
many years ago did the reaction occur?
type of reaction did you have?
you remember the details of the reaction? Did you have to go to the emergency
long after starting the medication did the reaction occur?
was the reaction managed?
happened when the medication was stopped?
you tolerated other forms of penicillin since the reaction? Have you had Keflex
(cephalexin), Augmentin (amoxicillin/clavulanate), or amoxicillin?
brand names to question patients in this situation is important, as many
patients wouldn’t recognize the jumble of letters that is
You can develop your own arsenal of questions to ask patients, but the important part is to talk to them. No further strategies are needed if you can rule out the documented allergy just from a 90-second conversation.
The other piece that is absolutely necessary before proceeding is looking through the patient’s medication history yourself. If a patient with a documented penicillin allergy received ceftriaxone without issue on an admission last year, you can go ahead and give full-dose ceftriaxone during this admission if needed. The patient interview and medication history review can rule out >50% of documented allergies in my experience. In these situations, you can skip directly to the last section of this post: allergy re-labelling.
In patients with a very low probability of allergic
reaction, a beta-lactam antibiotic can usually be given without pause. Situations
where you can rule out an allergy based on patient interview or medication
history can be “challenged” directly. This means giving the full dose of the
preferred antibiotic and monitoring for any adverse effects. Some institutions
also give a direct oral amoxicillin challenge with 250-500 mg of amoxicillin
once prior to the intended beta-lactam initiation. If the patient can tolerate
amoxicillin, any penicillin antibiotic can be given in the future without fear
of experiencing an IgE-mediated reaction.
When you are not able to completely rule out an allergic reaction, a graded challenge is often the next logical step in hospitalized patients. Graded challenges are used when there is a low probability of an allergic reaction, but there is still a degree of discomfort giving the entire dose up front. In general, 10% of the full dose is given, the patient is monitored closely for 30 minutes, and then the full dose is given if no issues arise. If the patient tolerates these doses, you can rule out immediate hypersensitivity reactions and document the tolerance in the medical record, which will be discussed at the end of this post.
In patients who have confirmed or a high probability of severe IgE-mediated reactions to beta-lactams, but a beta-lactam is necessary for treatment, desensitization can be used. The desensitization procedure usually involves at least 12 doses of escalating concentrations of the required medication. This procedure requires incredibly close monitoring, which at most hospitals requires admission to the intensive care unit for administration. If a patient is able to tolerate desensitization, the patient must then begin regularly scheduled doses of the beta-lactam immediately upon the protocol completion. If doses are missed, the patient must be desensitized again. Desensitization does not rule out the allergy. The patient is still considered allergic to that agent, but can tolerate the medication for the course required in that instance.
Penicillin (PCN) skin testing has increased in popularity recently due to its relative ease of use and efficacy at ruling out IgE-mediated allergic reactions. In addition to rescue medications that should be handy just in case (diphenhydramine, methylprednisolone, and epinephrine) the skin test consists of 4 elements:
Initially, a percutaneous puncture test is done on the
patient’s forearm with each of the elements and if tolerated, an intradermal
test of each is also performed. The entire process generally takes around 45-60
minutes to complete and offers a negative predictive value for penicillin
allergies of ~99%.2 Debate has surrounded the cost (both time and
materials for the procedure), but multiple studies have now shown penicillin
skin testing to be a cost-saving venture.2-5
Penicillin skin testing seems like a no-brainer, carrying the lowest risk of the procedures discussed thus far and its low overall cost for the health system. But in many institutions, it’s unclear who will perform the testing when allergy consultation is not available. In a 2015 survey of 736 infectious diseases providers, 57% responded saying that they do not have local options for skin testing.6 Does your institution?
The people of Twitter have spoken and it resulted in similar responses, with 62% of respondents not having penicillin skin testing available at their institution. Previous studies have reported on the successes of penicillin skin testing performed by allergists,7-9 & many more antimicrobial stewardship programs,10 infectious diseases fellows/physicians,11 nurses,12 and pharmacists.13,14 If you’ve read this far into the post, you likely are interested in allergy skin testing, so I’d implore you to own the process if your institution doesn’t already have skin testing available! ALK provides some excellent instructional videos on their website to guide you through the testing process. Pharmacists aren’t licensed to perform skin testing in all 50 states, but they are in many of them, which this 2019 article did an admirable job exploring.15
The last fundamental step in navigating beta-lactam allergies is updating the patient’s allergy label. With all of the previous interventions, the allergy documentation can be further described in the medical record, with desensitization being the only intervention that does not rule out IgE-mediated reactions altogether.
