My elderly patient has a WBC count of 60,000 without obvious hematologic malignancy.  How likely is it that his leukocytosis is related to an infection?

Although extremely high WBC count in the absence of myeloproliferative disease may be associated with solid tumors and other causes, infections are often the most common cause of leukemoid reaction (LR), including tuberculosis, Clostridiodes difficile colitis, shigellosis, salmonellosis, pneumonia, abscesses, as well as  parasitic infections (eg, malaria), fungal infections (mucormycosis), and viral diseases (eg, HIV, EBV, Chickungunya fever).1-4   

In a study of 173 hospitalized patients (mean age 69 y) with leukemoid reaction (defined in this study as WBC ≥30,000/µl), infection was the most common cause of LR (48%), followed by tissue ischemia/stress (28%), inflammation (eg, pancreatitis, diverticulitis without perforation) and obstetric diagnoses (7% each) and malignant tumor (5%).1 

In the same study, the most common infections were “sepsis”, pneumonia and urinary tract infections.  Bacteremia was documented in 13%, while Clostridiodes difficile toxin assay was positive in 7% of patients.  The highest WBC counts were observed in patients with either a positive blood culture or positive C. difficile toxin.  In-hospital mortality rate was very high at 62%.

Similarly, in a study involving 105 hospitalized patients, the most common cause was infection, followed by malignancy and other causes. 2 In a smaller study of 25 patients with “extreme” leukocytosis (defined as WBC ≥50,000/µl) infection was considered the cause in 52% and malignancy in 44% of patients; about one-third were bacteremic (eg, Pseudomonas sp, Streptococcus pneumoniae, E. coli).3

Bonus Pearl: Did you know that besides infections and malignancy, drugs (eg, corticosteroids, epinephrine) and ingestion of ethylene glycol have also been associated with LR? 1,3,4

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References

  1. Potasman I, Grupper M. Leukemoid reaction:Spectrum and prognosis of 173 adult patients. Clin Infect Dis 2013;57:e177-81. https://pubmed.ncbi.nlm.nih.gov/23994818/
  2. Portich JP, Faulhaber GAM. Leudemoid reaction: A 21st-century study. https://pubmed.ncbi.nlm.nih.gov/31765058/
  3. Halkes CJM, Dijstelbloem HM, Eelman Rooda SJ, et al. Extreme leucocytosis: not always leukaemia. The Netherlands J Med 2007;65:248-51. https://pubmed.ncbi.nlm.nih.gov/17656811/
  4. Kumar P, Charaniya R, Sahoo R, et al. Leukemoid reaction in Chickungunya fever. J Clin Diagn Res 2016;10:OD05-OD06. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948452/

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My elderly patient has a WBC count of 60,000 without obvious hematologic malignancy.  How likely is it that his leukocytosis is related to an infection?

“I go after Streptococcus pneumoniae and many other bacteria causing community-acquired pneumonia with vengeance but lately I have had a hard time keeping up with many gram-negatives, including some E. coli. Who am I?”

Additional hint: “The latest FDA warning against the use of my class of drugs has to do with increased risk of ruptures or tears in the aorta in certain patients, including the elderly and those with hypertension, aortic aneurysm or peripheral vascular disease.” 

Editor’s note: This post is part of the P4P “Talking Therapeutics” series designed to make learning about antibiotics fun. Individual antibiotics give a short description of themselves and you are asked to guess their names. Antimicrobial spectrum, common uses and potential adverse effects follow. Enjoy!

And the answer is…… HERE

Selected antimicrobial spectrum

                Gram-positives: Streptococcus pneumoniae, Staphylococcus aureus                         (some resistance even in MSSA), Enterococcus spp (urine;some resistance)

                Gram-negatives: Enterics (eg, E. coli, Klebsiella spp), Pseudomonas spp,                                 Stenotrophomonas maltophilia, H. influenzae, some ESBLs.

                 AVOID: MRSA, anaerobes

Common clinical uses: community-acquired pneumonia (CAP), healthcare-associated pneumonia (HAP), urinary tract infections (UTIs), legionnaire’s disease, abdominal infection (plus anaerobic coverage)

WATCH OUT! QT prolongation, C. difficile, central nervous system toxicity, seizures, myasthenia gravis, peripheral neuropathy, tendinopathy, drug interactions (eg. warfarin), and most recently aortic aneurysm diagnosis/dissection!

