Tag Archives: #freeopenaccessmedicine

COVID-19 Ultimate Resource List

There’s so much information about the novel coronavirus COVID-19 on the internet that it is hard to keep up with the onslaught of information. We wanted to compile the ultimate list of reputable resources for clinical providers to access when they need to, at a moment’s time.

Since information on COVID-19 is rapidly changing, these resources are not specific papers or blog posts, but rather websites that are maintaining up to date information on epidemiology, pathophysiology, and management. Resources span all types, including website behemoths like the WHO and CDC, as well as twitter accounts for people who get their news from social media.

Since this is an ultimate list but we don’t pretend to have ultimate knowledge of all resources, please send us resources that we may have missed and we will add them on here! We also acknowledge that this list is U.S. centric because we are from the States, but we would love input on resources for other countries so we can make this a more international list.

For the most up to date information:

Epidemiology:

Academic:

Clinical/Practical Management:

  • University of Washington – the holy grail of practical documents developed by people who are currently battling a COVID-19 outbreak. All documents can be utilized by others and adapted for their own institutional protocols.
  • University of Kentucky – have assessment, triage, and testing algorithms for use
  • University of Nebraska Medical Center – fantastic protocols on donning on/off PPE, videos, as well as other in-hospital quarantine protocols
  • IDStewardship – a very thorough, but easily read overview of potential treatment options for COVID-19 and how/when to use them
  • University of Liverpool – charts on drug drug interactions with experimental therapies for COVID-19
  • CIDRAP – focuses on the health policy aspect of COVID-19 news
  • Society of Critical Care Medicine – online training modules for disaster medicine, resource availability in U.S., and other fantastic resources for front-line clinical providers

Immunocompromised hosts:

Clinical Trials:

  • ClinicalTrials.gov – a currently-recruiting randomized controlled trial of remdesivir for COVID-19 treatment
  • CURE ID –  an FDA and NIH supported website where you can report and see new uses of existing drugs for difficult-to-treat infectious diseases. Download their mobile app too!

Blogs:

Podcasts:

  • TWiV – a podcast by virologists discussing virology; with recent episodes on COVID-19
  • IDSA Podcast – has weekly podcast series “Coronavirus: What’s happening now?”
  • JAMA Clinical Reviews – recent episodes on COVID-19 from various different viewpoints
  • NEJM Interviews – hosts short and to the point interviews with world experts

Twitter accounts:

Graphics:

Graphics Reuters – for the graphic enthusiasts out there
New York Times Coronavirus Maps – for the graphic enthusiasts out there

That’s it for now! Let us know if we missed any great resources!

Thank you for all the work that all of you do. Stay safe!

This list was compiled by Milana Bogorodskaya, Fatima Al-Dhaheri, and Ahmed Abdul Azim.

Coccidioides species

Disease: Coccidioidomycosis

Alias: Valley fever, San Joaquin fever

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…).

If you haven’t read the posts on Histoplasma capsulatum or Blastomyces species, go read it now!

This is the 3rd post out of 6 and will focus on our third shapeshifter, Coccidioides species.

CLICK HERE for a 2-page PDF handout of this information.

Morphology(1):

  • This shape shifter differs from others in that it does not shape shift by temperature but resembles other shape shifters in that it exists as a mold in the environment and a spherule (Image) inside the body.
  • Spherules are round, and contain endospores which are uninucleate and have walls and cytoplasmic inclusions
  • Can be mistaken for yeast if only endospores are seen (but endospores don’t bud like yeasts!)

Geography, Reservoir and Mode of Transmission

  • Endemic in southwest of the US and certain arid regions in South America
  • In the US, highest incidence in Arizona and California
  • Reservoir includes: soil (increased during dry periods after rain/storms/earthquakes or excavation work)
  • Mode of transmission: aerogenic
  • Race predilection: Filipino and African Americans at higher risk for disseminated disease (Board favorite!)

