Tag Archives: #ID

Non-infectious causes of fever

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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.

IDWeek 2018 Review

MISCELLANEOUS CONCEPTS, , , , , , , , , ,
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.

Procalcitonin

DIAGNOSTICS, , , ,

What is it?

  • A peptide produced by the human body
  • A precursor to calcitonin and thus consistently produced by the thyroid gland C cells
  • An acute phase reactant (and can be used as a marker of a bacterial infection in the body)

PCT activators

  • procalcitonin levels parallel severity of the infection/systemic inflammation
  • increases are detectable ~4 hours after exposure to endotoxin and peaks at 12-48 hours

Why isn’t procalcitonin produced in response to a
viral infection?

It is hypothesized that tumor necrosis factor (TNF) is essential to the synthesis of procalcitonin. When the body is exposed to a viral infection, the virus induces production of interferons which in turn suppresses TNF expression.

Why do we need it?

Studies have shown that up to 50% of antimicrobial use in the inpatient setting is unnecessary. Part of the reason is that we don’t always know who has a bacterial infection and who does not.

A blood test that can help differentiate types of infection and help shorten the duration of unnecessary antibiotics would be extremely helpful to physicians and beneficial to patients.

How does it work?

  • Procalcitonin level is measured in the blood with a blood-draw
  • Can be run from EDTA (purple) or heparin (green) tubes but NOT citrate-containing tubes
  • Levels correlate with severity of the infection/systemic inflammation

When/how do you use it?

The data on how best to use procalcitonin and when to use it remains controversial, and each institution may have their own guidelines on how best to utilize it.

Studies demonstrate that procalcitonin can be used to determine:

  • Whether to initiate antibiotic therapy
  • Duration of antibiotic therapy
  • Prognosis

The TWO scenarios with the most literature suggesting procalcitonin use is helpful are in guiding duration of antibiotic therapy in:

  1. Lower Respiratory Tract Infections (LRTI)
  2. Sepsis

Summary of some major trials in each area

  1. Lower respiratory tract infections
    A) Schuetz et al. 2017 (Cochrane Systematic Review)
    – Cochrane systematic review of RCTs to evaluate procalcitonin in guiding initiation or discontinuation of antibiotics
    – moderate to high quality evidence; 6708 participants, 26 trials
    Primary outcomes: 1) all-cause mortality, 2) treatment failure at 30 days
    All-cause mortality:6% vs. 10% (controls); p-value = 0.037
    Treatment failure: no significant difference (23-24% in both groups)
    Secondary outcomes: 1) antibiotic use, 2) antibiotic-related side effects,
    3) Hospital Length of Stay (LoS)
    # of antibiotic days: 2.4 day reduction in antibiotic exposure (5.7 vs 8.1 days)
    Side effects of antibiotics: 16.3% vs. 22.1% (control), (p-value <0.001)
    LoS in hospital and ICU: no difference
    Summary: improved mortality and increase in antibiotic-free days between the two groups
    B) Huang et al. 2018 (ProACT study)
    – Multicenter RCT, 1656 patients enrolled
    – Procalcitonin was checked in the ED and followed during hospital course if patient was admitted
    – There was no difference in # of antibiotic exposure days over 30 days, rates of adverse events, or hospital length of stay (LoS)
    – There was no difference even when stratified by diagnosis of acute bronchitis, COPD, CAP, and other LRTI.
    Summary: no change in # of antibiotic-exposure days or adverse effects between the two groups
  2. Severe sepsis/shock
    A) DeJong et al. 2016
    – Multicenter RCT in hospitals, 1575 enrolled
    Mortality: 20% vs. 25% (control) (p=0.0122)
    Median antibiotic duration: 7.5 days vs. 9.3 days (control); p-value <0.0001
    – There was a slightly higher risk of reinfection in the procalcitonin group (5% vs. 2.9%, p=0.0492)
    – No difference between ICU and hospital LoS between groups
    Summary: Use of procalcitonin reduced mortality and # of antibiotic exposure days but not LoS
    B) Andriolo et al. 2017 (Cochrane Systematic Review)
    – 10 trials, 1215 participants, low quality evidence
    – No significant differences in mortality at 28 days, ICU discharge, or hospital stay
    – Procalcitonin group had a mean 1.28 day less of antibiotic exposure than control group
    Summary: Use of pro-calcitonin reduced # antibiotic exposure days but not mortality
    C) Wirz et al. 2018
    –     Meta-analysis of RCTs
    – 4482 patients overall
    Mortality: lower in the procalcitonin group (21.1% vs. 23.7%, p=0.03)
    # of antibiotic days: lower in procalcitonin group (9.3 vs. 10.4d, p<0.001)
    Summary: Use of procalcitonin reduces mortality and # of antibiotic exposure days