Remember the key features of levofloxacin before you prescribe it!

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Selected references

  1. FDA. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients.  https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics. Accessed Nov 26, 2020,.
  2. Marangon FB, Miller D, Muallem MS, et al. Ciprofloxacin and levofloxacin resistance among methicillin-sensitive Staphylococcus aureus isolates from keratitis and conjunctivitis. Am J Ophthal 2004;137:453-58. https://www.ajo.com/article/S0002-9394(03)01287-X/pdf
  3. Yasufuku T, Shigemura K, Shirakawa T, et al. Mechanisms of and risk factors for fluoroquinolone resistance in clinical Enterococcus faecalis from patients with urinary tract infections. J Clin Microbiol 2011;49:3912-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209098/
  4.  Rawla P, Helou MLE, Vellipuram AR. Fluoroquinolones and the risk of aortic aneurysm or aortic dissection: A systematic review and meta-analysis. Cardiovasc Hematol Agents Med Chem 2019;17:3-10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865049/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

“I go after Streptococcus pneumoniae and many other bacteria causing community-acquired pneumonia with vengeance but lately I have had a hard time keeping up with many gram-negatives, including some E. coli. Who am I?”

Is cefepime an acceptable alternative to carbapenems in the treatment of cefepime susceptible extended spectrum beta-lactamase (ESBL) Gram-negatives?

Irrespective of in-vitro susceptibility results, cefepime should be avoided in the treatment of serious ESBL infections associated with bacteremia, pneumonia, intraabdominal infection, endocarditis, bone/joint infection or whenever a high bacterial inoculum is suspected. Cefepime should be considered only in non-severe infections (eg, uncomplicated urinary tract infection) when the minimum inhibitory concentration (MIC) is 2 mg/L or less (1).

 

To date, clinical studies comparing cefepime vs carbapenem have been small and/or retrospective, often with conflicting results (1). A 2016 propensity score-matched study of patients with ESBL bacteremia receiving cefepime therapy followed by carbapenem therapy vs carbapenem for the entire treatment duration found higher 14 day mortality in the cefepime group (41% vs 20% in the carbapenem group) (2).  Of note, 2 of the patients receiving cefepime who died were infected with an ESBL organism with MIC of 1 mcg/mL. 

 

Another study found cefepime to be inferior to carbapenem therapy in ESBL bacteremic patients with better outcome when cefepime MIC was 1 ug/m or less (3).

 

Two studies involving patients with ESBL UTIs found no significant difference between cefepime and carbapenem in clinical and microbiological response or in-hospital mortality, while another UTI study with a high rate of septic shock (33%) found that cefepime was inferior to carbapenem in clinical and microbiological response (2).

 

The diminished efficacy of cefepime for the treatment of ESBL infections may be related to its “inoculum effect” ie, marked increase in MIC with increased inoculum size compared to that used in standard laboratory susceptibility testing (1,4).   

 

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References

  1. Karaiskos I, Giamarellou H. Carbapenem-sparing strategies for ESBL producers: when and how. Antibiotics 2020;9,61. https://pubmed.ncbi.nlm.nih.gov/32033322/
  2. Wang R, Cosgrove S, Tschudin-Sutter S, et al. Cefepime therapy for cefepime-susceptible extended-spectrum beta-lactamase-producing Enerobacteriaceae bacteremia. Open Forum Infect Dis 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942761/
  3. Lee NY, Lee CC, Huang WH, et al. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis 203;56:488-95. https://academic.oup.com/cid/article/56/4/488/351224
  4. Smith KP, Kirby JE. The inoculum effect in the era of multidrug resistance:minor differences in inoculum have dramatic effect on MIC determination. Antimicrob Agents Chemother 2018;62:e00433-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105823/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is cefepime an acceptable alternative to carbapenems in the treatment of cefepime susceptible extended spectrum beta-lactamase (ESBL) Gram-negatives?

My 75 year old patient has an arterial oxygen tension (Pa02) less than 90 mmHg on room air. Does age affect PaO2?