Clinical presentation

  • Two-thirds of individuals remain asymptomatic or develop self-limiting respiratory symptoms. When symptomatic → pulmonary involvement in >95% of cases(2)
  • The disease can spread hematogenously to the following extrapulmonary sites: skin, soft tissue, skeleton, CNS (both meninges and spinal cord), eyes, heart, liver, kidneys, and prostate(1)
  • Primary presentation often associated with skin findings (erythema nodosum, erythema multiforme) and rheumatological findings (myalgia, arthralgia)(2)
  • Eosinophilia is often present!
  • Unlike pulmonary nodules in histoplasmosis that often calcify, nodules in coccidiomycosis become small ‘grapeskin’ cavities, and cavities are often thin walled and can be associated with pleural effusions(3)

Diagnosis

Your friendly Infectious disease doctors will always ask for tissue, and if classic spherules are seen in histopathology or culture confirms growth, that’s a slam dunk diagnosis! But we understand that is not always feasible, so in addition to clinical history + presentation, in order of importance:

  1. Tissue/culture
  2. Serology (keeping in mind that it can be false negative very early on in the disease)

Culture:

*Please alert the microbiology lab if you suspect coccidiomycosis and are sending them cultures! (culture needs to be specially handled in the lab due to the risk occupational transmission/infection — just like all dimorphic fungi covered in this review series).

  • Confirms diagnosis, growth usually detected 4-5 days (4)

Histopathology:

  • Presence of endospore-containing spherules is diagnostic (see Image, Morphology)
  • Tissue eosinophilia may be present, and as endospores mature into spherules,
  • Granulomatous reaction predominates

Antigen detection:

  • Urinary antigen not widely used, however urinary histoplasma antigen test could be positive in 50% of cases(4)

Serology:

  • IgM usually becomes detectable within 1-3 weeks therefore negative serology early in the disease doesn’t rule out the disease
  • IgG becomes detectable anywhere between 3rd/4th week to several months after becoming infected. This usually reflects degree of infection and can be used to monitor the disease(4)
  • Increasing titers (or titers >1:32) may suggest dissemination(4)

Molecular methods:

  • No commercially available tests

Management(5)

Pulmonary disease:

  • Mild pulmonary disease: no treatment
  • Asymptomatic nodule/cavity: no treatment
  • Symptomatic chronic cavity: fluconazole/itraconazole (at least) for 12 months

Extra-pulmonary disease:

  • Soft tissue/bone: fluconazole/itraconazole (at least) for 12 months
    (*except for severe disease → Lipid Amphotericin B as an initial therapy for about 3 months)

References:

  1. Walsh TJ, Hayden RT, and Larone DH. Larone’s medically important fungi, 6th edition. ASM Press, 2018.
  2. Salzer HJF, Burchard G, Cornely OA, et al. Diagnosis and Management of Systemic Endemic Mycoses Causing Pulmonary Disease. Respiration. 2018; 96(3):283-301.
  3. Knox KS. Letter to the Editor: Perspective on Coccidioidomycosis and Histoplasmosis. Am J Resp Crit Care Medicine. 2014; 189(6):752-753.
  4. Saubolle MA, McKellar PP, and Sussland D. Epidemiologic, clinical, and diagnostic aspects of coccidiomycosis. J Clin Microbiol. 2007; 45(1):26-30.
  5. Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clin Infect Dis. 2016; 63(6):e112–e146

Blastomyces species

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…).

If you haven’t read the first post on Histoplasma capsulatum, go read it now!

This is the 2nd post out of 6 and will focus on our second shapeshifter, Blastomyces dermatiditis.

CLICK HERE for a 2-page PDF handout of this information.

Morphology(1):

At 25°C-30°C (mold form): septate hyphae with short or long conidiophores where a pear-shaped conidia form at the apex of the conidiophore (has a lollipop-like appearance).
(Image A)

At 37°C (yeast form):
appear as yeast-like cells, thick walled and budding with a broad base
(Image B)

Geography, Reservoir and Mode of Transmission:

  • Endemic in North America (Ohio & Mississippi river valleys and the Great Lakes region)
  • Sporadic cases in Africa and India(2)
  • Reservoir includes: moist soil with decaying vegetative matter, decomposed wood
  • Mode of transmission: aerogenic, skin inoculation

Clinical presentation:

  • Incubation period: 30-45 days (3)
  • Spectrum of clinical disease:
    • Asymptomatic disease – occurs in ~50% of individuals
  • Acute pulmonary blastomycosis – resembles community-acquired pneumonia with variable presentation (infiltrates, consolidation +/- cavitation, reticulonodular patterns, small pleural effusions)(4)
    • Chronic pulmonary blastomycosis – can mimic presentation of TB, lung cancer, and histoplasmosis. Radiographic pattern often is described as alveolar or fibronodular infiltrations, mainly with an upper lobe distribution. Absence of mediastinal lymph node involvement in blastomycosis can distinguish it from Histoplasmosis.(4)
  • Extrapulmonary disease have been described in two-thirds of patients with chronic blastomycosis(3). Most frequent sites: skin, bones and genitourinary system.
  • Patients frequently present with cutaneous lesions without clinically active pulmonary disease.
  • CNS involvement is rare, except in immunocompromised hosts. As many as 40% of AIDs patients who have blastomycosis have CNS disease (mass lesions or meningitis)(5).