In an ideal world, inaccurate allergy labels should be removed from the medical record. Unfortunately, this practice often leads to redocumentation of the allergy at a later admission however.16 Many hospitals have integrated innovative ways to improve this repetitive cycle, as seen via providers’ personal experiences here, here, and here. For those without the tech support for any of this functionality though, the best thing to do is to document, document, document.
The majority of penicillin allergy labels do not belong to patients with true allergies and these unnecessary labels lead to worse patient outcomes. We should all strive for more accurate and detailed allergy documentation in our patients, which all starts with a patient interview. All of the interventions discussed above can be used to remove/relabel a beta-lactam allergy, with the exception of desensitization.
For those looking to learn more, I highly recommend a recent review published in JAMA that goes into further detail on penicillin allergies.17 Make sure to check out the supplementary material too, it has some super helpful resources, including a full allergy toolkit for penicillin skin testing and oral amoxicillin challenges!
Jones BM, Bland CM. Penicillin skin testing as an antimicrobial stewardship initiative. Am J Health-Syst Pharm. 2017;74:232-7
Mattingly TJ, Meninger S, Heil EL. Penicillin skin testing in methicillin-sensitive staphylococcus aureus bacteremia: A cost-effectiveness analysis. PLoS One. 2019; 14(1):e0210271. doi: 10.1371/journal.pone.0210271
Jones BM, Avramovski N, Concepcion AM, Crosby J, Bland CM. Clinical and Economic Outcomes of Penicillin Skin Testing as an Antimicrobial Stewardship Initiative in a Community Health System. Open Forum Infect Dis. 2019;6(4): ofz109. doi: 10.1093/ofid/ofz109
Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8(6):341-345
Trubiano JA, Beekmann SE, Worth LJ, et al. Improving antimicrobial stewardship by antibiotic allergy delabeling: evaluation of knowledge, attitude, and practices throughout the Emerging Infections Network. Open Forum Infect Dis. 2016; 3(3):ofw153
Macy E, Shu YH. The Effect of Penicillin Allergy Testing on Future Health Care Utilization: A Matched Cohort Study. J Allergy Clin Immunol Pract. 2017;5(3):705-710
Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol. 2006;97(5):681-687
Leis JA, Palmay L, Ho G, et al. Point-of-Care β-Lactam Allergy Skin Testing by Antimicrobial Stewardship Programs: A Pragmatic Multicenter Prospective Evaluation. Clin Infect Dis. 2017;65(7):1059-1065
Heil EL, Bork JT, Schmalzle SA, et al. Implementation of an Infectious Disease Fellow-Managed Penicillin Allergy Skin Testing Service. Open Forum Infect Dis. 2016;3(3):ofw155
Macy E, Roppe LB, Schatz M. Routine Penicillin Skin Testing in Hospitalized Patients with a History of Penicillin Allergy. Perm J. 2004;8(3):20-24
Chen JR, Tarver SA, Alvarez KS, Tran T, Khan DA. A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients. J Allergy Clin Immunol Pract. 2017;5(3):686-693
Wall GC, Peters L, Leaders CB, Wille JA. Pharmacist-managed service providing penicillin allergy skin tests. Am J Health Syst Pharm. 2004;61(12):1271-1275
Bland CM, Bookstaver PB, Griffith NC, et al. A practical guide for pharmacists to successfully implement penicillin allergy skin testing. Am J Health Syst Pharm. 2019;76(3):136-147
Rimawi RH, Shah KB, Cook PP. Risk of redocumenting penicillin allergy in a cohort of patients with negative penicillin skin tests. J Hosp Med. 2013;8(11):615-618
Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019;321(2):188-199
This post is the second in a three-part series covering the management of beta-lactam allergies, all to be released on FOAMid over the last few months of 2019. Part 1 explained the enormous impact that penicillin allergies have on patient outcomes. Today we’ll discuss the different types of allergic reactions and the potential for beta-lactam allergy cross reactivity. Let’s jump right in!
Types of Allergic
The most common way of grouping immune-mediated
hypersensitivity reactions is through the Gell & Coombs classification
method.2 Using this scheme, there are four types of allergic
Type I reactions are IgE-mediated reactions and commonly referred to as immediate-type hypersensitivity reactions, since they occur minutes to hours post-exposure to an allergen. Type I reactions include anaphylaxis, angioedema, hypotension, flushing, wheezing, hives, and urticaria.
Both types II and III reactions are IgG-mediated. Type II reactions, or cytotoxic reactions, include hemolytic anemia, thrombocytopenia, and neutropenia. Type III reactions are immune complex reactions, and include serum sickness, glomerulonephritis, and arthritis.
