Tag Archives: #foamID

A Rash of Beta-Lactam Allergies, Part 1: The Problem

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.

  1.  This post, “The Problem,” provides background and the impact of a reported beta-lactam allergy
  2. “The Education” will delve into the types of allergic reactions, as well as cross reactivity potential among beta-lactam antibiotics
  3. “The Solution” will then explore how to best assess a patient’s documented allergy

With that, let’s jump right in!

Overview

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 Outcomes

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:

Penicillin allergy patients:

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 techniques.

More to come in parts 2 and 3 of “A Rash of Beta-Lactam Allergies”!

by Jeff Pearson

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect. 2013;14(1):73-156
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. Solensky R. The time for penicillin skin testing is here. J Allergy Clin Immunol Pract. 2013; 1(3):264-265
  16. 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
  17. Sullivan TJ, Wedner HJ, Shatz GS, Yecies LD, Parker CW. Skin testing to detect penicillin allergy. J Allergy Clin Immunol. 1981; 66(3):171-180
  18. Trubiano JA, Chen C, Cheng AC, et al. Antimicrobial allergy ‘labels’ drive inappropriate antimicrobial prescribing: lessons for stewardship. J Antimicrob Chemother. 2016; 71:1715-1722
  19. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39:1267-1284
  20. 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

Latent vs. Active TB

Tuberculosis is the leading cause of death globally from an infectious agent. In 2017, an estimated 10 million people developed TB disease and an estimated 1.6 million died1. A recent study demonstrated that <57% of internal medicine housestaff across 7 academic institutions in the U.S. correctly answered 9 out of 10 questions assessing knowledge of assessment and diagnosis of tuberculosis2. This post addresses these questions and to helps clarify latent vs. active TB in a clinical setting.

The primary focus for this blog post is pulmonary TB. Be aware that although the most common presentation of TB is with pulmonary symptoms, TB can present anywhere in the body and sometimes can present without pulmonary symptoms.

But first, definitions.

Definitions

Latent infection – the bacteria lies dormant in the body and does not cause any symptoms, typically tests for latent infection (see later section) will be positive

Active disease – the individual is experiencing symptoms due to the infection in the body, typically with characteristic imaging findings and microbiological confirmation

Primary disease – immediate onset of active disease after infection

Reactivation disease – onset of active disease after a period of latent infection

Extra-pulmonary disease – presence of bacteria outside of the lungs (the primary organ of infection)

Disseminated disease – two or more noncontiguous sites resulting from lymphohematogenous dissemination

Miliary disease – lesions in the lung that resemble millet seeds; seen in some cases of disseminated TB

Step 1: Risk stratification

Risk factors for TB exposure

  • having close contact with individuals who have active tuberculosis (roommates, family, friends, caregivers)
  • living/had lived in a country that is endemic for TB
  • living/working in a prison
  • living/working in a homeless shelter
  • injecting drugs
  • living/working in any other facility/institution that has high rate of TB (hospitals, nursing homes, residential homes for HIV patients) 

*USPSTF gives a grade B recommendation for screening those at increased risk (see list above) for latent tuberculosis infection4

Risk factors for TB reactivation

A. Normal host

  • 5-10% of reactivating TB in a lifetime6,13
  • 50% of that 5-10% is within the first 2-5 years of infection6,13

B. Age – immunity weakens in the elderly

C. Immunosuppression

  • HIV
  • End stage renal disease
  • Diabetes mellitus
  • Lymphoma
  • Corticosteroid or TNF-alpha inhibitor use
  • Cigarette smoking

Step 2: Why is it important to distinguish latent TB from active TB?

The two syndromes are treated completely differently. Latent TB is non-infectious and does not require treatment to prevent progression of disease or transmission to others, but instead to prevent future reactivation. Active TB is infectious and needs to be treated to prevent spread of TB to others. The medications, doses and duration of therapy to treat these syndromes are also different from each other.

Active TB

A. Clinical symptoms

  • fevers/chills, night sweats, weight loss, SOB and/or cough
  • depending on site of TB disease, can have extrapulmonary symptoms (GI, CNS, spine, etc)
  • subacute to chronic onset of symptoms (typically > several weeks)

B. Imaging

  • will typically have active pulmonary abnormalities seen on imaging (this can be any type of abnormality – infiltrates, cavitary lesions, effusions, or solitary nodules)
  • although the most common cause of apical lung scarring is prior TB infection, lung abnormalities DO NOT have to be in the apices of the lungs (they can be anywhere)

Latent TB
(make diagnosis ONLY after you have excluded active TB)

A. Clinical symptoms

  • the patient is asymptomatic (= NO symptoms of active TB)

B. Imaging

  • there is no active lung abnormality on chest imaging
  • (calcified granulomas/nodules or anything that is deemed old, healed scarring is excluded)

*If there are any signs suggestive of active TB, then the patient should undergo active TB evaluation (discussed below). If there is no evidence of active TB, then treatment can be based on latent TB diagnostics (discussed below).

Step 3: Evaluating for TB – diagnostic tests

A. Active TB tests (pulmonary TB)

  • obtain 2-3 sputum samples, ideally at least 8 hours apart, may require sputum induction if patient is not able to cough up sputum.
  • one ideally should be in the morning (highest burden of TB in the morning due to pooling of secretions overnight)
  • obtaining a bronchoscopy sample only counts for one sample
  • send a nucleic acid amplification test (NAAT) on the 1st sputum sample

1. AFB smear – fluorochrome stain of the clinical specimen

  • sensitivity = 67.5% (95% CI, 60.6 to 73.9)8
  • specificity = 97.5% (95% CI, 97.0 to 97.9)8

2. AFB culture – the gold standard test for tuberculosis diagnosis

  • can take up to 6 weeks to grow for solid culture versus ~ 2 weeks for liquid culture

