My patient with community-acquired pneumonia (CAP) will be going home on an oral antibiotic. Is there a significant difference in the risk of Clostridium difficile infection among the usual CAP antibiotics?

Not all antibiotics are equal in their risk of CDI. Among the common antibiotics used for respiratory tract infections, doxycycline appears to be the least likely to be associated with CDI. 

A population-based case-control study of community-acquired CDI found that while recent exposure increased the risk of CDI for fluoroquinolones, macrolides, cephalosporins, sulfonamides and trimethoprim and penicillins, the risk of CDI with tetracycline use was not increased (1).  Similar findings (with the exception of sulfonamides also appearing risk-neutral) have been reported by others (2). 

Among patients receiving ceftriaxone, receipt of doxycycline has been associated with protection against development of CDI (3).  A 2018 systematic review and meta-analysis also concluded that tetracyclines were associated with a decreased risk of CDI; OR 0.55 (95% CI 0,40-0.75) for doxycycline alone (4). 

 

The most likely explanation for why doxycycline may be associated with lower risk of CDI is its in vitro activity against anaerobes, including C. difficile. Additionally, because of its ability to inhibit protein synthesis, doxycycline may attenuate C. difficile toxin production. Its high bioavailability and maximal absorption from the upper gastrointestinal tract may also mitigate its impact on gut flora, further reducing its risk of CDI (3). 

 

References
1. Delaney JAC, Dial S, Barkun A et al. Antimicrobial drugs and community-acquired Clostridium difficile-associated disease-UK. Emerg Infect Dis 2007:13;761-63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738472
2. Kuntz JL, Chirchilles EA, et al. Incidence of and risk factors for community-associated Clostridium difficile infection : A nested case-control study. BMC Infect Dis 2011;11:194. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154181/ 
3. Doernberg SB, Winston LG, Deck DH, et al. Does doxycycline protect against development of Clostridium difficile infection. Clin Infec Dis 2012;44:615-20. https://www.academia.edu/7814406/Does_Doxycycline_Protect_Against_Development_of_Clostridium_difficile_Infection
4. Tariq R, Cho J, Kapoor S, et al. Low risk of primary Clostridium difficile infection with tetracyclines: a systematic review and metanalysis. Clin Infect Dis 2018; 766:514-27. https://academic.oup.com/cid/article/66/4/514/4161552 

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My patient with community-acquired pneumonia (CAP) will be going home on an oral antibiotic. Is there a significant difference in the risk of Clostridium difficile infection among the usual CAP antibiotics?

How should I interpret the growth of “normal respiratory flora” from sputum of my patient with community-acquired pneumonia (CAP)?

Since the primary reason for obtaining a sputum culture in a patient with pneumonia is to sample the lower respiratory tract, you should first verify that the sputum was “adequate” by reviewing the gram stain. Absence of neutrophils (unless the patient is neutropenic) with or without epithelial cells on gram stain of sputum suggests that it may not be an adequate sample (ie, likely saliva)1, and therefore growth of normal respiratory flora (NRF) should not be surprising in this setting.  

Other potential explanations for NRF on sputum culture in patients with CAP include:2-5

  • Delay in sputum processing with possible overgrowth of oropharyngeal flora.
  • Pneumonia caused by pathogens that do not grow on standard sputum culture media (eg, atypical organisms, viruses, anaerobes).
  • Pneumonia caused by potential pathogens such as as Streptococcus mitis and Streptococcus anginosus group that may be part of the NRF.
  • Initiation of antibiotics prior to cultures (eg, in pneumococcal pneumonia).

Of note, since 2010, several studies have shown that over 50% of patients with CAP do not have an identifiable cause.3 So, growing NRF from sputum of patients with CAP appears to be common.

References

  1. Wong LK, Barry AL, Horgan SM. Comparison of six different criteria for judging the acceptability of sputum specimens. J Clin Microbiol 1982;16:627-631. https://www.ncbi.nlm.nih.gov/pubmed/7153311
  2. Donowitz GR. Acute pneumonia. In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases (2010). Churchill Livingstone, pp 891-916.
  3. Musher DM, Abers MS, Bartlett JG. Evolving understanding of the causes of pneumonia in adults, with special attention to the role of pneumococcus. Clin Infect Dis 2017;65: 1736-44. https://www.ncbi.nlm.nih.gov/pubmed/29028977
  4. Abers MS, Musher DM. The yield of sputum culture in bacteremic pneumococcal pneumonia after initiation of antibiotics. Clin Infect Dis 2014; 58:1782. https://www.ncbi.nlm.nih.gov/pubmed/24604901
  5. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. Bartlett JG, Gorbach SL, Finegold SM. Am J Med 1974;56:202-7. https://www.ncbi.nlm.nih.gov/pubmed/4812076
How should I interpret the growth of “normal respiratory flora” from sputum of my patient with community-acquired pneumonia (CAP)?

What is the sensitivity of nose swabs in detecting methicillin-resistant Staphylococcus aureus (MRSA) pneumonia?