Last, but certainly not least, are type IV reactions, which are T-cell mediated. Type IV reactions are commonly referred to as delayed hypersensitivity reactions, despite Types II, III, and IV all technically being delayed in nature by days to weeks post-exposure to an allergen. A maculopapular rash, interstitial nephritis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome are all considered type IV reactions.
As discussed in the first post, many recorded antibiotic allergies are not true allergies. But when a patient does actually have a true penicillin allergy, what are the chances that the patient will have a similar reaction to other beta-lactams?
While we would generally avoid penicillins in this
situation, other beta-lactams like cephalosporins and carbapenems could
potentially be used. Previous studies of 10-25% cross-reactivity between
cephalosporins and penicillins were primarily reported prior to 1982, when
cephalosporin manufacturing processes were often contaminated with penicillin.12
Since then, the documented rate of cross-reactivity has dropped dramatically, shown
in the table below.12
Cephalosporins that do not share a side chain with penicillin have a cross-reactivity risk of <2%
Cephalosporins that do share a similar side chain to penicillins (ex. cefoxitin and penicillin) have a cross-reactivity risk that is much higher
Side chain similarities don’t guarantee cross-reactivity,
but they do increase the risk above the previously stated 2% threshold
But hold on, I thought the cause of beta-lactam allergies
was the core beta-lactam ring that everyone remembers from their undergraduate
Not so fast. While this plays a part,
more recent literature has shown that the R1 and R2 side
chains also play a role in the allergy potential of cephalosporins. I
have adopted and updated a table from an excellent 2008 review paper by Daryl
DePestel and colleagues below.3
In this table, the 3s, 6s, and 7s stand for similar R1
or R2 side chains, as described in the cephalosporin skeleton
molecule, also seen below.
The R1 side chain is at the
7-position on the cephalosporin molecule and the 6-position on the penicillin
The R2 side chain is
at the 3-position, which only differs among cephalosporins and not penicillins.
There are a couple of important clinical points to note from this table. Probably most important for clinical practice is that cefazolin does not share side chains with any other beta-lactam agents. This can have huge consequences on the use of cefazolin in practice, especially when it comes to surgical site prophylaxis and the treatment of methicillin-susceptible Staphylococcus aureus infections, both situations that could use cefazolin as first line therapy.
And while aztreonam is known as a beta-lactam with limited cross-reactivity due to dissimilar side chains, it does actually share a side chain with ceftazidime and the more recently approved ceftolozane (marketed in combination with tazobactam).
Speaking of aztreonam, we’ve spent the majority of this post
discussing cephalosporin cross-reactivity risk. Now let’s spend a bit of time
reviewing the other agents defined in the initial table in this post:
carbapenems and aztreonam. Cross-reactivity between these agents and penicillins
is minimal, as seen by a number of studies published by an Italian group headed
by Antonino Romano and Francesco Gaeta.4,7,9
In their 2013 analysis, they found no patients had an allergic reaction to carbapenems, despite all 204 patients having a well-demonstrated T-cell-mediated hypersensitivity reaction to other beta-lactams (mostly penicillin).7
They went on to look at IgE-mediated hypersensitivity in their 2015 study, which found yet again no cases of hypersensitivity with either carbapenems OR aztreonam this time in a cohort of 212 patients with proven penicillin allergies.4
Then in 2016, they went back to T-cell-mediated hypersensitivity, examining 214 patients with proven reactions to penicillins and testing them against aztreonam. Once again, zero patients reacted to the aztreonam test doses or full dose.9
At this point, you may be questioning if the Italian group ever saw any reactions in their trial outcomes. The last study presented above that showed no reactions with aztreonam though tested more than just aztreonam. They also looked at cephalosporins and saw an 18.7% chance of positive skin testing with aminocephalosporins (cephalexin, cefadroxil, cefaclor).9 If you refer back to the previous cross-reactivity table, you can see that these three agents share a side chain with ampicillin and amoxicillin.
So while side chains play a key role in determining cross-reactivity among cephalosporins, we can be fairly confident that carbapenems and aztreonam are safe to administer in the majority of situations, especially when a non-severe penicillin allergy is documented. This will be covered in more detail in the next (and final) installment of “A Rash of Beta-Lactam Allergies,” coming to you soon!