Short answer: Yes! Most studies of blood gas concentrations have demonstrated a decrease in oxygen tension with age.1

Earlier studies have demonstrated a linear decrease in oxygen tension based on observations that included relatively small number of patients over the age of 60. 1 More recently, however, in a study of 532 consecutive patients admitted for elective surgery without overt cardiac, pulmonary, or metabolic disease, obesity or smoking, the mean PaO2 differed by age group as follows:

  • <30 years: 98.4 mmHg
  • 30-50 years: 88.7 mmHg
  • 51-70 years: 81.0 mmHg
  • >70 years: 76.5 mmHg

After age 70 years, decline in Pa02 may slow down or actually reverse, likely related to the “survival of the fittest” in more advanced years. 1,2 Some have suggested accepting a PaO2 80-85 mmHg as normal for subjects > 65 years of age. 3

The decrease in PaO2 with age is a result of increased heterogeneity of ventilation/perfusion ratio, especially reduced ventilation in the dependent parts of the lung. 3 Aging is also associated with a decrease in chest wall compliance, muscle (including the diaphragm) strength, forced expiratory volume in 1 second (FEV1), vital capacity, and diffusing capacity of carbon monoxide (DLC0)/alveolar volume.  

In addition, aging is associated with a reduction in response to hypoxia and hypercarbia, making older patients particularly vulnerable to complications from  heart failure and pneumonia4, especially in the current Covid-19 era.

Bonus Pearl: Did you know that poor response to hypoxic or hypercarbic states in the elderly is likely related to an age-related decline in efferent neural output to respiratory muscles?4

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References

  1. Blom H, Mulder M, Verwej W. Arterial oxygen tension and saturation in hospital patients: effect of age and activity. BMJ 1988;297:720-2. Doi:10.1136/bmj.297.6650.720 https://www.bmj.com/content/297/6650/720   
  2. Delclaux B, Orcel B, Housset B, et al. Arterial blood gases in elderly persons with chronic obstructive pulmonary disease (COPD). Eur Respir J 1994;7:856-61. https://www.researchgate.net/publication/15147788_Arterial_blood_gases_in_elderly_persons_with_chronic_obstructive_pulmonary_disease_COPD
  3. Janssens JP, Pache JC, Nicod LP. Physiological changes in respiratory function associated with ageing. Eur Respir J 1999;13:197-205. https://www.researchgate.net/publication/12689073_Physiological_changes_in_respiratory_function_associated_with_ageing
  4. Sharma G, Goodwin J. Effect of aging on respiratory system physiology and immunology. Clin Interventions in Aging 2006;1:253-60. https://pubmed.ncbi.nlm.nih.gov/18046878/

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

My 75 year old patient has an arterial oxygen tension (Pa02) less than 90 mmHg on room air. Does age affect PaO2?

5 Covid-19 facts worth keeping in mind as we deal with our pandemic anxiety

As an infectious disease physician who had the privilege of caring for many patients during the unsettling times of the early HIV epidemic and the more recent H1N1 pandemic influenza, I fully understand the widespread anxiety the current Covid-19 pandemic has inflicted on our society.

Here are 5 scientific facts that may be worth remembering as we try to deal with our pandemic anxiety.

 
1. On transmission in the community: For sure, Covid-19 is transmitted in the community but I am glad that it behaves more like influenza which is primarily contracted through close personal contact and droplets, and less like measles or chickenpox which are considered airborne with viral particles travelling lingering in the air for long periods of time. On average, a patient with Covid-19 may infect 2-3 susceptible contacts vs as many as 12 or more in the case of patients with measles or chickenpox (1, 2).

 
2. On transmission in healthcare settings: For sure, Covid-19 can be transmitted in the healthcare settings, just like other coronaviruses, such severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) coronaviruses. But the good news is that, in the absence of aerosol-producing procedures (eg, intubation, nebulizer therapy) it doesn’t seem to behave like an airborne virus (see above) and adherence to droplet and contact precautions, including donning of masks, gowns, eye protection and hand hygiene has been effective (3, 4).

 
3. On surface viability after cleaning/disinfection: For sure, the novel 2019 coronavirus SARS-CoV-2, the cause of Covid-19, can be found on surfaces outside of the body. But the good news is that, in contrast to hardy viruses such as norovirus, it succumbs to common disinfection and environmental cleaning procedures. That’s because  coronaviruses have a lipid envelope that easily falls apart under usual cleaning and disinfection of surfaces. That means that simple handwashing with soap and water (minimum 20 seconds), alcohol containing hand hygiene products, detergents and diluted bleach should easily inactivate it (5-9) and that’s good!