Diagnosis:

Your friendly Infectious disease doctors will alwaysask for tissue, and if classic broad-based budding yeast are appreciated in histopathology, that’s a slam dunk diagnosis! But we understand that is not always feasible, so in addition to clinical history + presentation, in order of importance:

  1. Tissue (histopathology, faster visualization, culture will have a long incubation time)
  2. Urine Antigen detection (keeping in mind issues with cross-reactivity as outlined below)

Culture:

*Please alert the microbiology lab if you suspect Blastomycosis and are sending them cultures! (culture needs to be specially handled in the lab due to risk occupational transmission/infection (just like all dimorphic fungi covered in this review series).

  • Most sensitive method, however long incubation time
  • For cutaneous lesions, important to obtain specimen from active leading edge

Histopathology:

  • Forms non-caseating granulomas
  • Classic appearance in clinical samples: Broad-based budding yeast (Image B, morphology)

Antigen detection:

High sensitivity for urine detection (93%) in largest published evaluation(2) but low specificity (79%) due to cross reactivity with Histoplasmosis, Paracoccidioidomycosis and Talaromycosis (previously known as penicilliosis)

Serology:

  • No role in diagnosis because of poor sensitivity and high cross-reactivity(4)

Molecular methods:

  • No commercially available tests

Management(3):

Pulmonary disease

  • Mild to moderate: Itraconazole 6-12 months
  • Moderate to severe: Lipid Amphotericin B for 1-2 weeks followed by →  Itraconazole for 6-12 months

Disseminated disease

  • Mild to moderate: Itraconazole for 6-12 months
  • Moderate to severe: Lipid Amphotericin B for 1-2 weeks followed by →  Itraconazole for 12 months

References:
1. Walsh TJ, Hayden RT, Larone DH. Larone’s medically important fungi, 6th edition, ASM press, 2018.
2. Saccente M and Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367–381.
3. Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, Threlkeld MG, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008 Jun 15;46(12):1801-12
4. Salzer HJF, Burchard G, Cornely OA, et al. Diagnosis and management of systemic endemic mycoses causing pulmonary disease. Respiration; 2018;96:283–301.
5. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med;1992:116

Histoplasma Capsulatum

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…)

This is the first post out of 6 and will focus on our first shapeshifter, Histoplasma capsulatum.

CLICK HERE for a 2-page PDF handout of this information.

Morphology:(3)

  • At 25°C-30°C (mold form):Young cultures – septate hyphae with smooth or spiny microconidia
  • Older cultures (several weeks old) – large, thick walled round macroconidia with knobby projections (Image)
  • At 37°C (yeast form): small, round budding cells 

Geography, Reservoir and Mode of Transmission:

  • Histoplasma has a world-wide distribution(4), but is mostly endemic in the Americas (Central/Eastern United States & Central and South America)
  • Reservoir includes: soil, areas of construction, animal droppings (i.e. bats – a board favorite!), and caves (another board favorite)
  • Mode of transmission: aerogenic

Clinical presentation:

  • Known as the ‘syphilis’ of the fungal world because it’s a great imitator, particularly of TB(4).
  • Disease presentation/severity depends on size of inoculum & immune status
    • Immunocompetent hosts: usually asymptomatic/self- limiting
    • Immunocompromised hosts: often progressive/severe/disseminated
  • Can present as:
    • Acute pulmonary disease: Either as diffuse or localized infiltrates +/- mediastinal lymphadenopathy
    • Chronic pulmonary disease: Cavitary lesions/nodules
    • Mediastinal disease: Mediastinal granulomas and fibrosis

Diagnosis:

1. Culture:

  • *Please alert the microbiology lab if you suspect histoplasmosis and are sending them cultures! (culture needs to be specially handled in the lab due to risk occupational transmission/infection (just like all dimorphic fungi covered in this review).
  • Sensitivity of both tissue and blood cultures depend on the presentation (pulmonary vs. disseminated), immune status and burden of disease(5)
  • Disseminated disease → ~74% will have positive cultures(6)
  • Pulmonary disease → ~42% will have positive cultures(6)
  • HIV/AIDS patients:
    → ~ 90% of respiratory cultures will be positive(7)
    →~50% of blood cultures will be positive(7)