Coombs P, Gell PG. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: G RR, P.G.H Gell, eds. Clinical aspects of immunology. Oxford, UK: Oxford University Press, 1968; 575-596
Frumin J, Gallagher JC. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother. 2009; 43:304-315
Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A. Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2015; 135:972-976
Joint Task Force on Practice Parameters; American Academy, American College, & Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010; 105:259-273
Legendre DP, Muzny CA, Marshall GD, Swiatlo E. Antibiotic hypersensitivity reactions and approaches to desensitization. Clin Infect Dis. 2014; 58(8):1140-1148
Romano A, Gaeta F, Valluzzi RL, et al. Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins. Allergy. 2013; 68:1618-1621
Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-reactivity among beta-lactams. Curr Allergy Asthma Rep. 2016; 16:24
Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016; 138:179-186
Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-reactivity and tolerability of cephalosporins in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol Pract. 2018; 6(5):1662-1672
Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019; 321(2):188-199
Trubiano JA, Stone CA, Grayson ML, et al. The 3 Cs of antibiotic allergy-classification, cross-reactivity, and collaboration. J Allergy Clin Immunol Pract. 2017; 5(6):1532-1542
This post marks part 1 of a 3-part series covering the management of beta-lactam allergies, all to be released on FOAMid over the next couple of months.
This post, “The Problem,” provides background and the impact of a reported beta-lactam allergy
“The Education” will delve into the types of allergic reactions, as well as cross reactivity potential among beta-lactam antibiotics
“The Solution” will then explore how to best assess a patient’s documented allergy
With that, let’s jump right in!
A whopping 10% of the general population has a reported penicillin (PCN) allergy. But only 1-10% of these people have a true allergy when tested. This leaves us with about 0.1-1% of the general population with a true penicillin allergy.
Why is there such a discrepancy between reported allergies and true allergies? A lot of it comes from inaccurate allergy histories, like the patient with GI upset as a child, but the allergy listed as an “unknown reaction.” Or better yet, the patient whose mother had an allergy and thus everyone in the family has been given that scarlet letter in their medical record.
Another important and lesser known reason for the allergy discrepancy is that 78% of patients with immediate hypersensitivity to penicillin see their penicillin allergy fade after 10 years (from this 1981 study). So those adult patients with childhood reactions? The odds are that they aren’t still allergic decades later.
Why should we care?
When it comes to infectious diseases, beta-lactam antibiotics are often our first- and second-line options for treatment. A documented penicillin allergy can essentially knock a practitioner down to third-line treatment in some situations. In just highlighting a few common infections and organisms, look at how often beta-lactams are brought up:
When a patient has a documented penicillin allergy, studies have proven that beta-lactam usage decreases while non-beta-lactam usage increases (Lee 2000, as well as half of the citations provided at the end of this post). And when beta-lactams are avoided, patients tend to do worse.
Impact on Patient
The impact of a penicillin allergy is real and detrimental to our patients. Rather than bore you with paragraphs upon paragraphs detailing the many studies looking into this fact, here are some take-home points hyperlinked to the primary literature supporting the claims:
There is clear evidence that reported beta-lactam allergies
pose a problem on the path to prescribing optimal treatment in infectious
diseases. We can combat the issue however through education and assessment
More to come in parts 2 and 3 of “A Rash of Beta-Lactam Allergies”!
Al-Hasan MN, Acker EC, Kohn JE, Bookstaver PB, Justo JA. Impact of penicillin allergy on empirical carbapenem use in gram-negative bloodstream infections: an antimicrobial stewardship opportunity. Pharmacotherapy. 2017; 38(1):42-50
Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015; 132:1435-1486
Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ. 2018; 361:k2400
Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018; 66(3):329-336
Borch JE, Andersen KE, Bindslev-Jensen C. The prevalence of suspected and challenge-verified penicillin allergy in a university hospital population. Basic Clin Pharmacol Toxicol. 2006; 98:357-362
Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect. 2013;14(1):73-156
Charneski L, Deshpande G, Smith SW. Impact of an antimicrobial allergy label in the medical record on clinical outcomes in hospitalized patients. Pharmacotherapy. 2011; 31(8):742-747
Conway EL, Lin K, Sellick JA, et al. Impact of penicillin allergy on time to first dose of antimicrobial therapy and clinical outcomes. Clin Ther. 2017; 39(11):2276-2283
Huang KHG, Cluzet V, Hamilton K, Fadugba O. The impact of reported beta-lactam allergy in hospitalized patients with hematologic malignancies requiring antibiotics. Clin Infect Dis. 2018; 67(1):27-33
Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding β-lactams in patients with β-lactam allergies. J Allergy Clin Immunol. 2016; 137(4):1148-1153
Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63(5):e61-e111
Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000;160(18):2819-2822
Macy E, Ngor EW. Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin. J Allergy Clin Immunol Pract. 2013; 1:258-263
Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014; 133(3):790-796
Solensky R. The time for penicillin skin testing is here. J Allergy Clin Immunol Pract. 2013; 1(3):264-265
Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014; 59(2):e10-e52
Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39:1267-1284
van Dijk SM, Gardarsdottir H, Wassenberg MW, Oosterheert JJ, de Groot MC, Rockmann H. The high impact of penicillin allergy registration in hospitalized patients. J Allergy Clin Immunol Pract. 2016; 4:926-931
When I was an aspiring Infectious Disease fellow, I marveled at how the ID doctors would come up with diseases that no one else had thought of. How did they do that?