 
4. On the course of Covid-19: For sure, Covid-19 can make people very sick and, tragically, may be fatal on occasion. But compared to diseases caused by other recent respiratory coronaviruses such as MERS or SARS, the overall mortality associated with Covid-19 is much lower (often ~ 2.0-3.0% or lower vs 36.0% for MERS and ~10.0% for SARS) (1). In fact, the majority of patients (~80%) may have no symptoms or only have mild disease (10). I am thankful that we are not dealing with a transmissible respiratory virus that has mortality rates like that of MERS.

 
5. On the timing of this pandemic: We are fortunate that this is 2020 not 1918-19 when a particularly virulent form of influenza, dubbed as “the mother of all pandemics” infected some 500 million people (a third of the world’s population at the time) and accounted for an estimated 50 million deaths (11). Imagine fighting a pandemic without the technology to identify its cause. Imagine fighting a pandemic without access to the miracles of modern science and medicine, including antibiotics for secondary bacterial pneumonia, artificial ventilation, dialysis, ICU support, and capability to screen for an infectious agent.  Imagine fighting a pandemic without scientific tools to develop effective antimicrobials or vaccines. Imagine fighting a pandemic without the luxury of the internet.

 
As unprepared as we all feel in combatting Covid-19, I take solace in the fact that our armamentarium and collective determination to mount an effective response to this pandemic has never been better. Even during these uncertain times, I reflect on what could have been and remain optimistic. Be safe!

 

 

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References:
1. Fauci AS, Lane HC, Redfield RR. Covid-19—Navigating the uncharted. N Eng J Med 2020. DOI:10.1056/NEJMe2002387. https://www.nejm.org/doi/full/10.1056/NEJMe2002387
2. Delamater PL, Street EJ, Leslie TF, et al. Complexity of the basic reproduction number (R0). Emerg infect Dis 2019;25:1-4. https://wwwnc.cdc.gov/eid/article/25/1/17-1901_article
3. Seto WH, Tsang D, Yung RWH, et al. Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS). Lancet 2003;361:1519-20. https://www.sciencedirect.com/science/article/pii/S0140673603131686
4. Ng K, Poon BH, Puar THK, et al. COVID-19 and the risk to health care workers: a case report. Ann Intern Med. 2020, March 16. https://annals.org/aim/fullarticle/2763329/covid-19-risk-health-care-workers-case-report
5. van Doremalen N, Bushmaker, Morris DH, et al. Aerosol and surface stability of HCoV-19 (SARS-CoV-2) compared to SARS-CoV-1. N Engl J Med 2020. https://doi.org/10.1101/2020.03.09.20033217
6. Kampf G. Efficacy of ethanol against viruses in hand disinfection. J Hosp Infect 2018;98:331-38. https://www.sciencedirect.com/science/article/pii/S0195670117304693
7. Grayson ML, Melvani S, Druce J, et al. Efficacy of soap and water and alcohol-based hand-rub preparations against live H1N1 influenza virus on the hands of human volunteers Clin Infect Dis 2009;48:285-91. https://www.ncbi.nlm.nih.gov/pubmed/19115974/
8. Service RF. Does disinfecting surfaces really prevent the spread of coronavirus? Science 2020, March 12. https://www.sciencemag.org/news/2020/03/does-disinfecting-surfaces-really-prevent-spread-coronavirus
9. CDC. Norovirus. https://www.cdc.gov/vitalsigns/norovirus/index.html
10. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020. First published Feb 28, 220, last updated March 6, 2020. https://www.nejm.org/doi/10.1056/NEJMoa2002032
11. Taubenberger JK, Morens DM. 1918 influenza: the mother of all pandemics. Emerg Infect Dis 2006;12:15-22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291398/

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

5 Covid-19 facts worth keeping in mind as we deal with our pandemic anxiety

Do statins have a role in treating novel Coronavirus infection, COVID-19?

There is currently no firm clinical evidence that statins improve the outcome of COVID-19. However, there are some theoretical reasons for believing that statins may have a role in the treatment of COVID-19.  That’s because beyond their cholesterol lowering action, statins may also have clinically relevant anti-inflammatory and antiviral (pleotropic) properties.  