2. Histopathology:

  • Appear as yeast form, predominantly phagocytosed within macrophages and histiocytes
  • Presence in tissue supports diagnosis, although does not necessarily indicate active infection (could be detected in non-active granulomas for years)
  • Characteristic pathology feature is the presence of granulomas (caseating or non-caseating)(6)

3. Antigen detection:

  • Preferred method of testing: rapid testing + non-invasive + highly sensitive.
  • Sensitivity: urinary antigen > serum antigen (across all spectrum of clinical presentations of histoplasmosis)(9)
  • Histoplasma serum antigen (MiraVista© EIA) have highest sensitivity in disseminated disease (91.8%) >chronic pulmonary disease (87.5%) >acute pulmonary disease (83%) >subacute histoplasmosis (30%)(8)
  • In HIV/AIDS patients with disseminated disease, Histoplasma antigen can be detected in 95% of cases
  • Mediastinal involvement in histoplasmosis (mediastinal granuloma, mediastinitis) doesn’t usually result in positive antigen testing
  • Histoplasma antigen can cross react with all the dimorphic fungi covered in this review series (less commonly for coccidioides spp.)

4. Serology:

  • Antibodies take 4-8 weeks to become detectable therefore not useful for acute diagnosis but can be helpful for subacute and chronic forms of the disease
  • Titers usually decrease with disease resolution, but slowly so titers cannot be used to monitor for treatment response
  • Immunocompromised patients, particularly those with humoral defects, might not mount an antibody response so serology testing isn’t as useful.

5. Molecular methods:

  • No currently FDA approved molecular assay for H. capsulatum for clinical use.
  • PCR assays available in reference labs but are not yet standardized

Management(12):

Clinical presentationMild/ModerateModerate/SevereChronic
Pulmonary<4weeks: none
>4weeks: itraconazole for 6-12 months
Lipid amphotericin B for 1-2 weeks followed by itraconazole for 12 weeksItraconazole for 12 months
DisseminatedItraconazole for 12 monthsLipid amphotericin B for 1-2 weeks followed by itraconazole for 12 monthsN/A

References:
1. Climate change: the role of the infectious disease community. Lancet Infect Dis. 2017; 17:1219.
2. Greer A, Ng V, and Fisman D. Climate change and infectious diseases in North America: the road ahead. CMAJ. 2008; 178:715–722.
3. Walsh, TJ, Hayden, RT, and Larone, DH. Larone’s medically important fungi, 6th edition, ASM press, 2018.
4. Queiroz-Telles F, Fahal AH, Falci DR, et al. Neglected endemic mycoses. Lancet Infect Dis. 2017;17:e367–e377.
5. Azar MM and Hage CA. Laboratory Diagnostics for Histoplasmosis. J Clin Microbiol. 2017; 55:1612–1620.
6. Hage CA, Azar MM, Bahr N, Loyd J, and Wheat LJ. Histoplasmosis: up-to-date evidence-based approach to diagnosis and management. Semin Respir Crit Care Med. 2015; 36:729–745. 
7. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115–132.
8. Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53:448–454. 
9. Wheat LJ and Kauffman CA. Histoplasmosis. Infect Dis Clin North Am. 2003;17:1–19.
10. Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin Infect Dis. 2009; 49:1878–1882. 
11. Saccente M and Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367–381.
12. Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45:807–825.

5 random facts about antimicrobials

Who doesn’t love to pick up random bits of information while they’re in line for their coffee or their morning signout? Here are 5 helpful pieces of information on antimicrobials to start off your day!

1.Cefepime vs. Piperacillin-tazobactam
Cefepime – cephalosporin
– DOES NOT cover gut anaerobes
– DOES NOT cover Enterococcus spp.
Piperacillin-tazobactam – penicillin derivative
– DOES cover gut anaerobes
– DOES cover penicillin-sensitive Enterococcus spp.