They obtain a detailed patient history. (It’s the ID doctors equivalent of a procedure!)
Contact or exposure to certain animals are associated with certain diseases.
These are examples of some of the questions to ask to ascertain whether your patient has been in contact with specific animals: – Do you have any pets? Do you have frequent contact with anyone else’s pets? – Do you have contact with any farm or wild animals? – What do you do for work (farmer, veterinarian, kennel worker, biologists, etc)? – What do you do for fun (hunting, fishing, cave explorer, raising chickens, etc)?
I’ve created an easy graphic to give you an idea of some diseases that are associated with different animals your patients might encounter. This is to help you quickly look up which infections you should consider in your differential if your patient reports an exposure to one of these animals.
*This list does not include ALL pathogens. This is just a list of the most common plus others to think about in certain situations. In places outside of North America, this list may look different. **This is not intended to take the place of a formal infectious disease consult. ***Use this chart in the context of the clinical presentation. It does not mean you should test for all these infections in every patient, but rather gives you a quick reminder to consider them in your differential.
Was this helpful? Did I miss something? Tell me what you’re thinking with a comment!
1. Centers for Disease Control and Prevention. Healthy Pets Healthy People. http://www.cdc.gov/healthypets/pets/cats.html (Accessed on Feb 23, 2019). 2. Day MJ. Pet-Related Infections. Am Fam Physician. 2016; 94(10):794-802. 3. Goldstein EJC and Abrahamian FM. Diseases Transmitted by Cats. Microbiol Spectr. 2015; 3(5). 4. Chomel BB. Emerging and Re-emerging Zoonoses of Dogs and Cats. Animals (Basel). 2014; 4(3):434-445. 5. Dyer JL, Yager P, Orciari L et al. Rabies surveillance in the United States during 2013. J Am Vet Med Assoc. 2014; 245(10):1111-1123. 6. Boseret G, Losson B, Mainil JG, et al. Zoonoses in pet birds: review and perspectives. Vet Res. 2013; 44(1): 36. 7. Kwon-Chung KJ, Fraser JA, Doering TL, et al. Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis. Cold Spring Harb Perspect Med. 2014; 4(7):a019760. 8. National Association of State Public Health Veterinarians, Inc. (NASPHV), Centers for Disease Control and Prevention (CDC). Compendium of measures to prevent disease associated with animals in public settings, 2011: National Association of State Public Health Veterinarians, Inc. MMWR Recomm Rep 2011; 60:1. 9. Kotton CN. Zoonoses from pets other than dogs and cats. UpToDate. Published Jan 2019. Accessed on Feb 23, 2019.
This post is co-written with the guest writer Ahmed Abdul Azim, MD.
Not all fevers are caused by infections.
It is important that every patient presenting with fever is evaluated for an infection….. but what do you do when no infection is found?
Why are non-infectious causes of fever important to know?
If a patient is treated for a presumed infectious fever when they don’t have an infection:
there is a delay in identifying the correct diagnosis
they are exposed to prolonged courses of unnecessary antibiotics
Definition of fever
Fever = 38.3°C (101°F) or above1
Pyrogenic agents = substances that can induce a fever.
a) Exogenous pyrogens – external substances that activate our immune system to induce a fever (ex. microbial toxins)
b) Endogenous pyrogens – cytokines that induce fever in our body
(ex. IL-1, IL-6, tumor necrosis factor, IFN-α, ciliary neutrotrophic factor, and likely others)
Non-infectious causes of fever:
1. Rheumatologic/autoimmune – activation of immune system that stimulates the production of pyrogenic cytokines
– the cause of ~30% of fevers of unknown origin
a) Adult-onset Still’s disease – younger patients, daily fevers >39°C, rash, arthritis
b) Giant cell arteritis – older patients, vision changes, jaw claudication
c) Others – polyarteritis nodosa, Takayasu’s arteritis, granulomatosis with polyangiitis, etc.