3. PCR = NAAT (nucleic acid amplification test) – this is a DNA test using amplification methods

  • GeneXpert MTB/RIF assay is a brand test that combines the NAAT with rapid test for rifampin resistance sensitivity and specificity are high in pulmonary tuberculosis but is lower when used on specimens other than sputum.
    • sensitivity: 98% (for smear-positive, culture-positive specimens in HIV-negative patients)9
    • specificity: 99%9
  • this test can be run on both AFB smear negative and positive specimens (although sensitivity is lower on AFB smear negative specimens)
  • more specific than the smear because it tests directly for tuberculosis genes, whereas positive AFB smears can be due to non-tuberculous mycobacteria or other acid-fast staining bacteria (i.e. Nocardia)
  • positive result → TB diagnosis
    negative result → does not rule out TB

B. Latent TB tests

1. Tuberculin Skin Test (TST) = Purified Protein Derivative (PPD)

  • intradermal injection of tuberculin material (many different materials available)
  • causes a delayed-type hypersensitivity response in individuals whose immune system has been exposed to TB before
  • positive test = induration at the injection site within 48-72 hours
  • negative test = no induration

Threshold for treatment

TB, tuberculosis; CXR, chest X-ray; HIV, human immunodeficiency virus; IBW, ideal body weight

*individuals who have received the BCG vaccine in the past may also test positive with this test since their immune systems have been exposed to TB via the vaccine (although immunity tends to wane within 10 years if vaccine is administered in infancy)

2. Interferon Gamma Release Assay (IGRA) = QuantiFERON-TB Gold or Plus  OR T-SPOT.TB

  • blood test for detection of cell-mediated immune response to TB antigen
  • not affected by BCG vaccine or BCG treatment
  • 80-90% sensitivity, >95% specificity (sensitivity is diminished in immunocompromised hosts)5
  • the QuantiFERON-TB Gold test is made up of 3 tubes:
    • negative control (everyone should not react)
    • positive control (everyone should react), and the
    • TB antigen that is recognized by CD4 cells
  • **QuantGold-PLUS (a new test) has added a 4th tube with TB antigen that binds to CD8 cells thereby increasing sensitivity of the test12
  • positive test → patient’s blood reacted to the TB antigen and positive control but not the negative control
  • negative test → patient’s blood did not react to the TB antigen but did react to the positive control
  • indeterminate test → patient’s blood did not react to the positive control so test is invalid (this typically happens when the patient is immunocompromised and cannot mount an immune response to the positive control and thus would not react to the TB antigen either – even if they were exposed to TB)

*Indeterminate result DOES NOT mean it is in the middle between negative and positive. It means the test cannot provide a valid result.

*all latent diagnostic tests can cross-react in individuals infected with non-tuberculous mycobacteria (TST more so than the IGRA)

*Neither test is 100% sensitive and specific – if the patient has high pre-test probability for TB exposure and for future TB reactivation, ID physicians will sometimes treat for latent TB despite the negative tests 

Step 4: Treating TB

Treatment is complex and both choice of medication and duration depends on a variety of clinical and microbiological factors. Here is a basic overview of the difference in treatment between latent and active TB.

A. Latent TB (CDC)

*This is a useful calculator to determine the risks and benefits of TB reactivation vs. side effects from treatment in an individual patient. 

            a) Isoniazid – daily for 6 to 9 months

            b) Rifampin – daily for 4 months

            c) Rifapentine and isoniazid – weekly for 3 months

B. Active TB
— depends on susceptibility of bacteria and clinical syndrome
— RIPE therapy is the standard first-line therapy for fully-susceptible pulmonary TB infection with 2 months of all four drugs followed by 4 months of rifampin and isoniazid.

  R = rifampin

  I = isoniazid

  P = pyrazinamide

  E = ethambutol

*Ethambutol can be discontinued if drug susceptibility testing confirms a fully susceptible strain

*Patients with extensive disease e.g. cavitation or who remain smear and/or culture positive at 2 months may require a longer duration of therapy.

Don’t forget to:

  • give daily Vitamin B6 with isoniazid to prevent peripheral neuropathy
  • get baseline eye exam when starting ethambutol to enable monitoring for optic neuritis, particularly in patients with abnormal renal function
  • evaluate for other co-morbidities such as HIV, hepatitis B or C, diabetes or substance use

References:

1. Global Tuberculosis Report 2018: Executive Summary. World Health Organization. Published Sept 2018. Accessed Mar 10, 201

2. Chida N, Brown C, Mathad J, et al. Internal Medicine Residents’ Knowlesge and Practice of Pulmonary Tuberculosis Diagnosis. OFID. 2018; 5(7).

3. Tuberculosis (TB). Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/tb. Accessed Feb 13, 2019.

4. US Preventive Services Task Force. Screening for Latent Tuberculosis Infection in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016; 316(9):962-969. doi:10.1001/jama.2016.11046

5. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Disease Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017; 64(2):111-115. doi: 10.1093/cid/ciw778

6. Horsburgh CR. Priorities for the Treatment of Latent Tuberculosis Infection in the United States. N Engl J Med. 2004; 350:2060-2067. DOI: 10.1056/NEJMsa031667

7. Pai M, Behr MA, Dowdy D, et al. Primer: Tuberculosis. Nature Reviews. 2016; 2:1-23.

8. Mathew P, Yen-Hong K, Vazirani B, Eng RHK, and Weinstein MP. Are Three Sputum Acid-Fast Bacillus Smears Necessary for Discontinuing Tuberculosis Isolation? J Clin Microbiol. 2002; 40(9):3482-3484. doi: 10.1128/JCM.40.9.3482-3484.2002

9. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, and Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2014 Jan 21;(1):CD009593. doi: 10.1002/14651858.CD009593.pub3.

10. Zeka AN, Tasbakan S, and Cavusoglu C. Evaluation of the GeneXpert MTB/RIF Assay for Rapid Diagnosis of Tuberculosis and Detection of Rifampin Resistance in Pulmonary and Extrapulmonary Specimens. 2011; 49(12):4138-4141. doi:10.1128/JCM.05434-11.  