*It’s important to remember that all these trials have varying adherence to the protocols, various study populations, and centers with varying practice patterns that all affect the results of the studies.

**Procalcitonin should NOT typically be used for determine whether to initiate antibiotics in pneumonia or sepsis given the high risk of a poor outcome with a false negative result.

How to use it

  1. Obtain procalcitonin at time of diagnosis and repeat every 1-2days.
  2. Stop antibiotics when procalcitonin level is <0.1-0.5ng/ml or decreased by at least 50-90% from peak value

*Procalcitonin can also be used when it is unclear whether a patient has a bacterial infection or not to help guide further management.

Other potential uses of PCT

  • Presence of bacterial infection in patients with COPD exacerbations, heart failure exacerbations, or bronchitis
  • Aspiration pneumonia vs. pneumonitis
  • Post-operative infections
  • Fevers of unknown origin
  • UTI therapy duration
  • Bacterial vs. viral meningitis
  • Febrile neutropenia
  • Lower limb swelling
    (distinguishing between stasis dermatitis vs. thrombosis vs. cellulitis)
  • Antibiotic stewardship
  • And many others

Pharmacodynamics/kinetics

  • short half-life (25-30 hours)
  • dialyzed; in ESRD, levels tend to be higher prior to dialysis than after dialysis
    peak levels tend to correlate with severity of infection
  • if inflammation is resolving, levels should decrease by ~50% every 1-2 days.
    ⇒mild elevation = 0.15-2ng/mL
    a) localized bacterial infection
    b) ESRD without recent hemodialysis
    c) noninfectious systemic inflammatory response
    ⇒significant elevation > 2ng/mL
    a) bacterial sepsis or severe localized bacterial infection
    b) severe non-infectious inflammatory stimuli (major burn, severe trauma, acute multisystem organ failure, bowel ischemia, stroke, major abdominal or cardiothoracic surgery)
    c) false positive from malignancy

False positives

  • Malaria
  • Candida spp.
  • Pneumocystis jiroveci
  • Pulmonary TB and some other non-tuberculosis mycobacterial infections
  • Severe systemic stress (trauma, severe burns, surgery, cardiac arrest/shock, Addisonian crisis, pancreatitis, intracranial hemorrhage)
    *possibly due to gut translocation of LPS
  • CKD/ESRD
  • Patients receiving:
    1) T-cell antibody therapy
    2) ATG
    3) Alemtuzumab
    4) Rituximab
    5) IL-2 therapy
    6) Granulocyte transfusion
  • Mushroom poisoning
  • Immediate postnatal period
  • Neuroendocrine tumors/medullary thyroid cancer/small cell lung cancer

False negatives

  • atypical bacteria (i.e. Chlamydia and Mycoplasma pneumoniae, Legionella spp.)
  • localized bacterial infections (tonsillitis, sinusitis, cystitis, uncomplicated SSTI, empyema/abscess, osteomyelitis)
  • if drawn too early in infection (typically rises within 2-5 hours)

Practical advice

  • Procalcitonin levels are NOT impaired in immunocompromised hosts (ICH)
    ⇒however, little information is known regarding use of procalcitonin in this patient population
    ⇒these patients have a low threshold for antibiotic initiation and prolonged duration thus no recommendations can be made to use procalcitonin to guide management in ICH at this time
    ⇒not enough data exists yet to support routine clinical use.
  • Not enough data exists yet to support routine clinical use in surgical patients
    surgical patients may have a higher baseline procalcitonin level after certain surgeries
  • Procalcitonin can be thought of similarly to B-natriuretic peptide (BNP) and as a more sensitive C-reactive protein (CRP). It can be used within a broader clinical context to support a diagnosis or decision regarding antibiotics and is useful in RULING OUT bacterial causes.