Antibiotic Cefepime Piperacillin/tazobactam
Class Cephalosporin Penicillin derivative
Gut anaerobic coverage? No Yes
Enterococcus coverage? No Yes (if susceptible)

 

2. Cephalosporins in general DO NOT cover Enterococcus spp.

3. Ertapenem vs. meropenem vs. imipenem vs. doripenem
Ertapenem – DOES NOT cover Pseudomonas spp.
Meropenem/Imipenem/Doripenem – DO cover Pseudomonas spp.
*None of the carbapenems cover MRSA

4. Ineffective antimicrobials
Daptomycin – inactivated by the surfactant in the lungs
– DO NOT use daptomycin to treat lung infections
*Remember: Linezolid, Lung (you can use Linezolid for lung infections)

Echinocandins (ex. micafungin, caspofungin, anidulafungin) – do not reach therapeutic levels in the urinary tract
– DO NOT use echinocandins to treat pyelonephritis or urinary tract infections

Tigecycline – accumulates in the tissues and has low concentration levels in the bloodstream
– DO NOT use tigecycline to treat bloodstream infections

5. Bone marrow toxicity due to linezolid increases after 2 weeks of exposure
– Avoid using linezolid for more than two weeks at a time when possible

 

Do you have any random facts of ID knowledge? Let me know in the comments section below!

 

References:

1. Mandell, Douglas, and Bennett. Principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier, c2010. 7th edition.
2. Zhanel, G.G. et al. 2007. Comparative review of the carbapenems. Drugs. 67(7):1027-1052.
3. Gerson, S.L. et al. 2002. Hematologic effects of linezolid: summary of clinical experience. Antimicrobial Agents and Chemotherapy. 46(8): 2723-2726.
4. Malani, A.N. et al. 2014. Candida urinary tract infections: treatment options. 5(2): 277-284.
5. Jeu, L. et al. 2004. Daptomycin: a cyclic lipopeptide antimicrobial agent. Clinical Therapeutics. 26(11): 1728-1757.

Peer-reviewed by Jeff Pearson, PGY-2 pharmacy 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

 

 

Blood culture contaminants

There are some bacteria out there that usually don’t cause disease. They tend to just hang out and not cause any harm. When we see them in the bloodstream, they often are contaminants, meaning they were introduced during collection of the sample, and are not truly in the bloodstream. Figuring out which ones are contaminants and which ones are not can be tricky. Some are almost always (see * below) contaminants while others are NEVER contaminants. Some can be a contaminant or an infection, like streptococcus viridans group.

*Important to note: any organism can cause an infection in the right context, even those who are usually deemed as contaminants. If you are unsure whether a true infection is present, it’s always best to call an infectious disease specialist to assist with management.

Contaminant =  growth of bacteria in the blood culture bottle that were not present in the patient’s bloodstream and thus introduced during the collection of the sample (Dawson et al.)

NEVER assumed to be contaminants:

Staphylococcus aureus
Streptococcus pneumoniae
Group A/B streptococcus
Listeria monocytogenes
Neisseria meningitidis
Gram negative bacilli
Fungus (yeast or mold)
…Amongst many other numerous organisms that will take too long to mention in a list

Common blood contaminants:

Coagulase-negative staphylococci
Propionibacterium acnes
Micrococcus spp.
Corynebacterium spp.
Bacillus spp. (*except Bacillus anthracis which causes anthrax!!)

What if multiple bacteria are growing?!

  • multiple growth of bacteria can suggest contamination.
  • however, it again depends on the pathogens involved. If all are skin flora, then probably contaminant. If any of the aforementioned ‘USUALLY NOT CONTAMINANTS’ are present, then it is not a contaminant!

 

Where do contaminants come from:

  1. Patient’s skin
  2. Equipment used to obtain sample and transfer it to culture bottle
  3. Provider’s skin
  4. General environment

 

Factors to consider when deciding whether culture
is contaminant or not:

  1. Patient’s clinical status
    • are there any signs or symptoms to suggest infection with this microbe?
    • Example:
      • You would not expect a patient with pneumonia to grow CoNS in their blood.
      • However, you would take CoNS seriously in a patient with recent valve replacement and fevers.
  1. Microbiology of the species – see above
  2. Time to positivity of blood culture – studies have shown that the average time of positivity of true infections is ~12 hours vs. ~24 hours for contaminants
  3. Inoculum of the isolate – how much growth is there?
    • If only 1 out of 4 blood culture bottles are positive –> MORE LIKELY contaminant
    • If >1 out of 4 blood culture bottles are positive –> true pathogen
  1. Any foreign material? – Contaminants become pathogens when they infect hardware and prosthetic valves/grafts. If those are present and there is a possibility they are infected, would not disregard any pathogen as a contaminant.
  2. Patient’s response to antibiotics and isolate’s susceptibility pattern – clues to whether an isolate is a contaminant or a true infection
    • Contaminant: patient does not respond to antibiotics that treat the blood culture isolate
    • True pathogen: patient DOES respond to antibiotics that treat the blood culture isolate
    • Contaminant: patient responds to antibiotics despite blood culture isolate resistant
    • True pathogen: patient does not respond to antibiotics and isolate is resistant

 

FUN FACT: A retrospective review looked at 626 blood cultures and discovered that by 48 hours, 98% of aerobic gram-positive and gram-negative bloodstream infections were identified.