Anti-inflammatory: Anti-inflammatory effect of statins is well known and is thought to occur through a variety of molecular pathways of the innate and adaptive immune systems as well as attenuation of several circulating proinflammatory cytokines.1 Although observational studies have suggested that statins lower hospitalization and mortality among outpatients hospitalized with infection, pneumonia or sepsis, several randomized controlled trials (RCTs) have failed to show any mortality benefit among ICU patients with sepsis and ARDS treated with statins.2

In contrast, an RCT involving patients with sepsis (majority with pneumonia, mean CRP 195 mg/dL) reported significant reduction in progression to severe sepsis among statin-naïve patients  placed on atorvastatin 40 mg/day at the time of hospitalization.3 So, perhaps timing of statin therapy before florid sepsis and ARDS is an important factor.  

Some have suggested that statins may decrease the fatality rate of a related Coronavirus, Middle East Respiratory Syndrome (MERS) virus, by blunting exuberant inflammatory response that may result in a fatal outcome. 4

Antiviral: Statins may also have antiviral properties, including activity against influenza, hepatitis C virus, Zika and dengue viruses.2,5 Whether statins have activity against coronaviruses such as the agent of COVID-19 is unclear at this time.

It’s interesting to note that cholesterol may have an important role in the membrane attachment, fusion and replication of many enveloped viruses, including influenza.5 Covid-19 is also an enveloped virus.

So what do we do? Based on the current data, it makes sense to continue statins in patients who have known clinical indications for their use and no obvious contraindications because of COVID-19 (eg. rhabdomyolysis).6 As for statin-naïve patients, particularly those in early stages of sepsis and increased risk of cardiovascular events, benefit may outweigh the risk.  Only proper clinical studies will give us more definitive answers.

Bonus Pearl: Did you know that lipids make up a major component of the envelope in enveloped viruses and that cholesterol makes up nearly one-half of total lipid and over 10% the total mass of influenza viruses?

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References

  1. Tousoulis D, Psarros C, Demosthenous M, et al. Innate and adaptive inflammation as a therapeutic target in vascular diseae: The emerging role of statins. J Am Coll Cardiol 2014;63:2491-2502. https://www.sciencedirect.com/science/article/pii/S0735109714011553?via%3Dihub
  2. Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124618/pdf/atm-04-21-421.pdf
  3. Patel JM, Snaith C, Thickette DR. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) Critical Care 2012;16:R231. https://ccforum.biomedcentral.com/track/pdf/10.1186/cc11895
  4. Espano E, Nam JH, Song EJ, et al. Lipophilic statins inhibit Zika virus production in Vero cells. Scientific Reports 2019;9:11461. https://www.nature.com/articles/s41598-019-47956-1
  5. Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543-12551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC262566/
  6. Virani SS. Is there a role for statin therapy in acute viral infections. Am Coll Cardiol March 18, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/09/is-there-a-role-for-statin-therapy-in-acute-viral-infections-covid-19

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Do statins have a role in treating novel Coronavirus infection, COVID-19?

Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

Repurposing of older drugs such as chloroquine or hydroxychloroquine (HC) and more recently, azithromycin (AZ), has received much attention recently in the treatment of Covid-19. Both HC and AZ have immune modulating and antiviral activity that may potentially be effective in our fight against Covid-19.

 
Chloroquine/HC: Chloroquine is an old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. It is active in mice against a variety of viruses, including some enteroviruses, Zika virus, and influenza A H5N1 (1). Both chloroquine and HC are active in vitro against Covid-19, though HC appears to be more active (2).

 
Azithromycin: A macrolide often used for treatment of bacterial respiratory tract infections but also with anti-inflammatory and antiviral activity. Azithromycin has been shown to augment interferon response in rhinovirus-infected bronchial epithelial cells as well as in an experimental mouse model of asthma exacerbation (3,4). It also has activity against Zika virus (5). As recently as 2016, some authors opined that macrolides may be useful in pandemic influenza characterized by excessive inflammatory cytokine production because of their anti-inflammatory and interferon-boosting potential (6).

 
March 2020 French clinical trial: A small non-randomized clinical trial involving 36 confirmed Covid-19 patients (mean age 45 y) reported that HC (200 mg 3x/day x 10 days) was associated with rapid viral clearance from nasopharynx, often within 3-6 days (7). The effect was even more pronounced when AZ (500 mg 1st day, followed by 250 mg daily x 4 days) was added in 6 patients.