 

Take-home points:

  • Use of procalcitonin and its algorithms should NOT override or replace clinical judgment.
  • Serial measurements and trends are more helpful than one isolated value.
  • A rising procalcitonin level is not, by itself, an indication to broaden antibiotic therapy.
  • In order to use procalcitonin effectively, its essential to understand which pathogens induce elevations in procalcitonin.
  • The use of procalcitonin has been most studied in LRTI and sepsis. The utility of procalcitonin in other situations remains unknown.

 

References:

  1. Jin M and Khan A. Procalcitonin: Uses in the Clinical Laboratory for the Diagnosis of Sepsis. Laboratory Medicine. 2010; 41(3):173-177.
    https://doi.org/10.1309/LMQ2GRR4QLFKHCH9
  2. Lin JLJ and Yap SL. Editor: Staros E. Medscape: Procalcitonin. Updated: Nov 24, 2015. https://emedicine.medscape.com/article/2096589-overview#a4
  3. Rhee C and Mansour M. Procalcitonin use in lower respiratory tract infections. In: Ramirez JA, File TM, and Bond S. UpToDate. Waltham, Mass.: UpToDate, 2018. https://www.uptodate.com/contents/procalcitonin-use-in-lower-respiratory-tract-infections. Accessed September 8th, 2018.
  4. Andriolo BN, Andriolo RB, Salomão R, and Atallah ÁN. Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2017;1:CD010959.
  5. Gilbert DN. Use of Plasma Procalcitonin levels as an adjunct to clinical microbiology. J Clin Microbiol. 2010; 48(7):2325-2329. doi: 10.1128/JCM.00655-10
  6. de Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016; 16:819-827. doi: http://dx.doi.org/10.1016/S1473-3099(16)00053-0
  7. Jensen JU, Heslet L, Jensen TH, Espersen K, Steffensen P, and Tvede M. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med. 2006; 34:2596-2602.
  8. Riedel S, Melendez JH, An AT, Rosenbaum JE, and Zenilman JM. Procalcitonin as a marker for the detection of bacteremia and sepsis in the emergency department. Am J Clin Pathol. 2011; 135(2):182-189. doi: 10.1309/AJCP1MFYINQLECV2.
  9. Kollef MH. Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia. In: Manaker S and Finlay G, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. https://www.uptodate.com/contents/clinical-presentation-and-diagnostic-evaluation-of-ventilator-associated-pneumonia. Accessed September 10, 2018.
  10. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017; 10:CD007498. doi: 10.1002/14651858.CD007498.pub3
  11. Huang DT, Yealy DM, Filbin MR, Brown AM, Chang CCH, Doi Y, et al. Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection. NEJM. 2018; 379:236-49. doi: 10.1056/NEJMoa1802670.
  12. Wirz Y, Meier MA, Bouadma L, Luyt CE, Wolff M, Chastre J, et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: a patient-level meta-analysis of randomized trials. Critical Care. 2018; 22:191. https://doi.org/10.1186/s13054-018-2125-7.

5 things that ID fellows wish you knew

MISCELLANEOUS CONCEPTS, , , , , , , , , , , ,

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

PATHOGENS, , , , , , , , ,

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.

CAP vs. HCAP vs. HAP vs. VAP

SYNDROMES, , , , , , , , , ,

This post is written by a guest writer, Jeff Pearson, PharmD. 

2019 UPDATE: The new CAP guidelines have been published! See our more recent post for more up-to-date information on community-acquired pneumonia treatment.

In 2016, the Infectious Diseases Society of America (IDSA) published updated guidelines for the treatment of hospital-acquired pneumonia (HAP) & ventilator-associated pneumonia (VAP).

The plan was to release new community-acquired pneumonia (CAP) guidelines shortly thereafter.

Those CAP guidelines have now been pushed back to be tentatively published in summer 2018.

