pneumonia

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

FA Manian MD, MPH, , , , , , , , , , , , , Leave a comment

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

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , 1 Comment

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)?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , Leave a comment

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. 3 

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)?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

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)?

Should I continue to vaccinate my 65 years or older patients with pneumococcal conjugate vaccine (PCV13)?

FA Manian MD, MPH, , , , , , , Leave a comment

The 2020 U.S. Advisory Committee on Immunization Practices (ACIP) has revised its previous 2014 guidelines from routinely vaccinating all adults 65 years or older with PCV13 to a more selective vaccination approach based on shared clinical decision-making in the absence of immunocompromising conditions, cerebrospinal fluid leak or cochlear implant. 1

More specifically, ACIP recommends that we “regularly” offer PCV13 for patients 65 years or older who have not previously received PCV13 in the following settings:

  • Residents of nursing homes or other long-term care facilities
  • Residents of settings with low pediatric PCV13 uptake
  • Travelers to settings with no pediatric PCV13 program

ACIP also recommends that we consider offering the PCV13 to patients with chronic heart, lung, or liver disease, diabetes, or alcoholism, those who smoke cigarettes, or those with more than 1 chronic medical condition.

Why the change in recommendations? The primary reason is sharp declines in pneumococcal disease in unvaccinated children and adults due to the widespread use of PCV7 and PCV13 in children, resulting in prevention of transmission of vaccine-type strains.  

These recommendations do not apply to the pneumococcal 23-valent polysaccharide vaccine (PPSV23), however. All adults 65 years or older should continue to receive a dose of PPSV23. 

Bonus Pearl: If a decision is made to administer PCV13 to an adult 65 years old or older, PCV13 should be administered first, followed by PPSV23 at least 1 year later.

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References

  1. Freedman M, Kroger A, Hunter P, et al. Recommended adult immunization schedule, United States, 2020. Ann Intern Med 2020; [Epub ahead of print 4 February 2020]. Doi: https://doi.org/10.7326/M20-0046.
  2. Matanock A, Lee G, Gierke R, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: updated recommendations of the advisory committee on immunization practices. MMWR 2019;68:1069-75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871896/pdf/mm6846a5.pdf

 

Should I continue to vaccinate my 65 years or older patients with pneumococcal conjugate vaccine (PCV13)?

How long should I treat my patient with urinary tract infection and E. Coli bacteremia?

FA Manian MD, MPH, , , , , , , , , , , , , , , Leave a comment

Although traditionally 7 to 14 days of antibiotic therapy has been recommended for Gram-negative bacteremia, more recent studies suggest that shorter antibiotic treatment courses are as effective as longer treatments for a variety of infections, particuarly those due to Enterobacteriaceae (eg, E. Coli, Klebsiella sp) in patients with low severity illness (1). 

Keep in mind that short course therapy may not apply to all patients with UTI and bacteremia, such as those with prostatitis (not included in the most recent study [1,2]), which requires longer course of antibiotics (3)

 
A 2019 randomized-controlled study involving primarily patients with bacteremia caused by E. Coli or Klebsiella sp. (~75%) with most cases associated with UTI (~70%) found that 7 days was as effective as 14 days of treatment in hemodynamically stable patients who are afebrile for at least 48 hours without an ongoing focus of infection (1). More specifically, there was no significant difference between the 2 groups in the rates of relapse of bacteremia or mortality at 14 or 28 days.

 
An accompanying editorial concluded that “7 days of treatment may be sufficient for hospitalized, non-critically ill patients with Gram-negative bacteremia and with signs of early response to treatment” (4)  Again, the accent should be on hemodynamically stable patients who respond rapidly to treatment. 