It’s worth emphasizing that most subjects in this study were either asymptomatic (17%) or had mild disease with upper respiratory tract infection symptoms only (61%). Pneumonia was diagnosed in only 6 patients.  A significant number of patients in the treatment arm also dropped out of the study, some due to ICU transfer.

 
Although such preliminary reports appear promising, the proof of the efficacy and safety of HC and/or AZ in the treatment of Covid-19 awaits larger properly designed clinical studies. Stay tuned!

 

 

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References
1. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.ncbi.nlm.nih.gov/pubmed/32147496
2. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respirartory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020, March 9. https://www.ncbi.nlm.nih.gov/pubmed/32150618
3. Menzel M, Akbarshai H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients. Scientific Reports 2016;6:28698. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923851/
4. Menzel M, Akbarshai H, Uller L. Azithromycin exhibits interferon-inducing properties in an experimental mouse model of asthma exacerbation. Eur Resp J 2015;46:PA5095. https://erj.ersjournas.com/content/46/suppl_59/PA5095
5. Retallack H, Di Lullo E, Knopp AC, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Nat Acad Sci USA 2016;113:14408-13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167169/
6. Porter JD, Watson J, Roberts LR, et al. Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III-IFN-augmenting activity in airway epithelium. J Antimicrob Chemother 2016;71:2767-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031920/
7. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19:results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents—In Press 17 March 2020-DOI: 10.1016/j.ijantimicag.2020.105949 . https://www.sciencedirect.com/science/article/pii/S0924857920300996

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why might hydroxychloroquine and azithromycin be effective against the novel Coronavirus SARS-CoV-2/Covid-19?

Key clinical pearls in the medical management of hospitalized patients with coronavirus (Covid-19) infection

First, a shout-out to dedicated healthcare workers everywhere who have selflessly given of themselves to care for the sick during this pandemic. Thank you! Together, I know we will get through it!

Although our understanding of Covid-19 infection is far from complete, in the spirit of clarity and brevity of my posts on Pearls4Peers, here are some key points I have gleaned from review of existing literature and the CDC that may be useful as we care for our hospitalized patients with suspected or confirmed Covid-19 infection.

  • Isolation precautions.1 Per CDC, follow a combination of airborne (particularly when aerosol generating procedures is anticipated, including nebulizer treatment) and contact precaution protocols. Routinely use masks or respirators, such as N-95s (subject to local availability and policy) and eye protection. Don gowns (subject to local availability and policy) and gloves and adhere to strict hand hygiene practices.

 

  • Diagnostic tests1-9
    • Laboratory tests. Routine admission labs include CBC, electrolytes, coagulation panels and liver and renal tests. Other frequently reported labs include LDH, C-reactive protein (CRP) and procalcitonin. Testing for high sensitivity troponin I has also been performed in some patients, presumably due to concern over ischemic cardiac injury or myocarditis.2 Check other labs as clinically indicated.
    • Chest radiograph/CT chest. One or both have been obtained in virtually all reported cases with CT having higher sensitivity for detection of lung abnormalities.
    • EKG. Frequency of checking EKGs not reported in many published reports thought 1 study reported “acute cardiac injury” in some patients, based in part on EKG findings.4 Suspect we will be checking EKGs in many patients, particularly those who are older or are at risk of heart disease.
    • Point-of-care ultrasound (POCUS). This relatively new technology appears promising in Covid-19 infections, including in rapid assessment of the severity of pneumonia or ARDS at presentation and tracking the evolution of the disease. 9 Don’t forget to disinfect the probe between uses!