*This shows that unless there is a high suspicion for anaerobe growth, antibiotics can be de-escalated at 48 hours if there is no growth. (Pardo, J., Klinker, K.P, et al. 2014. Time to positivity of blood cultures supports antibiotic de-escalation at 48 hours. Annals of Pharmacology. 48 (1): 33-40).)

TAKE HOME POINTS:

  • Microbes known to be common contaminants CAN cause disease in certain circumstances
  • Always repeat blood culture when first one is positive for microbes
  • If you’re not sure if it’s a contaminant or not ⇒ call ID
    (it’s always better to double check rather than to miss a true infection)

 

References:

1. Dawson, S. 2014. Blood culture contaminants. Journal of Hospital Infection; 87, 1-10. DOI: 10.1016/j.jhin.2014.02.009
2. Pardo, J., Klinker, K.P, et al. 2014. Time to positivity of blood cultures supports antibiotic de-escalation at 48 hours. Annals of Pharmacology. 48 (1): 33-40).
DOI: 10.1177/1060028013511229
3. Hossain, B., Islam, M.S., et al. 2016. Understanding bacterial isolates in blood culture and approaches used to define bacteria as contaminants: a literature review. Pediatric Infectious Disease Journal. 35(5): S45-51.
DOI: 10.1097/INF.0000000000001106
4. Pien, B.C., Sundaram, P., and et al. 2010. The clinical and prognostic importance of positive blood cultures in adults. American Journal of Medicine. 123 (819-828).
DOI: 10.1016/j.amjmed.2010.03.021

Aspiration pneumonia vs. Aspiration pneumonitis

Why this matters:

Let me briefly tell you a story that was published in JAMA:  A patient was admitted to the hospital for seizures and intubated for airway protection. CXR showed infiltrates so patient was started on antibiotics and despite rapid improvement in 24 hours, received a 7 day course of antibiotics ‘just in case’. He was re-admitted to the hospital a week later with severe C.diff infection that did not improve despite adequate treatment and died in the hospital.

 

Antibiotics can cause harm. Sometimes they can be life-saving but risks and benefits need to be weighed each time.

 

Did that patient have aspiration pneumonia or aspiration pneumonitis?

 

Aspiration pneumonia = clinical evidence of pneumonia due to a bacterial infection

Aspiration pneumonitis = chemical lung injury due to gastric acid in the lower airways

– 13-26% can progress to develop bacterial pulmonary superinfections

 

Aspiration pneumonitis Aspiration pneumonia
Fever Low grade only/- +/-
Cough/SOB ++ ++
Hypoxia ++ ++
CXR infiltrate Resolves w/in 48-72 hrs Takes weeks to resolve
Sputum culture negative Positive/negative; purulent
Time to sx resolution Quick (48-72 hrs) Slow (>72 hrs)
Bronchoscopy Bronchial erythema Bronchial purulence

 

Risk factors for aspiration pneumonia:

  1. Risk of aspiration
  • altered mental status
  • esophageal disorders (inc. GERD)
  • neurological disorders that promote dysphagia (i.e. ALS, stroke, etc.)
  • seizures
  • vomiting
  • heavy alcohol use
  • recent intubation, bronchoscopy, upper endoscopy, or NG tube (any mechanical disruption of the natural mechanisms that prevent aspiration)
  1. Risk of aspirating increased inoculum of bacteria
  • poor dental hygiene
  • acid-suppressive medications (H2-blockers, PPIs) – loss of gastric acidity allows more pathogens to survive in the stomach ⇒ higher inoculum is present when aspiration occurs

Prevention of aspiration:

  • aspiration is pretty common in small amounts
  • it becomes pathogenic when a patient has chronic, recurrent aspiration or when the inoculum of bacteria in the aspirate increases to reach the threshold for causing chemical lung injury +/- bacterial infection.
  • there are not enough data to suggest that any interventions help to prevent recurrent aspiration