 
Bonus Pearl: While on the subject of shorter course antibiotic therapy, a 2016 “mantra” article nicely summarizes more recent suggestions for common infectious disease conditions (5). Obviously, clinical judgment should be exercised in all cases.
• Community-acquired pneumonia                               3-5 days (vs 7-10 days)
• Nosocomial pneumonia                                                 8 days or less (vs 10-15 days)
• Pyelonephritis                                                                  5-7 days (vs 10-14 days)
• Intraabdominal infection                                             4 days (vs 10 days)
• COPD acute exacerbation                                             5 days or less (vs >6 days)
• Acute bacterial sinusitis                                               5 days (vs 10 days)
• Cellulitis                                                                            5-6 days (vs 10 days)

 

 

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References
1. Yahav D, Franceschini E, Koppel F, et al. Seven versus 14 days of antibiotic therapy for uncomplicated Gram-negative bacteremia: A noninferiority randomized controlled trial. Clin Infect Dis 2019; 69:1091-8. https://academic.oup.com/cid/article/69/7/1091/5237874       2. Yahav D, Mussini C, Leibovici L, et al. Reply to “Should we treat bacteremic prostatitis for 7 days”.  Clin Infect Dis 2010;70:751-3. DOI:10:1093/cid/ciz393.

3.  De Greef J, Doyen L, Hnrard S, et al. Should we treat bacteremic prostatitis for 7 days? Clin Infect Dis 2020;70:351https://academic.oup.com/cid/article-abstract/70/2/351/5488067?redirectedFrom=fulltext
4. Daneman D, Fowler RA. Shortening antibiotic treatment durations for bacteremia. Clin Infect Dis 2019;69:1099-1100. https://academic.oup.com/cid/article-abstract/69/7/1099/5237877?redirectedFrom=fulltext
5. Spellberg B. The new antibiotic mantra: “ Shorter is better”. JAMA Intern Med 2016;176:1254-55. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2536180

How long should I treat my patient with urinary tract infection and E. Coli bacteremia?

Should I routinely select antibiotics with activity against anaerobes in my patients with presumed aspiration pneumonia?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Anaerobes have been considered a major cause of aspiration pneumonia (AP) based on studies published in 1970’s (1-3). More recent data, however, suggest that anaerobes no longer play an important role in most cases of AP (4-7) and routine inclusion of specific anti-anaerobic drugs in their treatment is no longer necessary.

 
An important reason for anaerobes not playing an important role in AP in the current era is the change in the demographics of patients who may be affected. Patients reported in older studies often suffered from alcohol use disorder, drug ingestion, seizure disorders and acute cerebrovascular accident. In contrast, more recent data show that AP often occurs in nursing home residents, the elderly with cognitive impairment, and those with dysphagia, gastrointestinal dysmotility or tube feeding (8,9).

 
In addition, many cases of AP reported in older studies involved delay of 4 or more days before seeking medical attention and, not surprisingly, often presented with lung abscess, necrotizing pneumonia, empyema, or putrid sputum, features that are relatively rare in the current era.

 
Further supporting the diminishing role of anaerobes in AP, are recent microbiological studies of the respiratory tract in AP revealing the infrequent isolation of anaerobes and, even when isolated, often coexisting with aerobic bacteria. The latter observation is important because, due to the alteration in the redox potential (9,10), treatment of aerobic bacteria alone may lead to less oxygenation consumption and less favorable environment for survival of anaerobes in the respiratory tract.

 
We should also always consider the potential adverse effects of unnecessary antibiotics with anaerobic activity in our frequently debilitated patients, including gastrointestinal dysbiosis (associated with Clostridiodes difficile infections and overgrowth of antibiotic-resistant pathogens such as vancomycin-resistant enterococci (VRE), hypersensitivity reactions, drug interactions, and central nervous system toxicity (11,12).
Thus, the weight of the evidence does not justify routine anaerobic coverage of AP in today’s patients.