11. Menzies D. Use of the tuberculin skin test for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults. UpToDate. Available from: https://www.uptodate.com/contents/use-of-the-tuberculin-skin-test-for-diagnosis-of-latent-tuberculosis-infection-tuberculosis-screening-in-adults#H9. Accessed Feb 13, 2019.

12. QuantiFERON®-TB Gold Plus (QFT®-Plus) ELISA [Package Insert]. Hilden, Germany: Qiagen; 2016.

13. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982; 125(3 Pt 2):8.

Non-infectious causes of fever

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?

thermometer2.png

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.

2. Malignancy – tumor cells release pyrogenic cytokines

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
3) Allopurinol
4) Others

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) Exogenous thyroid hormone
2) Anticholinergic drugs
3) Sympathomimetic agents

cold winter tablet hot

e) Idiosyncratic drug reactions

1) Serotonin syndromes – linezolid, SSRIs
2) Neuroleptic malignant syndrome
– anti-psychotics, dopamine antagonists
3) Malignant hyperthermia syndrome
– inhaled anaesthetics, paralytic agents
4) G-6-PD deficiency – dapsone, primaquine, nitrofurantoin, etc.

4. Other causes

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.

 

References:

  1. 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.
  2. 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.
  3. 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.
  4. Obermeyer Z, Samra JK, and Mullainathan S. Individual Differences in Normal Body Temperature: Longitudinal Big Data Analysis of Patient Records. BMJ. 2017; 359:j5468.
  5. 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.
  6. Lipsky, BA and Hirschmann JV. Drug Fever. JAMA. 1981; 245(8):851-854.
  7. Mackowiak, PA. Southwestern Internal Medicine Conference: Drug Fever: Mechanisms, Maxims and Misconceptions. Am J Med Sci. 1987; 294(4):275-286.
  8. Patel, RA and Gallagher JC. Drug fever. Pharmacotherapy. 2010; 30(1):57-69.
  9. Johnson DH and Cunha BA. Drug fever. Infect Dis Clin North Am. 1996; 10(1):85-91.
  10. 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.
  11. 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.
  12. 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.

Prevention of Clostridium difficile infection

Often, the focus of medical education is on clinical diagnosis and management of disease. But what about prevention? Prevention is key. Here are some ways for both the patient and healthcare provider to prevent further infections:

Prevent C.diff infographic

 

  1. Reduce transmission as much as possible
    1. Wash hands with soap and water after leaving the room of a patient with active C. difficile infection (CDI) OR use an alcohol-based hand sanitizer if a sink is not available
    2. Advocate healthcare facilities to:
      • place sinks nearby patient rooms
      • consider sink placement in the future construction of healthcare facilities
    3. Educate your patients and those who live with them to:
      • wash their hands well after using the toilet
      • have infected individuals use separate toilets and toilet accessories during treatment, if possible
  1. Avoid unnecessary antibiotic use
    • Avoid prescribing an antibiotic if low likelihood of bacterial infection
    • Narrow broad-spectrum antibiotics as soon as possible
    • Discontinue antibiotics as soon as possible
  2. Consider prophylactic PO vancomycin for patients with history of recurrent C. difficile infection
    • A retrospective review demonstrated that administration of PO vancomycin 125mg twice a day was associated with a lower incidence of recurrent C. difficile infection (4.2% vs. 26.6%, p<0.001)3 
  1. Educate yourself on the risks and benefits of probiotic use and be able to relay that information to your patients if they ask.
    • Some studies show no reduction in incidence of C. difficile infection with probiotic use6,7
    • Other studies (including a Cochrane review) show significant reduction in C. difficile infection incidence with probiotic use8,9,10,11
    • Studies have demonstrated that probiotics are more likely to reduce C. difficile infection incidence:
      • in patients with a baseline risk of C. difficile infection > 5%8,9
      • when probiotics are administered at higher doses10
      • when the probiotic consists of multiple strains10
      • when probiotics were administered within 2 days of antibiotic initiation11
    • This is the IDSA Clinical Practice Guidelines for C. difficile infection statement on probiotics:
      “There are insufficient data at this time to recommend administration of probiotics for primary prevention of CDI outside of clinical trials (no recommendation).”
      The guidelines cite the bias towards probiotics in many trials that enrolled mostly patients at very high risk of C.difficile infection and the potential for probiotics to cause harm by introducing new infections to hospitalized patients.

 Any prevention strategies I didn’t mention? What do you think is the most effective prevention strategy? I would love to hear your thoughts!

 

References

  1. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018; 66(7):1-48.
  2. Jorgensen JH, Pfaller MA, Carroll KC, et al. Manual of Clinical Microbiology, Eleventh Edition.
  3. Van Hise NW, Bryant AM, Hennessey EK, et al. Efficacy of Oral Vancomycin in Preventing Recurrent Clostridium difficile Infection in Patients Treated With Systemic Antimicrobial Agents. Clin Infect Dis. 2016; 63(5):651-653.
  4. Kelly CP, Lamont JT, and Bakken JS. Clostridium difficile infection in adults: Treatment and prevention. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-treatment-and-prevention]. Accessed May 25, 2018.
  5. Davidson LE and Hibberd PL. Clostridioides difficile and probiotics. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridioides-formerly-clostridium-difficile-and-probiotics]. Accessed Nov 13, 2018.
  6. Allen SJ, Wareham K, Wang D, Bradley C, Hutchings H, Harris W, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013; 382(9900): 1249-57.
  7. Ehrhardt S, Guo N, Hinz R, Schoppen S, May J, Reiser M, et al. Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial. Open Forum Infect Dis. 2016; 3(1):ofw011.
  8. Goldenberg JZ, Yap C, Lytvyn L, Lo CK, Beardsley J, Mertz D, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017; 12:CD006095.
  9. Johnston BC, Lytvyn L, Lo CK, Allen SJ, Wang D, Szajewska H, et al. Microbial Preparations (Probiotics) for the Prevention of Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants. Infect Control Hosp Epidemiol. 2018; 39(7): 771-781.
  10. Johnston BC, Ma SSY, Goldenberg JZ, Thorlung K, Vandvik PO, Loeb M, et al. Probiotics for the Prevention of Clostridium difficile-Associated Diarrhea. Ann of Intern Med. 2012; 157:878-888
  11. Shen NT, Maw A, Tmanova LL, Pino A, Ancy K, Crawford CV, et al. Timely Use of Probiotics in Hospitalized Adults Prevents Clostridium difficle Infection: A Systematic Review With Meta-Regression Analysis. Gastroenterology. 2017; 152(8): 1889-1900.