 

Microbiology:

  1. Flora – oral cavity and stomach (strep spp., H.flu, anaerobes, aerobic GNR)
  2. Community: strep spp., haemophilus influenza > anaerobes
  3. Hospital/long term care facilities:
    staphylococcus aureus, aerobic gram-neg bacilli >> anaerobes
    – these pathogens colonize the oral cavity
    Staph and aerobic GNR are more likely to be the infectious cause in these patients due to their intrinsic higher pathogenicity
  4. Anaerobespeptostreptococcus, fusobacterium nucleatum, Prevotella, Bacteroides spp.
  5. Most of these infections are polymicrobial

 

Diagnosis:

– usually a clinical diagnosis

sputum culture may help to isolate aerobic gram-neg bacilli or staph aureus to alter antimicrobial therapy

– “anaerobic bacteria are virtually never detected in pulmonary infections due to lack of access to specimens that are uncontaminated with the normal flora of the upper airways” (UpToDate) and we also do not culture sputum anaerobically so obligate anaerobes would not be able to grow in a typical sputum culture.

CXR should be ordered to assess for evidence of an infiltrate

  • Imaging: does location of infiltrate matter? YES.
    • aspiration in sitting position: lower lobes
    • aspiration in lying position: lower lobes OR posterior segment of upper lobes

 

Workup:

  • consider repeat CXR to evaluate for resolution of pulmonary infiltrate if patient has clinically improved within 48 hours ⇒ if CXR infiltrate resolved and symptoms resolved, likely pneumonitis and can discontinue the antibiotics.

So far, no trials looking at the utility of pro-calcitonin in differentiating aspiration pneumonitis vs. pneumonia that I know of, although would be a great study to do!

 

When to suspect anaerobic involvement
in pneumonia:

  • indolent course
  • risk factors for aspiration
  • absence of rigors
  • no main isolated pathogen on sputum cultures
  • putrid odor sputum
  • evidence of periodontal disease
  • imaging shows cavitation/necrosis or empyema

 

Treatment:

1. To treat or not to treat

  • It seems difficult to imagine coming into a patient’s room who is in respiratory distress with a leukocytosis and possible fever, and deciding to withhold antibiotics. At that time, everyone will likely start antibiotics.
  • Consider clinically re-evaluation at 48 hours – if CXR infiltrates and symptoms have resolved, it’s likely aspiration pneumonitis and you can probably stop antibiotics

2. Anaerobes: to treat or not to treat

  • community-acquired: always treat for anaerobes in addition to other common pathogens (see above)
  • hospital-acquired: consider treating if patient has poor dentition (that predisposes them to pathogenic anaerobic infections)

3. Antibiotic regimens (with anaerobic coverage)

  1. Community-acquired
    a) Amoxicillin-clavulanate or Ampicillin-sulbactam
    b) Ceftriaxone + metronidazole
    c) Clindamycin (if penicillin/cephalosporin allergic, not ideal regimen due to high resistance rates to certain pathogens)
    d) Moxifloxacin
  2. Hospital-acquired or recent history of antibiotics – cover for drug-resistant pathogens as well
    a) Vancomycin + Piperacillin-tazobactam
    b) Vancomycin + Carbapenem (if history of MDR pathogens)
  3. Duration – 7 days for uncomplicated pneumonia
    *For complicated pneumonia, duration of antibiotics will depend on the complication as well as patient’s clinical status and rate of recovery

 

Complications:

  1. ARDS (can happen both in pneumonitis and pneumonia)
  2. Lung abscess
  3. Empyema

 

Take-home points:

  • Aspiration pneumonitis ≠ Aspiration pneumonia
  • Re-evaluate patient in 48 hours and decide whether patient needs to continue antibiotics
  • Anaerobes are less likely to play a pathogenic role in hospital-acquired pneumonia (consider treatment for anaerobes if patient has poor dentition)

 

References:

1. Bartlett, J. G. 2017. Aspiration pneumonia in adults. Uptodate.
2. Finegold, S.M. 1991. Aspiration Pneumonia. CID. 13(9), S737-S742. DOI: 10.1093/clinids/13.Supplement_9.S737
3. Mandell, L. A. et al. 2007. IDSA guidelines for CAP. Section on aspiration pneumonia. 2007. CID. 44(S2): S27-72. DOI: 10.1086/511159
4. Dragan, V. et al. 2018. Prophylactic antimicrobial therapy for acute aspiration pneumonitis. CID. DOI: 10.1093/cid/ciy120
5. Loeb, M.B. et al. 2003. Interventions to prevent aspiration pneumonia in older adults: a systematic review. Journal of American Geriatric Society. 51(7):1018.
DOI: 10.1046/j.1365-2389.2003.51318.x
6.
Joundi, R.A. et al. 2015. Antibiotics “Just-In-Case” in a Patient with aspiration pneumonitis. JAMA Internal Medicine: Teachable moment – Less is more. 175(4); 489-490. DOI:10.1001/jamainternmed.2014.8030

Bactericidal vs. Bacteriostatic antibiotics

Does it matter whether we use a bactericidal antibiotic or a bacteriostatic one? Surely, the bactericidal one would be more effective, right? The answer is not that simple.

Bactericidal = antibiotics that kill bacteria

Bacteriostatic = antibiotics that inhibit the growth of bacteria (i.e. prevent the bacteria from continuing to grow/proliferate) without killing bacteria in vitro OR it is able to kill the bacteria in vitro but at a slower rate than bactericidal agent does.

– there is thought out there that bacteriostatic agents require more activity from the immune system to eradicate the bacteria (this has not been studied well in literature and there is no data to support or negate this hypothesis).

Bactericidal drugs:                                          Bacteriostatic drugs:
Aminoglycosides                                                Glycylcyclines (tigecycline)
Beta-lactams                                                        Lincosamides (clindamycin)
Fluoroquinolones                                               Macrolides (azithromycin, fidaxomicin)
Glycopeptides (vancomycin)                           Oxazolidinones (linezolid, tedizolid)
Lipopeptides (daptomycin)                             Streptogramins (quinipristin/dalfopristin)
Nitroimidazoles/nitrofurans                           Sulphonamides (sulfamethoxazole)
(metronidazole/nitrofurantoin)                     Tetracyclines
Rifampin

*Keep in mind – bactericidal and bacteriostatic effects depend on several factors, including the amount of:
1) bacterial inoculum: the burden of bacteria can change the antibiotic’s properties
2) the pathogen: certain antibiotics are “cidal” to certain pathogens, while “static” to others
–examples:
a)  vancomycin is “cidal” against staph and strep, but “static” against enterococci
b) azithromycin is “cidal” against strep, but “static” against staph
c) linezolid may be “cidal” against strep, but “static” against staph/enterococci
3) medium/location of infection: certain antibiotics are more effective in certain parts of the body (IV vancomycin doesn’t penetrate GI mucosa, tigecycline doesn’t achieve high concentrations in the bloodstream, etc.)

Why could this be potentially clinically irrelevant?

A systematic review published in CID in 2017 looked at all the 59 randomized-controlled trials on clinical outcomes when using bactericidal vs. bacteriostatic agents. They found that 49 (81%) of the trials showed no differences in clinical outcomes when using “cidal” vs. “static” agents.

Similarly, studies demonstrated that using linezolid (a bacteriostatic agent) against MRSA was non-inferior to vancomycin (a bactericidal agent) against MRSA.
Because clinical outcomes depend on 3 factors:

  1. The host
  2. The pathogen
  3. The drug (with many internal factors coming into play as listed below
    -Tissue penetration
    -Pharmacokinetics
    -Drug interactions
    -Optimal dosing

TAKE-HOME POINTS:

  1. Antibiotics can be bacteriostatic for some pathogens and bactericidal for others
  2. Clinical outcomes depend on a variety of factors and the bactericidal property of an antibiotic ultimately appears to have little clinical relevance.

References:

  • Nemeth, J., Oesch, G., and Kuster, S.P. 2015. Bacteriostatic versus bactericidal antibiotics for patients with serious bacterial infections: systematic review and meta-analysis. Journal of antimicrobial chemotherapy. 70:382-395.
  • French, G.L. 2006. Bactericidal agents in the treatment of MRSA infections – the potential role of daptomycin. Journal of Antimicrobial Chemotherapy. 58 (6): 1107-1117.
  • Wald-Dicker, N, Holtom, P, and Spellberg, B. 2017. Busting the myth of “static vs. cidal”: A systemic literature review. CID
  • Panckey, G.A. and Sabath, L.D. 2004. Clinical relevance og bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections. CID, 38(6): 864-870.