 

  • Treatment 1-8
    • Specific therapies are not currently available for treatment of Covid-19 infections, but studies are underway.
    • Supportive care includes IV fluids, 02 supplementation and nutrition, as needed. Plenty of emotional support for patients and their families will likely be needed during these times.
    • Antibiotics have been used in the majority of reported cases, either on admission or during hospitalization when superimposed bacterial pneumonia or sepsis could not be excluded.
      • Prescribe antibiotics against common community-acquired pneumonia (CAP) pathogens, including those associated with post-viral/influenza pneumonia such as Streptococcus pneumoniae (eg, ceftriaxone), and Staphylococcus aureus (eg, vancomycin or linezolid if MRSA is suspected) when concurrent CAP is suspected.
      • Prescribe antibiotics against common hospital-acquired pneumonia (HAP) (eg, vancomycin plus cefepime) when HAP is suspected.
    • Corticosteroids should be avoided because of the potential for prolonging viral replication, unless indicated for other reasons such as COPD exacerbation or septic shock. 1
    • Monitor for deterioration in clinical status even when your hospitalized patient has relatively minor symptoms. This is because progression to lower respiratory tract disease due to Covid-19 often develops during the 2nd week of illness (average 9 days).
    • ICU transfer may be necessary in up to 30% of hospitalized patients due to complications such as ARDS, secondary infections, and multi-organ failure.

 

Again, thank you for caring for the sick and be safe! Feel free to leave comments or questions.

 

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References

  1. CDC. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
  2. Ruan Q, Yang K, Wang W, Jiang L, et al. Clinical predictors of mortality due to COVID-19 based on analysis of data of 150 patients with Wuhan, China. Intensive Care Med 2020. https://link.springer.com/article/10.1007/s00134-020-05991-x
  3. Holshue ML, BeBohlt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020;382:929-36. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  4. Huang C, Wang Y, Li Xingwang, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)30183-5.pdf
  5. Young BE, Ong SWX, Kalimuddin S, et al. Epideomiologic features and clinical course of patients infected with SARS-CoV-2 Singapore. JAMA, March 3, 2020. Doi.10.1001/jama.2020.3204 https://www.ncbi.nlm.nih.gov/pubmed/32125362
  6. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical chacteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-13. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30211-7/fulltext
  7. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl Med 2020, Feb 28, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
  8. Zhang J, Zhou L, Yang Y, et al. Therapeutic and triage strategies for 2019 novel coronavirus disease in fever clinics. Lancet 2020;8: e11-e12. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30071-0/fulltext 9.
  9. Peng QY, Wang XT, Zhang LN, et al. Findings of lung ultrasonography of novel corona virus pneumonia during the 2019-2020 epidemic. Intensive Care Med 2020. https://doi.org/10.1007/s00134-020-05996-
Key clinical pearls in the medical management of hospitalized patients with coronavirus (Covid-19) infection

When should I consider a switch to oral antibiotics and discharge from hospital in my recently admitted elderly patient with community-acquired pneumonia (CAP)?

A frequently used validated set of clinical stability criteria in patients with CAP and supported by the 2019 ATS/IDSA CAP guidelines consists of a temperature ≤37.8 ᵒC (100.0 ᵒF) AND no more than 1 CAP-related sign of clinical instability as listed below: 1-3

  • Heart rate >100/min
  • Systolic blood pressure <90 mm Hg
  • Respiration rate >24 breaths/min
  • Arterial oxygen saturation <90% or Pa02<60 mm Hg (room air)

Using these criteria, the risk of clinical deterioration serious enough to necessitate transfer to an intensive care unit may be 1% or less, 1 while failure to achieve clinical stability within 5 days is associated with higher mortality and worse clinical outcome. 2 The median time to clinical stability (as defined) for CAP treatment is 3 days.1  

A 2016 randomized-controlled trial involving patients hospitalized with CAP found that implementation of above clinical stability criteria was associated with safe discontinuation of antibiotics after a minimum of 5 days of appropriate therapy.

Potential limitations of the above study include heavy use of quinolones (80%), underrepresentation of patients with severe CAP (Pneumonia Risk Index, PSI, V), and exclusion of nursing home residents, immunosuppressed patients, those with chest tube, or infection caused by less common organisms, such as Staphylococcus aureus or Pseudomonas aeruginosa.

Lack of clinical stability after 5 days of CAP treatment should prompt evaluation for complications of pneumonia (eg, empyema, lung abscess), infection due to  organisms resistant to selected antibiotics, or an alternative source of infection/inflammatory/poor response. 2

References

  1. Halm, EA, Fine MJ, Marrie TJ, et al. Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines. JAMA 1998;279:279:1452-57. https://reference.medscape.com/medline/abstract/9600479
  2. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. Am J Respir Crit Care Med 2019;200:e45-e67. https://www.ncbi.nlm.nih.gov/pubmed/31573350
  3. Uranga A, Espana PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia. A multicenter randomized clinical trial. JAMA Intern Med 2016;176:1257-65. https://www.ncbi.nlm.nih.gov/pubmed/27455166/
When should I consider a switch to oral antibiotics and discharge from hospital in my recently admitted elderly patient with community-acquired pneumonia (CAP)?