 

 

 

 

IDWeek 2018 Review

Dolores Park SF
Mission Dolores Park in San Francisco – photo courtesy of Ahmed Abdul Azim @triplea87

 

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:

 

It’s impossible to cover everything so if you attended IDWeek and have other studies to suggest to everyone, let us know in the comments.

5 things that ID fellows wish you knew

3rdtimeisthe charm

1. Yeast in the sputum does not always need treatment.

We often see yeast pop up in sputum cultures and BAL cultures in ICU patients. However, yeast in hospitalized patients is typically Candida species, which are NOT typical pulmonary pathogens. Candida pneumonia is rare. In a recent study that looked at how often yeast isolated from sputum/BAL culture in ICU patients truly are reflective of Candida pneumonia, they found that 5/701 samples were consistent with Candida pneumonia (0.7%).  3/5 patients had severe gastric contents aspiration and 4/5 were immunocompromised.1

What does this mean? Unless the patient recently had significant aspiration or is immunocompromised, Candida spp. in the sputum is unlikely to be a true pathogen.

Other potential yeasts can include Cryptococcus spp., Histoplasma capsulatum, Blastomycosis spp., Coccidioides spp., and Paracoccidioides spp. These can represent true clinical infections. Treatment for these infections is different from Candida spp. and risk should be assessed given the patient’s clinical context.

 

2. It’s all about “source control”.

This means that if the area of infection can be physically removed or debrided, it should be done to optimize the chance of cure. This can also help increase diagnostic yield for targeted antibiotic therapy. Examples:

  • If there is an abscess, it should be drained, if possible.
  • If there is an infected foreign body, it should be removed, if possible.
  • If there is infected bone, it should be debrided/removed, if possible.

The STOP-IT trial in 2015 showed that in patients with intra-abdominal abscesses who received adequate source control (drainage of abscess or surgical resection), 3-5 days of antibiotics post-source control was non-inferior to 8-10 days of antibiotics after source control.2

There are obviously times when source control is not possible, too risky, or may cause more harm than benefit. However, anytime a patient has an infection, source control should be considered in the initial management strategy.

 

3. Do not treat asymptomatic bacteriuria and do not send urine cultures on asymptomatic patients.

  • The urogenital tract is not a sterile area and bacteria are often found that are not causing any symptoms or harm to the patient.
  • Antibiotics that are started for asymptomatic bacteriuria can cause harm.
  • If a patient has a urinary catheter, replace urinary catheter and resend a urine culture.
  • Pyuria in asymptomatic bacteriuria does not require treatment3.

 

The 2 times to treat asymptomatic bacteriuria:

  1. Pregnant patients
  2. Patients who are about to undergo a urologic procedure

 

A Cochrane review published in 2015 evaluated 9 randomized-controlled-trials (and a total of 1614 non-pregnant adults) who looked at antibiotic treatment vs. placebo for asymptomatic bacteriuria, and demonstrated that there was no difference in development of symptomatic urinary tract infections, UTI complications, or death between the two groups. The treatment group had a 3.77 increased risk of antibiotic side effects.4

 

4. Beta-D-glucan results need to be taken in the context of the patient’s clinical picture.

Not all fungal infections cause elevated beta-D-glucan and not all elevated beta-D-glucan levels indicate a fungal infection.

Initial studies that looked at beta-D-glucan test characteristics were done in immunocompromised patients. In that group, the test performed well, with sensitivity ranging 64-95% and specificity ranging from 92-95% (variation depending on prevalence and test level cutoff for positivity).5-7

However, in the non-immunocompromised population in the intensive care units, the test has not shown to have the same specificity. The sensitivity remains high in the 80%-90% range while specificity drops as low as 38% in non-neutropenic patients with known candida colonization.8-10

5. Send a GeneXpert© NAAT test with the first AFB smear and remember that there is no such thing as a “TB rule out”.

The current CDC/IDSA guidelines in evaluation of active pulmonary tuberculosis is to:

  • obtain 3 sputum AFB smears/cultures at least 8-24 hours apart.11
  • ideally obtain at least one smear as an early morning sample (highest concentration of mycobacteria at that time).11
  • send a GeneXpert© nucleic acid amplification test (NAAT) on the 1st sputum specimen.11
    ⇒ This test can detect tuberculosis genes as well as detect rifampin susceptibility and usually comes back quickly.
  • A bronchial (BAL) specimen can count as one sputum sample.11
  • In the US from 2011-2013, only 46% of patients with TB had a positive AFB smear.
    ⇒ Three negative sputum AFB smears does not “rule out” TB. The patient can still have TB, but the probability of TB is lower and they are less likely to be infectious if all three smears are negative.11,12,13

 

 

References:

  1. Schnabel RM, Linssen, CF, Guion CF, van Mook WN, and Bergmans DC. Candida pneumonia in Intensive Care Unit? OFID. 2014;1(1) ofu026. doi:https://doi.org/10.1093/ofid/ofu026
  2. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection. NEJM. 2015; 372:1996-2005. doi:10.1056/NEJMoa1411162
  3. Nicolle LE, Bradley S, Colgan R, et al. Infectious Diseases Society of America Guidelines for the Diagnosis and Treatment of Asymptomatic Bacteriuria in Adults. CID. 2005; 40: 643-654.
  4. Trestioreanu, AZ, Lador A, Sauerbrun-Cutler M, and Leibovici, L. Antibiotics for asymptomatic bacteriuria. The Cochrane Database of Systematic Reviews. 2015. doi:10.1002/14651858.CD009534.pub2
  5. Odabasi Z, Mattiuzzi G, Estey E, et al. β- d -Glucan as a Diagnostic Adjunct for Invasive Fungal Infections: Validation, Cutoff Development, and Performance in Patients with Acute Myelogenous Leukemia and Myelodysplastic Syndrome. Clin Infect Dis. 2004; 2(15):199-205. doi:https://doi.org/10.1086/421944
  6. Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter Clinical Evaluation of the (1→3) β-D-Glucan Assay as an Aid to Diagnosis of Fungal Infections in Humans. Clin Infect Dis. 2005; 41(5): 654-659. doi:https://doi.org/10.1086/432470
  7. Obayashi T, Negishi K, Suzuki T, and Funata N. Reappraisal of the serum (1–>3)-beta-D-glucan assay for the diagnosis of invasive fungal infections–a study based on autopsy cases from 6 years. Clin Infect Dis. 2008;46(12):1864-70. doi:10.1086/588295
  8. Mohr JF, Sims C, Paetznick V, et al. Prospective survey of (1à3)-beta-D-glucan and its relationshop to invasive candidiasis in the surgical intensive care unit setting. J Clin Microbio. 2011; 49(10):58-61. doi:10.1128/JCM.01240-10
  9. Liew YX, Teo J, Ai-Ling Too I, et al. Candida Surveillance in Surgical Intensive Care Unit (SICU) in a Tertiary Institution. BMC Infect Dis. 2015; 15(256):1-8. doi:10.1186/s12879-015-0997-6
  10. Lo Cascio G, Koncan R, Stringari G, et al. Interference of confounding factors on the use of (1,3)-beta-D-glucan in the diagnosis of invasive candidiasis in the intensive care unit. Eur J Clin Microbiol Infect Dis. 2015; 34(2):357-365. doi:10.1007/s10096-014-2239-z
  11. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL et al. Official American Thoracic Society/Infectious Disease Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. 2017; 64(2):111-115. doi: 10.1093/cid/ciw778
  12. Mase S, Ramsay A, Ng N, Henry M, Hopewell PC, Cunningham J, Urbanczik R, Perkins M, Aziz MA, Pai M. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis. 2007;11(5):485-95. PMID:17439669
  13. CDC. Reported Tuberculosis in the United States, 2013. Atlanta, GA: U.S. Department of Health and Human Services, CDC, October 2014.

Clostridium difficile

In light of the recently published IDSA guidelines on C. difficile, I thought I would write up a summary of the guidelines as well as provide some of the background microbiology of the organism for review.

Structure

  • obligate anaerobes
  • gram-positive bacilli
    – form spores (= dormant, non-reproductive structure that the bacteria can reduce itself to in order to survive for extended periods of time in extreme conditions)
  • produce toxins (toxin A and toxin B) that cause disease

 

clostridium-difficile gram stain

Environment

  • animal and human feces
  • soil
  • sewage

 

Mechanism of pathogenicity

*Not all strains of C. difficile are pathogenic – only the ones who produce toxins can cause C. difficile disease

Pathogenesis:

Transmission occurs with ingestion of spores via the fecal-oral route ⇒ spores activate in the colon to replicating bacteria ⇒ bacteria release toxins ⇒ toxins cause breakdown of the colon cells’ cytoskeleton framework ⇒ apoptosis ⇒ breakdown of the mucosal wall ⇒ DIARRHEA!

 

Risk factors for acquiring C. difficile:

  1. ANTIBIOTIC EXPOSURE
  2. Exposure to healthcare facilities
  3. Age and immunosuppression
  4. ?Gastric acid suppression (use of proton pump inhibitors or H2 receptor blockers)
    — the evidence-based-medicine jury is still out on this one

 

Clinical features

  • symptoms can develop during antibiotic treatment or up to 6 weeks after the course of antibiotics has been finished
  • patients can also become infected even without exposure to antibiotics (both in the healthcare setting but also in the community setting)
  • carrier state = a patient who is colonized with C. difficile but is currently asymptomatic

1.Symptoms and physical exam signs:

  • Non-bloody, WATERY DIARRHEA (≥ 3 loose stools in 24 hours)
    *occasionally patients can develop ileus with severe infection which will not result in diarrhea but rather lack of bowel movements
  • Abdominal pain/cramping
  • Fever and chills
  • Abdominal distention/tenderness
  • Nausea/anorexia

2.Laboratory findings:

  • High white blood count (occasionally precedes the diarrhea by 1-2 days)
  • Elevated creatinine
  • Elevated lactate and low albumin (in fulminant cases)

 

Pseudomembranous colitis = inflammation of the colon causing elevated white and yellow-colored plaques to form and coalesce together to create a pseudomembrane on the colon wall that can be seen by colonoscopy.

 

Diagnostics

  1. When to test: when patient has new onset, ≥ 3 unformed stools that cannot be explained by another cause (i.e. laxative use)
  2. Options for testing:

* C. difficile can be grown in culture, but anaerobes take a while to grow and it would not provide an answer as to whether the strain is toxigenic (i.e. produces toxin) or not, so it is not commonly used for clinical diagnostic purposes.