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References
1. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Am J Med. 1974;56(2):202-7. https://www.ncbi.nlm.nih.gov/pubmed/4812076
2. Bartlett JG, Finegold SM. Anaerobic pleuropulmonary infections. Medicine (Baltimore). 1972;51(6):413-50. https://www.ncbi.nlm.nih.gov/pubmed/4564416
3. Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest. 1975;68(4):560-6. https://www.ncbi.nlm.nih.gov/pubmed/1175415
4. Finegold SM. Aspiration pneumonia. Rev Infect Dis. 1991;13 Suppl 9:S737-42. https://www.ncbi.nlm.nih.gov/pubmed/1925318
5. Bartlett JG. How important are anaerobic bacteria in aspiration pneumonia: when should they be treated and what is optimal therapy. Infect Dis Clin North Am. 2013;27(1):149-55. https://www.ncbi.nlm.nih.gov/pubmed/23398871
6. El-Solh AA, Pietrantoni C, Bhat A, Aquilina AT, Okada M, Grover V, et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med. 2003;167(12):1650-4. https://www.ncbi.nlm.nih.gov/pubmed/12689848
7. Marik PE, Careau P. The role of anaerobes in patients with ventilator-associated pneumonia and aspiration pneumonia: a prospective study. Chest. 1999;115(1):178-83. https://www.ncbi.nlm.nih.gov/pubmed/9925081
8. Bowerman TJ, Zhang J, Waite LM. Antibacterial treatment of aspiration pneumonia in older people: a systematic review. Clin Interv Aging. 2018;13:2201-13. https://www.ncbi.nlm.nih.gov/pubmed/30464429
9. Mandell LA, Niederman MS. Aspiration Pneumonia. N Engl J Med. 2019 Feb 14;380(7):651-663. doi: 10.1056/NEJMra1714562. https://www.ncbi.nlm.nih.gov/pubmed/30763196
10. Walden, W. C., & Hentges, D. J. (1975). Differential effects of oxygen and oxidation-reduction potential on the multiplication of three species of anaerobic intestinal bacteria. Applied microbiology, 30(5), 781–785. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC187272/
11. Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect Dis. 2001;1(2):101-14. https://www.ncbi.nlm.nih.gov/pubmed/11871461
12. Bhalla A, Pultz NJ, Ray AJ, Hoyen CK, Eckstein EC, Donskey CJ. Antianaerobic antibiotic therapy promotes overgrowth of antibiotic-resistant, gram-negative bacilli and vancomycin-resistant enterococci in the stool of colonized patients. Infect Control Hosp Epidemiol. 2003;24(9):644-9. https://www.ncbi.nlm.nih.gov/pubmed/14510245

 

Contributed by Amar Vedamurthy, MD, MPH, Mass General Hospital, Boston, MA

Should I routinely select antibiotics with activity against anaerobes in my patients with presumed aspiration pneumonia?

My patient with diabetes mellitus is now admitted with pneumonia. Does diabetes increase the risk of pneumonia requiring hospitalization?

FA Manian MD, MPH, , , , , , , , , , , Leave a comment

The weight of the evidence to date suggests that diabetes mellitus (DM) does increase the risk of pneumonia-related hospitalization.1-3

A large population-based study involving over 30,000 patients found an adjusted relative risk (RR) of hospitalization with pneumonia of 1.26 (95% C.I 1.2-1.3) among patients with DM compared to non-diabetics.  Of note, the risk of pneumonia-related hospitalization was significantly higher in type 1 as well as type 2 DM and among patients whose A1C level was ≥9.1  Another population-based study found a high prevalence of DM (25.6%) in patients hospitalized with CAP, more than double that in the population studied.2  A 2016 meta-analysis of observational studies also found increased incidence of respiratory tract infections among patients with diabetes (OR 1.35, 95% C.I. 1.3-1.4).

Not only does DM increase the risk of pneumonia-related hospitalization, but it also appears to adversely affect its outcome with increased in-hospital mortality.2 Among patients with type 2 DM,  excess mortality has also been reported at 30 days, 90 days and 1 year following hospitalization for pneumonia. 4,5 More specifically, compared to controls with CAP, 1 year mortality of patients with DM was 30% (vs 17%) in 1 study. 4

Potential reasons for the higher incidence of pneumonia among patients with DM include increased risk of aspiration (eg, in the setting of gastroparesis, decreased cough reflex), impaired immunity (eg, chemotaxis, intracellular killing), pulmonary microangiopathy and coexisting morbidity. 1,3,5,6