What changes should I consider in my treatment of hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic society (ATS) and Infectious Diseases Society of America (IDSA)?

Compared to 2007,1 the 2019 ATS/IDSA guidelines2 propose changes in at least 4 major areas of CAP treatment in inpatients, with 2 “Do’s” and 2 “Dont’s”:

  • Do select empiric antibiotics based on severity of CAP and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (see related pearl on P4P)
  • Do routinely treat CAP patients who test positive for influenza with standard CAP antibiotics
  • Don’t routinely provide anaerobic coverage in aspiration pneumonia (limit it to empyema and lung abscess) (see related pearl on P4P)
  • Don’t routinely treat CAP with adjunctive corticosteroids in the absence of refractory shock

β-lactam plus macrolide is recommended for both non-severe and severe CAP.  β-lactam plus respiratory fluoroquinolone is an alternative regime in severe CAP, though not endorsed as strongly as β-lactam plus macrolide therapy (low quality of evidence).  Management per CAP severity summarized below:

  • Non-severe CAP
    • β-lactam (eg, ceftriaxone, cefotaxime, ampicillin-sulbactam and newly-added ceftaroline) plus macrolide (eg, azithromycin, clarithromycin) OR respiratory fluoroquinolone (eg, levofloxacin, moxifloxacin)
    • In patients at risk of MRSA or P. aeruginosa infection (eg, prior isolation of respective pathogens, hospitalization and parenteral antibiotics in the last 90 days or locally validated risk factors—HCAP has been retired), obtain cultures/PCR
    • Hold off on MRSA or P. aeruginosa coverage unless culture/PCR results return positive.
  • Severe CAP
    • β-lactam plus macrolide OR β-lactam plus respiratory fluoroquinolone (see above)
    • In patients at risk of MRSA or P. aeruginosa infection (see above), obtain cultures/PCR
    • Add MRSA coverage (eg, vancomycin or linezolid) and/or P. aeruginosa coverage (eg, cefepime, ceftazidime, piperacillin-tazobactam, meropenem, imipenem) if deemed at risk (see above) while waiting for culture/PCR results

Duration of antibiotics is for a minimum of 5 days for commonly-targeted pathogens and a minimum of 7 days for MRSA or P. aeruginosa infections, irrespective of severity or rapidity in achieving clinical stability.

For patients who test positive for influenza and have CAP, standard antibacterial regimen should be routinely added to antiinfluenza treatment.

For patients suspected of aspiration pneumonia, anaerobic coverage (eg, clindamycin, ampicillin-sulbactam, piperacillin-tazobactam) is NOT routinely recommended in the absence of lung abscess or empyema.

Corticosteroids are NOT routinely recommended for non-severe (high quality of evidence) or severe (moderate quality of evidence) CAP in the absence of refractory septic shock.

Related pearls on P4P:

2019 CAP guidelines on diagnostics:                                        https://pearls4peers.com/2020/02/14/what-changes-should-i-consider-in-my-diagnostic-approach-to-hospitalized-patients-with-community-acquired-pneumonia-cap-in-light-of-the-2019-guidelines-of-the-american-thoracic-society-ats-and-inf/ 

Anerobic coverage of aspiration pneumonia: https://pearls4peers.com/2019/07/31/should-i-routinely-select-antibiotics-with-activity-against-anaerobes-in-my-patients-with-presumed-aspiration-pneumonia/

References

  1. Mandell LA, Wunderink RG, Anzueto A. Infectious Disease Society of America/American Thoracic Society Consensus Guidelines on the Management guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72. https://www.ncbi.nlm.nih.gov/pubmed/17278083
  2. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. Am J Respir Crit Care Med 2019;200:e45-e67. https://www.ncbi.nlm.nih.gov/pubmed/31573350

 

What changes should I consider in my treatment of hospitalized patients with community-acquired pneumonia (CAP) in light of the 2019 guidelines of the American Thoracic society (ATS) and Infectious Diseases Society of America (IDSA)?