What it is Advantages Disadvantages
Toxin EIA assay Antibody assay that detect toxins High specificity (>84%) Low sensitivity (31-99%)
GDH assay Detects GDH (an enzyme produced by C. difficile) High NPV (>99%)

Quick turn-around

Cannot distinguish toxigenic vs. non-toxigenic C. difficile strains
NAAT/PCR PCR method that detects toxin production gene High NPV (>99%)

Quick turn-around

Poor specificity and PPV

*Changes depending on whom specimens are collected on (low suspicion vs. high suspicion)

EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NPV, negative predictive value; PPV, positive predictive value; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction.

Many healthcare facilities are currently doing only PCR testing. It’s highly sensitive and the results return quickly (usually within 24 hours).

The problem: this practice is yielding a lot of false positives (patients who are carriers but do not truly have an active infection) which ⇒ over-treatment ⇒ patient discomfort, potential side effects, infection control consequences for the hospital, and extra costs.

Why: This is thought to be due to the fact that a lot of tests are sent inappropriately (on patients that have diarrhea but no other evidence of infection such as leukocytosis, AKI, abdominal pain, fever, etc.)

Solution (as proposed by IDSA guidelines):

  1. A multiple step algorithm:
  • GDH assay + EIA assay
  • GDH assay + EIA assay with NAAT as a tiebreaker
  • NAAT + EIA assay

                  OR

  1. We can agree to be more mindful of when we send the test (when the pre-test probability is high) and continue to use the NAAT/PCR method alone.

Bottom line: Many hospitals are switching over to the two-step testing method for multiple reasons:

  • behavior change is difficult to implement and sustain
  • provides more accurate incidence of nosocomial-acquired infections in the hospital

WHEN YOU THINK OF SENDING A C. DIFFICILE TEST, ask yourself:

  1. Does this patient have an unexplained fever, leukocytosis, or new abdominal pain/distention, in addition to the diarrhea (or in presence of ileus)?
    if yes ⇒ send the test
  1. If not, is there another explanation for the diarrhea?
    (i.e. laxatives, new medications (especially antibiotics), part of already known illness, etc.)
    if yes ⇒ consider removing the potential cause (if possible) and re-evaluate or monitor for worsening symptoms
    if not ⇒ send the test

 

Treatment

The IDSA has a really great table to reference when choosing treatment options for your C. difficile infected patient.

***PO Metronidazole is no longer the 1st-line agent for C. diff infection treatment***

C.diff treatment chart

                                                                                                            McDonald et al. CID 2018

 

Recurrence

Recurrence of C. difficile infection = reappearance of symptoms within 2-8 weeks after completion of therapy

  • up to 25% of patients will experience a recurrence
  • once patient had one recurrence, they are at higher risk for future recurrences

 

TAKE-HOME POINTS:

  • The MAJOR risk factor for C. difficile infection is ANTIBIOTIC EXPOSURE
    ⇒ DO NOT give antibiotics to those who do not truly need them
  • Symptoms/signs include watery diarrhea, abdominal cramping/pain, and elevated WBC and creatinine
  • C. difficile infection CAN cause ileus (i.e. no diarrhea)
  • Only send test when you have a high pre-test probability to avoid false positives
  • Metronidazole is NO LONGER recommended for treatment of C. difficile

 

Got questions? Disagree? Leave your comments below!

 

References

  1. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018. 66(7):1-48. [PMID: 29562266]
  2. Jorgensen JH, Pfaller MA, Carroll KC, et al. Manual of Clinical Microbiology, Eleventh Edition.
  3. Lamont JT. (2018). Clostridium difficile infection in adults: Epidemiology, microbiology, and pathophysiology. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-epidemiology-microbiology-and-pathophysiology]. Accessed May 25, 2018.
  4. Lamont JT, Kelly CP, and Bakken JS. Clostridium difficile infection in adults: Clinical manifestations and diagnosis. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-clinical-manifestations-and-diagnosis]. Accessed May 25, 2018.
  5. Kelly CP, Lamont JT, and Bakken JS. Clostridium difficile infection in adults: Treatment and prevention. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-treatment-and-prevention]. Accessed May 25, 2018.

Oral vs. IV antimicrobials

What’s the difference between oral (PO) and IV medications? When do you use PO vs. IV antimicrobials? When are they interchangeable? These are the questions we’ll address in this post.

info intravenously picture
by Dalya Ferguson, MD

Bioavailability is an important concept to understand when considering IV to PO interchange.

Bioavailability = the measure of the amount of an orally administered medication that reaches the bloodstream.

Antimicrobials with >90% bioavailability are the antimicrobials we can target for
IV to PO interchange.

Antimicrobials where bioavailability >90%:
(therefore, can be switched to PO)

  • Metronidazole
  • Fluoroquinolones (levofloxacin, moxifloxacin, *ciprofloxacin has ~70% bioavailability but still has enough to achieve adequate levels in the bloodstream)
  • Trimethoprim-Sulfamethoxazole
  • Tetracyclines (doxycycline, minocycline)
  • Linezolid
  • Rifampin
  • Fluconazole/Voriconazole
  • Clindamycin
  • Azithromycin (only ~40% bioavailable, but the concentration achieved by
    oral ingestion is just as effective as IV for treatment)

 

IV medication = medication given intravenously
– medication takes effect immediately after the infusion
– administers a bolus of the medication quickly (within 5 minutes)
– requires an IV line
– bypass first pass metabolism in the liver

PO medication = medication administered per oral route
– medication takes effect in ~30 minutes to 6 hours
– requires ability to swallow, absorb the medication, and also undergoes
first pass metabolism prior to reaching the circulatory system

Why is PO preferable to IV?

  • Cheaper3
  • Does not require IV access
  • Easier and faster to administer
  • No IV complications (i.e. phlebitis, thrombosis, bloodstream infection)
  • Avoidance of a long-term catheter such as a PICC line
  • Less unnecessary fluid administration

 

When to consider IV antimicrobials?