Bonus Pearl: Did you know that worldwide DM has reached epidemic levels, such that if DM were a nation, it would surpass the U.S. as the 3rd most populous country! 7

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References

  1. Kornum JB, Thomsen RW, RUS A, et al. Diabetes, glycemic control, and risk of hospitalization with pneumonia. A population-based case-control study. Diabetes Care 2008;31:1541-45. https://www.ncbi.nlm.nih.gov/pubmed/17595354
  2. Martins M, Boavida JM, Raposo JF, et al. Diabetes hinders community-acquired pneumonia outcomes in hospitalized patients. BMJ Open Diabetes Research and Care 2016;4:e000181.doi:10.1136/bmjdrc-2015000181. https://drc.bmj.com/content/4/1/e000181
  3. Abu-Ahour W, Twells L, Valcour J, et al. The association between diabetes mellitus and incident infections: a systematic review and meta-analysis of observational studies. BMJ Open Diabetes Research and Care 2017;5:e000336. https://drc.bmj.com/content/5/1/e000336. 
  4. Falcone M, Tiseo G, Russo A, et al. Hospitalization for pneumonia is associated with decreased 1-year survival in patients with type 2 diabetes. Results from a prospective cohort study. Medicine 2016;95:e2531. https://www.ncbi.nlm.nih.gov/pubmed/26844461
  5. Kornum JB, Thomsen RW, Rus A, et al. Type 2 diabetes and pneumonia outcomes. A population-based cohort study. Diabetes Care 2007;30:2251-57. https://www.ncbi.nlm.nih.gov/pubmed/17595354
  6. Koziel H, Koziel MJ. Pulmonary complications of diabetes mellitus. Pneumonia. Infect Dis Clin North Am 1995;9:65-96. https://www.ncbi.nlm.nih.gov/pubmed/7769221
  7. Zimmet PZ. Diabetes and its drivers: the largest epidemic in human history? Clinical Diabetes and Endocrinology 2017;3:1 https://clindiabetesendo.biomedcentral.com/articles/10.1186/s40842-016-0039-3  

 

My patient with diabetes mellitus is now admitted with pneumonia. Does diabetes increase the risk of pneumonia requiring hospitalization?

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , Leave a comment

 Absolutely! Although trauma, toxins, exertion, and medications are often listed as common causes of rhabdomyolysis, infectious etiologies should not be overlooked as they may account for 5% to 30% or more of rhabdomyolysis cases (1,2).

Rhabdomyolysis tends to be associated with a variety of infections, often severe, involving the respiratory tract, as well as urinary tract, heart and meninges, and may be caused by a long list of pathogens (1).  Among bacterial causes, Legionella sp. (“classic” pathogen associated with rhabdomyolysis), Streptococcus sp. (including S. pneumoniae), Salmonella sp, Staphylococcus aureus, Francisella tularensis have been cited frequently (3).  Some series have reported a preponderance of aerobic gram-negatives such as Klebsiella sp., Pseudomonas sp. and E. coli  (1,2).   Among viral etiologies, influenza virus, human immunodeficiency virus, and coxsackievirus are commonly cited (2,3).  Fungal and protozoal infections (eg, malaria) may also be associated with rhabdomyolysis (5).

So how might sepsis cause rhabdomyolysis? Several potential mechanisms have been implicated, including tissue hypoxemia due to sepsis, direct muscle invasion by pathogens (eg, S. aureus, streptococci, Salmonella sp.), toxin generation (eg, Legionella), cytokine-mediated muscle cell toxicity (eg, aerobic gram-negatives) as well as muscle ischemia due to shock (1,5).

Bonus Pearl: Did you know that among patients with HIV infection, infections are the most common cause (39%) of rhabdomyolysis (6)? 

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References

1. Kumar AA, Bhaskar E, Shantha GPS, et al. Rhabdomyolysis in community acquired bacterial sepsis—A retrospective cohort study. PLoS ONE 2009;e7182. Doi:10.1371/journa.pone.0007182. https://www.ncbi.nlm.nih.gov/pubmed/19787056.