This post is meant to cover some common misconceptions about the treatment of pneumonia and clinical pearls while we patiently await the release of the new guidelines.

Let’s start with the basics:

HCAP & CAP – those presenting to the hospital with pneumonia
HAP & VAP – those that developed pneumonia >48 hours after admission to the hospital or mechanical ventilation, respectively.

CAP vs HCAP vs HAP vs VAP

But I thought the term HCAP was gone…

While the 2016 guidelines no longer address HCAP, HCAP as an entity has not disappeared (despite what some may tell you). It will likely be discussed in the as-of-yet unreleased CAP guidelines. But in the meantime, feel free to use the algorithm presented above for guidance.

Previous guidelines from 2005 grouped HCAP in with HAP and VAP in terms of treatment. But since then, it’s been determined that not all HCAP patients require MRSA and Pseudomonas coverage. Many can be treated as typical CAP patients.

High-risk HCAP patients =

  • multiple risk factors for multi-drug resistant organisms (see green-box above)
  • require ICU admission to justify broad spectrum antibiotic treatment.

Treatment:

CAP/low risk HCAP
—–NO MRSA or Pseudomonas coverage
—–YES atypical pneumonia pathogens coverage (i.e. mycoplasma, legionella, chlamydia spp.)
Ex. Levofloxacin; ceftriaxone + azithromycin*

High-risk HCAP
—–YES MRSA and Pseudomonas coverage
—–YES atypical pneumonia pathogens coverage (i.e. mycoplasma, legionella, chlamydia spp.)
Ex. Vancomycin + cefepime + azithromycin*

HAP
—–YES MRSA and Pseudomonas coverage
—–Consider double pseudomonal coverage if patient is hemodynamically unstable
—–NO atypical pneumonia pathogen coverage
Ex. Vancomycin + cefepime*

VAP
—–YES MRSA and Pseudomonas coverage
—–Consider double pseudomonal coverage if patient is hemodynamically unstable
—–NO atypical pneumonia pathogen coverage
Ex. Vancomycin + cefepime + tobramycin*

*These are example regimens. Please reference your own institution’s pneumonia guidelines for additional information.

 

Duration of Treatment = 7 days!!!

* This can likely be even shorter in cases of CAP.
** From the IDSA: “There exist situations in which a shorter or longer duration of antibiotics may be indicated, depending upon the rate of improvement of clinical, radiologic, and laboratory parameters.” 2

TAKE-HOME POINTS:

  • HCAP is still an entity – but it has been separated from HAP
  • CAP and HCAP – pneumonia <48 hours into a hospital stay
    HAP and VAP – pneumonia >48 hours into a hospital stay
  • CAP and low risk HCAP – NO need for MRSA and Pseudomonas coverage
    High risk HCAP, HAP, and VAP – DO need MRSA and Pseudomonas coverage
  • Duration of treatment = 7 days

 

2019 UPDATE: The new CAP guidelines have been published! See our more recent post for more up-to-date information on community-acquired pneumonia treatment.

References:

  1. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44:S27-S72
  2. 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
  3. Dinh A, Ropers J, Davido B, et al. Effectiveness of three days of beta-lactam antibiotics for hospitalized community-acquired pneumonia: a randomized non-inferiority double-blind trial [abstract]. ECCMID Madrid, Spain, April 22, 2018.

Guest author: Jeff Pearson is a senior pharmacist in infectious diseases at Brigham and Women’s Hospital in Boston, where he serves as the point person for the hospital’s antimicrobial stewardship program. In addition to precepting Brigham pharmacy residents throughout the year, he also precepts Northeastern University and MCPHS University pharmacy students. Dr. Pearson received his Doctor of Pharmacy from Northeastern University in 2014. He completed his PGY-1 residency at Mount Auburn Hospital and PGY-2 residency in infectious diseases at Beth Israel Deaconess Medical Center.  He can be found on Twitter @jeffpears0n.

Peer-reviewed by Milana Bogorodskaya, MD

5 random facts about antimicrobials

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

Oral vs. IV antimicrobials

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

ANTIMICROBIALS, , , , , , , , ,

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:
Clindamycin — Community-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

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