  • when patient is unable to take PO or unable to absorb the medication
  • when you want immediate effect of the medication
  • when the spectrum of activity desired is only available with IV antibiotics
  • when no PO option is available to treat the pathogen
  • when PO medications will not achieve high enough concentrations or penetrations to the location of the infection
    • Critically ill patients; sepsis/bacteremia
    • Endocarditis
    • CNS/ocular infection
    • Osteomyelitis/Septic arthritis (*a study is currently under way, looking at whether certain oral antibiotics are non-inferior to IV antibiotics in
      bone infections7)
      *You may occasionally see these syndromes treated with oral antibiotics, because each case is different. But in general, consider these syndromes as ones where IV antibiotics are preferred, especially as initial therapy.

 

TAKE HOME POINTS:

  • IV antimicrobials are NOT “stronger” or “better” than oral antimicrobials
    – it depends on each individual medication
  • PO antibiotics should be used unless there is a reason to use IV antibiotics (and not the other way around)
  • When PO and IV versions of an antimicrobial are similar, make every concerted effort to make sure your patients are not on IV medications unnecessarily

 

Questions? Comments? Suggestions for future posts? Leave a comment below.

 

 

References:

  1. Kwong, L.H et al. (2015). An unsupported preference for intravenous antibiotics. PLoS medicine, 12(5): e1001825. DOI: 10.1371/journal.pmed.1001825
  2. MacGregor, R.R. et al. (1997). Oral administration of antibiotics: a rational alternative to the parenteral route. 24: 457-467. PMID: 9114201
  3. Chan, R. et al. (1995). Oral versus intravenous antibiotics for community acquired lower respiratory tract infection in a general hospital: open, randomized, controlled trial. BMJ. 310: 1360-1362. PMID: 7787537
  4. Baddour et al. (2016). Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications. Circulation. 132: 1435-1486.
    DOI: 10.1161/CIR.0000000000000296.
  5. Tunkel, A.R. et al. (2004). Practice Guidelines for the Management of Bacterial Meningitis. CID. 39: 1267-1284. DOI: 10.1086/425368
  6. World Health Organization, Occupational Health. (date published unknown). Comparison of pharmacokinetics and efficacy of oral and injectable medicine [Powerpoint slides]. Retrieved from http://www.who.int/occupational_health/activities/5injvsora.pdf
  7. Li, H.K et al. (2015). Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomized controlled trial. BMC Trials. 16:583. DOI: https://doi.org/10.1186/s13063-015-1098-y
  8. Wisplinghoff, H. et al. (2004). Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 39(3): 309-317. DOI: 0.1086/421946

 

Peer-reviewed by Jeff Pearson, 2nd year PharmD resident

Antimicrobials: spectrum of activity

One of the most difficult concepts to understand is the spectrum of activity of different antimicrobials. We are all taught each antimicrobial in silos of the other ones and I always found it difficult to create conceptual charts in my head. Thankfully, I’ve found some amazing charts on the internet (from reputable sources, of course) that shows antimicrobials in relation to one another that may be helpful to you.

Here, I will present the best ones I’ve found so far for antibiotics, antivirals, and antifungals for you to use as a reference guide. At the bottom, I will list a few caveats to take into account when using these charts, because as always, ID is never as simple as the charts imply.

Antibiotics

Antibiotic spectrum of activityIntensive Care Drug Manual: Wellington ICU. Appendix 5.

Re-writing the fine print of the chart in case it’s not easily readable:
*For simplicity, atypical organisms are not included above. Partial columns indicate incomplete coverage. ESBL-producing organisms are not susceptible to most antibiotics containing a beta-lactam ring; carbapenems are the usual agent of choice.
1: C. difficile should only be treated with metronidazole or vancomycin
2: ESCHAPPM are β-lactamase producing organisms. These are Enterobacter, Serratia, Citrobacter freundii, Hafnia, Acinetobacter/Aeromonas, Proteus (not mirabilis), Providencia & Morganella morganii. See my 1st post on SPICE organisms for more info.
3: Not effective against Clostridium

4: Metronidazole is not effective against Peptostreptococcus
5: Teicoplanin is not effective against Enterococcus faecium
6: Gentamicin is not appropriate mono therapy for Staphylococcus aureus & should only be used in conjunction with a β-lactam
7: Due to increasing MIC, Cefuxorime is not recommended therapy for Moraxella
8: Although it has other actions, Ceftazidime should only be used for Pseudomonas

*This chart is intended as a guide, pending specific identification & sensitivities – it does not replace expert ID advice. Local antibiotic sensitivities & preferences will vary.

My notes:
ClindamycinCommunity-acquired MRSA strains have been found to be resistant to clindamycin and thus, this is often not a safe option for empiric therapy against MRSA.
Rifampin
usually used as an adjunct with another antibiotic against most infection. Would not recommend its use in isolation against infections.
Co-trimazole/Trimethoprim
would not use against enterococcus or empirically against MRSA in the hospital/ICU
Moxifloxacin — has some anaerobic coverage while levofloxacin and ciprofloxacin do not.
Metronidazole – no longer the 1st choice for C.diff infection. Instead, use PO vancomycin or PO fidaxomicin. (Thanks to a commenter for pointing that out to me!)

 

Antivirals

This chart was made by me but inspired by Aliyah Baluch, MD, Msc from USF who did an amazing review of antimicrobials used in stem cell transplant recipients. I thought it was a great way to demonstrate the spectrum of activity of antivirals and I hadn’t seen anything similar prior to that. Check out IDpodcasts.net for other lectures on ID topics.

 

antiviral spectrum of activity

*This chart only covers the herpes virus family, and does not include other virus families
*Just because foscarnet and cidofovir are considered the most broad-spectrum of the bunch does not mean they are always the best options. These drugs are quite toxic and should only be used in special circumstances, often with the involvement of an ID specialist.

Antifungals

This is a great chart taken from a wonderful review on antifungals from Mayo Clinic Proceedings.