a) Lymphomas and leukemias – most common; seen in high burden of disease
b) Myelodysplastic syndromes
c) Renal cell carcinoma – ~20% of cases present with fevers
d) Hepatocellular carcinoma or liver metastases
e) Atrial myxomas
3. Drug-induced fever – 3-5% of drug-related adverse reaction in hospitalized patients include fevers6 – typically occurs 7-10 days after drug initiation, but can be as soon as 24 hours and as far away as a few years from drug initiation7 – patients typically appear “inappropriately” well
– eosinophilia (>500/mm3) occurs in 20-25% of patients with drug-induced fevers10 – PATHOPHYSIOLOGY:
a) Hypersensitivity reaction – due to activation of T cell immune response by drug, its metabolite, or the formation of an immune complex
– typically occurs ~3-10 days after drug exposure
– typically resolves 72-96 hours after discontinuation of drug (but can be more delayed)
– symptoms will recur immediately upon rechallenge
1) Antimicrobials – most common cause of drug fever
– minocycline, beta-lactams (penicillin-based > cephalosporins10), sulfonamides, nitrofurantoin
2) Anticonvulsants – carbamazepine, phenytoin, phenobarbital
– DRESS syndrome – a severe type of drug hypersensitivity reaction
(typically occurs 2-6 weeks after drug exposure)
b) Administration-related – typically last <48 hours
1) Vaccines – stimulation of the immune system → release of pyrogenic cytokines
2) Amphotericin B – exogenous pyrogenic agents
c) Pharmacologic action of the drug– transient fever; self-resolving
1) Anti-neoplastic agents – cause severe and rapid tumor cell lysis → release of endogenous pyrogenic agents → inflammatory response (fever)
2) Antimicrobials – cause rapid death of microbes → microbial cell lysis → release of exogenous pyrogenic substances → inflammatory response (fever)
– ex. Jarisch-Herxeimer reaction in syphilis treatment with penicillin
d) Altered thermoregulation – disturbance of the central hypothalamic thermoregulation function and/or increased heat production
1) Transfusion of blood cells – RBCs, platelets, WBCs
2) Central fevers – fevers due to central thermodysregulation due to CNS damage
– more common with CNS hemorrhage and brain tumors11 – fever onset within 72 hours of sustaining CNS hemorrhage
3) Thromboembolism – typically <102°F
4) Endocrine – thyroid storm; adrenal insufficiency
5) Pulmonary – ARDS, aspiration pneumonitis, cryptogenic organizing pneumonia
6) Intra-abdominal – acute pancreatitis, cholecystitis, mesenteric ischemia
*Non-infectious causes of fevers are diagnoses of exclusion. A patient MUST have an appropriate workup for infectious causes prior to considering any of the non-infectious causes of fever.
*A lot of these diagnoses need to be made based on clinical symptoms and signs and requires a high degree of suspicion.
*Fever is a sign of an underlying inflammatory process. DO NOT TREAT THE FEVER — TREAT THE UNDERLYING CAUSE.
O’Grady NP, Barie PS, Bartlett JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med. 2008; 36(4):1330-1349.
Dekker AR, Verheij TJ, and van der Velden AW. Inappropriate Antibiotic Prescription for Respiratory Tract Indications: Most Prominent in Adult Patients. Family Practice. 2015; 32(4):401-407.
Mackowiak PA, Wasserman SS, and Levine MM. A Critical Appraisal of 98.6°F, the Upper Limit of the Normal Body Temperature, and Other Legacies of Carl Reinhold August Wunderlich. JAMA. 1992; 268(12):1578-1580.
Obermeyer Z, Samra JK, and Mullainathan S. Individual Differences in Normal Body Temperature: Longitudinal Big Data Analysis of Patient Records. BMJ. 2017; 359:j5468.
Westbrook A, Pettila V, Nichol A, et al. Transfusion Practice and Guidelines in Australian and New Zealand Intensive Care Units. Intensive Care Med. 2010; 36(7):1138-1146.
Lipsky, BA and Hirschmann JV. Drug Fever. JAMA. 1981; 245(8):851-854.
Mackowiak, PA. Southwestern Internal Medicine Conference: Drug Fever: Mechanisms, Maxims and Misconceptions. Am J Med Sci. 1987; 294(4):275-286.
Patel, RA and Gallagher JC. Drug fever. Pharmacotherapy. 2010; 30(1):57-69.
Johnson DH and Cunha BA. Drug fever. Infect Dis Clin North Am. 1996; 10(1):85-91.
Oizumi K, Onuma K, Watanabe A, et al. Clinical Study of Drug Fever Induced by Parenteral Administration of Antibiotics. Tohoku J Exp Med. 1989; 159(1): 45-56.