2. Blanco JR, Zabaza M, Sacedo J, et al. Rhabdomyolysis of infectious and noninfectious causes. South Med J 2002;95:542-44. https://www.ncbi.nlm.nih.gov/pubmed/12005014

3. Singh U, Scheld WM. Infectious etiologies of rhabdomyolysis:three case reports and review. Clin Infect Dis 1996;22:642-9. https://www.ncbi.nlm.nih.gov/pubmed/8729203

4. Shih CC, Hii HP, Tsao CM, et al. Therapeutic effects of procainamide on endotoxin-induced rhabdomyolysis in rats. PLOS ONE 2016. Doi:10.1371/journal.pone.0150319. https://www.ncbi.nlm.nih.gov/pubmed/26918767

5. Khan FY. Rhabdomyolysis: a review of the literature. NJM 2009;67:272-83. http://www.njmonline.nl/getpdf.php?id=842

6. Koubar SH, Estrella MM, Warrier R, et al. Rhabdomyolysis in an HIV cohort: epidemiology, causes and outcomes. BMC Nephrology 2017;18:242. DOI 10.1186/s12882-017-0656-9. https://bmcnephrol.biomedcentral.com/track/pdf/10.1186/s12882-017-0656-9

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

My postop patient now has fever with atelectasis on her chest X-ray one day after surgery. Does atelectasis cause fever?

FA Manian MD, MPH, , , , , , Leave a comment

Although fever and atelectasis often coexist during the early postop period, there is no evidence that atelectasis causes fever.

A 2011 systematic analysis of 8 published studies found that all but 1 study failed to find a significant association between postop fever and atelectasis.1  A 1988 study reported a significant association between postop fever during the first 48 h and atelectasis on day 4 postop, but not each postop day.2  Even in this study, however, fever as a predictor of atelectasis performed poorly with a sensitivity of 26%, specificity of 75% and accuracy of 43%.

In another study involving postop cardiac surgery patients, despite a fall in the incidence of fever from day 0 to day 2, the incidence of atelectasis based on serial chest X-rays actually  increased. 3

Experimental studies in dogs and cats in the 1960s also support the lack of a causative relationship between atelectasis and fever. 4,5 Although fever was observed within 12 hrs of placement of cotton plugs in the left main bronchus of these animals, almost all animals also developed pneumonia distal to the plug.  Antibiotic treatment was associated with resolution of fever but not atelectasis.

So if it’s not atelectasis, what’s the explanation for early postop fever? The great majority of postop fevers during the first 4 days postop are unlikely to be related to infections. Instead, a more plausible explanation is the inflammatory response to the tissue injury as a result of the surgery itself causing release of cytokines (eg, interleukin-1 and -6 and tumor necrosis factor) associated with fever. 6

References

  1. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever. Where is the clinical evidence? CHEST 2011;140:418-24. https://www.ncbi.nlm.nih.gov/pubmed/21527508
  2. Roberts J, Barnes W, Pennock M, et al. Diagnostic accuracy of fever as a measure of postoperative pulmonary complications. Heart Lung 1988;17:166-70. https://www.ncbi.nlm.nih.gov/pubmed/3350683
  3. Engoren M. Lack of association between atelectasis and fever. CHEST 1995;107:81-84. https://www.ncbi.nlm.nih.gov/pubmed/7813318
  4. Lansing AM, Jamieson WG. Mechanisms of fever in pulmonary atelectasis. Arch Surg 1963;87:168-174. https://jamanetwork.com/journals/jamasurgery/fullarticle/561080
  5. Jamieson WG, Lansing AM. Bacteriological studies in pulmonary atelectasis. Arch Surg 1963;87:1062-66. https://www.ncbi.nlm.nih.gov/pubmed/14063816
  6. Narayan M, Medinilla SP. Fever in the postoperative patient. Emerg Med Clin Nam 2013;31:1045-58. https://www.ncbi.nlm.nih.gov/pubmed/24176478 

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My postop patient now has fever with atelectasis on her chest X-ray one day after surgery. Does atelectasis cause fever?