Screenshot-2018-3-18 Current Concepts in Antifungal Pharmacology - pdfLewis, R.E. Mayo Clin Proc 2011

References:

1.Lewis, R.E. (2011). Current Concepts in Antifungal Pharmacology. Mayo Clinic Proceedings. 86(8):805-817. DOI: 10.4065/mcp.2011.0247
2.IDpodcasts.org: Bugs, Drugs, and Stem Cells podcast. July 2017. http://idpodcasts.net/podcasts/bugs-drugs-and-stem-cells/
3.Intensive Care Drug Manual: Wellington ICU. Appendix 5. Updated 2017. http://drug.wellingtonicu.com/
4.Santos, C.A.Q. (2016). Cytomegalovirus and other beta-herpesviruses. Seminars in Nephrology. 36(5): 351-361.
DOI: 10.1016/j.semnephrol.2016.05.012
5.Razonable, R.R. (2011).
Antiviral Drugs for Viruses Other Than Human Immunodeficiency Virus. Mayo Clinic Proceedings. 86(10): 1009–1026. DOI:  10.4065/mcp.2011.0309

Peer-reviewed by Jeffrey Pearson, 2nd year pharmacy resident

 

 

CNS penetration of antimicrobials

Have you ever noticed how the indicated dosages for antimicrobials increase for CNS infections? This is because antimicrobials have a difficult time penetrating the blood brain barrier and the blood-CSF barrier, leading to difficulty of some antimicrobials to achieve therapeutic concentration levels in the CSF to properly treat a CNS infection.

Overview-of-the-two-main-barriers-in-the-CNS-blood-brain-barrier-and-blood

(Bhaskar et al. 2010.)

Disclaimer: the penetration of antimicrobials into the CSF is much more complicated than three columns and a list of antibiotics. It’s been shown that levels of drugs differ between ventricular, cisternal, and lumbar CSF. Additionally, the treatment of CNS infections depends on more than just the CNS penetration of a certain antimicrobial, thus if any questions arise, please discuss with your ID consultants and ID pharmacists.

For the sake of this review, we will keep it simple.

Antimicrobials can be broken down into 3 rough
categories:

Excellent/Good penetration of the CSF Good penetration only in inflamed meninges Poor penetration of the CSF
Fluoroquinolones Glycopeptides (vancomycin) Beta-lactams3
TMP/SMX Macrolides (azithromycin) Aminoglycosides
Metronidazole Rifampin Tetracyclines (doxy, tigecycline)
Chloramphenicol Ethambutol Clindamycin4
Fosfomycin1 Daptomycin
Isoniazid Colistin
Pyrazinamide Fusion inhibitors (enfurvitide)
Zidovudine Tenofovir
5-flucytosine Amphotericin B5
Voriconazole/fluconazole Echinocandins
Pyrimethamine Itraconazole/posaconazole
Atovaquone?2
Albendazole >>> Praziquantel

1 only FDA-approved for UTI treatment
2 no studies have been published looking at CNS penetration; however has been used successfully in clinical CNS infections
3 overcome by increase in dosages – higher dosages of beta-lactams obtain adequate levels in the CSF and tend to be 1st line agents in bacterial meningitis due to their efficacy and bactericidal properties
4 however has been shown to effectively treat susceptible CNS infections
5 however clinical trials have shown good outcomes when used in treatment of CNS infections

*If the class of drug was not mentioned in this list, it is likely because no studies have been done to assess CNS penetration of that drug.

Why are beta-lactams recommended for empiric
bacterial meningitis treatment?  

Despite the poor CSF penetration, beta-lactams have the most research documenting successful treatment of community-acquired meningitis compared to other antibiotic classes.

  • When the beta-lactam dose is increased, CNS penetration increases.
  • Beta-lactams are well-tolerated even at high dosages
  • Ceftriaxone treats S. pneumoniae, N. meningitidis, H.influenzae, and many aerobic gram-negatives such as E.coli and K. pneumoniae.

*Vancomycin is added to empiric regimens to treat the ceftriaxone-resistant S. pneumoniae strains that have been seen in community-acquired meningitis.

empiric meningitis tx IDSA guidelines                                                            (IDSA practice guidelines for Bacterial Meningitis, 2004.)

TAKE HOME POINTS:

  • Not all antimicrobials penetrate the BBB. Take into account an antimicrobial’s CNS penetration properties when treating CNS infections
  • Beta-lactams are still 1st line therapy for empiric meningitis treatment due to their efficacy against the most common pathogens and ability to achieve high levels with increased doses of the medication
  • When treating CNS infections, deviation from the guidelines warrants involvement of the ID pharmacist and the ID consult team to ensure the best treatment regimen for the patient

 

 

References:

1. Bhaskar, S., Tian, F. et al. (2010). Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: Perspectives on tracking and neuroimaging. Particle and fibre toxicology. 7(1)3. DOI: 10.1186/1743-8977-7-3.
2. Nau, R., Sorgel, F, and Eiffert, H. (2010). Penetration of Drugs through the Blood-Cerebrospinal fluid/Blood-Brain Barrier for the treatment of central nervous system infections. Clinical Microbiology Reviews. 23(4): 858-883. DOI: 10.1128/CMR.00007-10
3. Letendre, S. (2011). Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Topics in antiviral medicine. 19(4): 137-142.
4. Marra, C. (2014). Central nervous system penetration of ARVs: Does it matter? [powerpoint]. Presented at Northwest Aids Education and Training Center on May 15th, 2014.
5. Cherubin, C.E., Eng, R.H, et al. (1989). Penetration of newer cephalosporins into cerebrospinal fluid. Review of Infectious Diseases.11(4):526-548.
6. Tunkel, A.R., Hartman, B.J, et al. (2004). Practice Guidelines for the management of bacterial meningitis. CID. 39:1267-1284.

Peer-reviewed by Jeffrey Pearson, 2nd year ID pharmacy resident