Hocker SE, Tian L, Li G, et al. Indicators of Central Fever in the Neurologic Intensive Care Unit. JAMA Neurology. 2013; 70(12):1499-1504.
Porat R and Dinarello CA. Pathophysiology and treatment of fever in adults. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/pathophysiology-and-treatment-of-fever-in-adults]. Accessed Dec 26, 2018.
During the first week of October, the Infectious Diseases Society of America (IDSA) hosted its’ annual Infectious Diseases conference (IDWeek) in San Francisco, California.
There are a variety of reviews of the conference on the internet (the most famous being the Mini Really Rapid Review by Dr. Paul Sax) but I want to highlight the studies that are pertinent to physicians in other specialties outside of ID.
Two major studies highlighted the ongoing pressures and scope for over-prescription of antibiotics and need for antimicrobial stewardship
In one study, 66.1% of patients were prescribed antibiotics for respiratory tract infections and antibiotic prescribing was associated with higher patient satisfaction. Given that most respiratory tract infections are viral, 66% is a lot!
Another study showed that 20% of antibiotics are prescribed without an in-person visit. Of all the 509,534 antibiotic prescriptions, 46% were not associated with an infection-related diagnosis. This highlights the need for better provider and patient education in antibiotic stewardship.
IV drug use may be an independent risk factor for candidemia.
This study showed an increasing incidence of candidemia and higher numbers of patients with candidemia who are persons who inject drugs without other risk factors. Something to keep in mind when you see patients who inject drugs in your hospital.
And for those of you in San Francisco, watch out for these microbes:
A precursor to calcitonin and thus consistently produced by the thyroid gland C cells
An acute phase reactant (and can be used as a marker of a bacterial infection in the body)
procalcitonin levels parallel severity of the infection/systemic inflammation
increases are detectable ~4 hours after exposure to endotoxin and peaks at 12-48 hours
Why isn’t procalcitonin produced in response to a
It is hypothesized that tumor necrosis factor (TNF) is essential to the synthesis of procalcitonin. When the body is exposed to a viral infection, the virus induces production of interferons which in turn suppresses TNF expression.
Why do we need it?
Studies have shown that up to 50% of antimicrobial use in the inpatient setting is unnecessary. Part of the reason is that we don’t always know who has a bacterial infection and who does not.
A blood test that can help differentiate types of infection and help shorten the duration of unnecessary antibiotics would be extremely helpful to physicians and beneficial to patients.
How does it work?
Procalcitonin level is measured in the blood with a blood-draw
Can be run from EDTA (purple) or heparin (green) tubes but NOT citrate-containing tubes
Levels correlate with severity of the infection/systemic inflammation
When/how do you use it?
The data on how best to use procalcitonin and when to use it remains controversial, and each institution may have their own guidelines on how best to utilize it.
Studies demonstrate that procalcitonin can be used to determine:
Whether to initiate antibiotic therapy
Duration of antibiotic therapy
The TWO scenarios with the most literature suggesting procalcitonin use is helpful are in guiding duration of antibiotic therapy in:
Lower Respiratory Tract Infections (LRTI)
Summary of some major trials in each area
Lower respiratory tract infections A)Schuetz et al. 2017 (Cochrane Systematic Review) – Cochrane systematic review of RCTs to evaluate procalcitonin in guiding initiation or discontinuation of antibiotics
– moderate to high quality evidence; 6708 participants, 26 trials Primary outcomes: 1) all-cause mortality, 2) treatment failure at 30 days All-cause mortality:6% vs. 10% (controls); p-value = 0.037 Treatment failure: no significant difference (23-24% in both groups) Secondary outcomes: 1) antibiotic use, 2) antibiotic-related side effects,
3) Hospital Length of Stay (LoS) # of antibiotic days: 2.4 day reduction in antibiotic exposure (5.7 vs 8.1 days) Side effects of antibiotics: 16.3% vs. 22.1% (control), (p-value <0.001) LoS in hospital and ICU: no difference Summary: improved mortality and increase in antibiotic-free days between the two groups B)Huang et al. 2018 (ProACT study) – Multicenter RCT, 1656 patients enrolled
– Procalcitonin was checked in the ED and followed during hospital course if patient was admitted
– There was no difference in # of antibiotic exposure days over 30 days, rates of adverse events, or hospital length of stay (LoS)
– There was no difference even when stratified by diagnosis of acute bronchitis, COPD, CAP, and other LRTI. Summary: no change in # of antibiotic-exposure days or adverse effects between the two groups
Severe sepsis/shock A) DeJong et al. 2016 – Multicenter RCT in hospitals, 1575 enrolled Mortality: 20% vs. 25% (control) (p=0.0122) Median antibiotic duration: 7.5 days vs. 9.3 days (control); p-value <0.0001
– There was a slightly higher risk of reinfection in the procalcitonin group (5% vs. 2.9%, p=0.0492)
– No difference between ICU and hospital LoS between groups Summary: Use of procalcitonin reduced mortality and # of antibiotic exposure days but not LoS B) Andriolo et al. 2017 (Cochrane Systematic Review) – 10 trials, 1215 participants, low quality evidence
– No significant differences in mortality at 28 days, ICU discharge, or hospital stay
– Procalcitonin group had a mean 1.28 day less of antibiotic exposure than control group Summary: Use of pro-calcitonin reduced # antibiotic exposure days but not mortality C) Wirz et al. 2018
– Meta-analysis of RCTs
– 4482 patients overall Mortality: lower in the procalcitonin group (21.1% vs. 23.7%, p=0.03) # of antibiotic days: lower in procalcitonin group (9.3 vs. 10.4d, p<0.001) Summary: Use of procalcitonin reduces mortality and # of antibiotic exposure days
*It’s important to remember that all these trials have varying adherence to the protocols, various study populations, and centers with varying practice patterns that all affect the results of the studies.
**Procalcitonin should NOT typically be used for determine whether to initiate antibiotics in pneumonia or sepsis given the high risk of a poor outcome with a false negative result.
How to use it
Obtain procalcitonin at time of diagnosis and repeat every 1-2days.
Stop antibiotics when procalcitonin level is <0.1-0.5ng/ml or decreased by at least 50-90% from peak value
*Procalcitonin can also be used when it is unclear whether a patient has a bacterial infection or not to help guide further management.
Other potential uses of PCT
Presence of bacterial infection in patients with COPD exacerbations, heart failure exacerbations, or bronchitis
Aspiration pneumonia vs. pneumonitis
Fevers of unknown origin
UTI therapy duration
Bacterial vs. viral meningitis
Lower limb swelling
(distinguishing between stasis dermatitis vs. thrombosis vs. cellulitis)
And many others
short half-life (25-30 hours)
dialyzed; in ESRD, levels tend to be higher prior to dialysis than after dialysis
peak levels tend to correlate with severity of infection
if inflammation is resolving, levels should decrease by ~50% every 1-2 days.
⇒mild elevation = 0.15-2ng/mL
a) localized bacterial infection
b) ESRD without recent hemodialysis
c) noninfectious systemic inflammatory response
⇒significant elevation > 2ng/mL
a) bacterial sepsis or severe localized bacterial infection
b) severe non-infectious inflammatory stimuli (major burn, severe trauma, acute multisystem organ failure, bowel ischemia, stroke, major abdominal or cardiothoracic surgery)
c) false positive from malignancy
Pulmonary TB and some other non-tuberculosis mycobacterial infections
Severe systemic stress (trauma, severe burns, surgery, cardiac arrest/shock, Addisonian crisis, pancreatitis, intracranial hemorrhage)
*possibly due to gut translocation of LPS
if drawn too early in infection (typically rises within 2-5 hours)
Procalcitonin levels are NOT impaired in immunocompromised hosts (ICH) ⇒however, little information is known regarding use of procalcitonin in this patient population
⇒these patients have a low threshold for antibiotic initiation and prolonged duration thus no recommendations can be made to use procalcitonin to guide management in ICH at this time
⇒not enough data exists yet to support routine clinical use.
Not enough data exists yet to support routine clinical use in surgical patients surgical patients may have a higher baseline procalcitonin level after certain surgeries
Procalcitonin can be thought of similarly to B-natriuretic peptide (BNP) and as a more sensitive C-reactive protein (CRP). It can be used within a broader clinical context to support a diagnosis or decision regarding antibiotics and is useful in RULING OUT bacterial causes.
Use of procalcitonin and its algorithms should NOT override or replace clinical judgment.
Serial measurements and trends are more helpful than one isolated value.
A rising procalcitonin level is not, by itself, an indication to broaden antibiotic therapy.
In order to use procalcitonin effectively, its essential to understand which pathogens induce elevations in procalcitonin.
The use of procalcitonin has been most studied in LRTI and sepsis. The utility of procalcitonin in other situations remains unknown.
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Wirz Y, Meier MA, Bouadma L, Luyt CE, Wolff M, Chastre J, et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: a patient-level meta-analysis of randomized trials. Critical Care. 2018; 22:191. https://doi.org/10.1186/s13054-018-2125-7.