In MRSA pneumonia, the sensitivity of nasal swab PCR may vary from as low as 24.2% to 88% (1-3). A 2018 meta-analysis found an overall sensitivity of 70.9% (community-acquired pneumonia/healthcare-associated pneumonia [HCAP] 85%, ventilator-associated pneumonia 40%) with overall negative predictive value of 96.5% (based on an overall MRSA pneumonia prevalence of 10%) (4). 

A single center  study involving  patients with possible HCAP and a low clinical pulmonary infection score (CPIS) — for whom antibiotics may not be necessary anyway (5)—suggested that discontinuation of empiric vancomycin in patients without an adequate respiratory culture and a negative nose and throat culture may be reasonable (6).

However, a prospective study of ICU patients concluded that “clinicians cannot reliably use the results of initial negative MRSA nasal swab results to withhold empirical MRSA coverage from patients who otherwise are at risk for MRSA infection” (3).

The previously cited 2018 meta-analysis study (4) cautions against use of MRSA screening in patients with structural lung disease (eg, cystic fibrosis or bronchiectasis) because colonization may be more frequent in the lower respiratory tract in these patients and screening tests may therefore be discordant (4).

Collectively, the available data suggest that it is reasonable to use a negative MRSA screen to help exclude pneumonia due to this pathogen in patients in whom MRSA infection is not highly suspected or those who are not severely ill.

 

References

  1. Rimawi RH, Ramsey KM, Shah KB, et al. Correlation between methicillin-resistant Staphylococcus aureus nasal sampling, and S. aureus pneumonia in the medical intensive care unit. Infect Control Hosp Epidemiol 2014;35:590-92. https://www.ncbi.nlm.nih.gov/pubmed/24709733
  2. Dangerfield B, Chung A, Webb B, et al. Predictive value of methicillin-resistant Staphylococcus aureus (MRSA) nasal swab PCR assay for MRSA pneumonia. Antimicrob Agents Chemother 2014;58:859-64. https://www.ncbi.nlm.nih.gov/pubmed/24277023
  3. Sarikonda KV, Micek ST, Doherty JA, et al. Methicillin-resistant Staphylococcus aureus nasal colonization is a poor predictor of intensive care unit-acquired methicillin-resistant Staphylococcus aureus infections requiring antibiotic treatment. Crit Care Med 2010;38:1991-1995. https://www.ncbi.nlm.nih.gov/pubmed/20683260
  4. Parente DM Cunha CB Mylonakis E et al. The clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA pneumonia: A diagnostic meta-analysis with antimicrobial stewardship implications. Clin Infect Dis 208;67:1-7.
  5. Napolitano LM. Use of severity scoring and stratification factors in clinical trials of hospital-acquired and ventilator-associated pneumonia. Clin Infect Dis 2010;51:S67-S80. https://www.ncbi.nlm.nih.gov/pubmed/20597675
  6. Boyce JM, Pop O-F, Abreu-Lanfranco O, et al. A trial of discontinuation of empiric vancomycin therapy in patients with suspected methicillin-resistant Staphylococcus aureus health care-associated pneumonia. Antimicrob Agents Chemother 2013;57:1163-1168. http://aac.asm.org/content/57/3/1163.full.pdf
What is the sensitivity of nose swabs in detecting methicillin-resistant Staphylococcus aureus (MRSA) pneumonia?

In hospitalized patients with community-acquired pneumonia (CAP), has empiric treatment with beta-lactam plus macrolide or a quinolone been shown to be superior to beta-lactam monotherapy ?

Actually no!

In fact, a 2015 study of CAP from Netherlands, published in New England Journal of Medicine, demonstrated that empiric treatment with beta-lactam monotherapy was not inferior to strategies using a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality, or length of hospital stay (1). To help exclude Legionella pneumonia (often accounting for <5% of CAP[2]), urine Legionella antigen was routinely performed in this study.

So once Legionella has been reasonably excluded, unless suspicion for other atypical causes of CAP (i.e. Mycoplasma pneumoniae or Chlamydophila pneumoniae) remains high, empiric monotherapy with a beta-lactam (e.g. ceftriaxone) may be just as effective in many cases of CAP.

References

1. Postma DF1, van Werkhoven CH, van Elden LJ, et al. CAP-START Study Group Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372:1312-23.  https://www.ncbi.nlm.nih.gov/pubmed/25830421  

2. von Baum H, Ewig S, Marre R, et al. Competence Network for Community Acquired Pneumonia Study Group. Community-acquired Legionella pneumonia: new insights from the German competence network for community acquired pneumonia. Clin Infect Dis 2008;46:1356. https://www.ncbi.nlm.nih.gov/pubmed/18419436

Contributed by Jessica A. Hennessey, MD, PhD, Mass General Hospital, Boston, MA

In hospitalized patients with community-acquired pneumonia (CAP), has empiric treatment with beta-lactam plus macrolide or a quinolone been shown to be superior to beta-lactam monotherapy ?

My 65 year old patient has had several bouts of bacterial pneumonia in the past 2 years. Her total serum immunoglobulins are within normal range. Could she still be immunodeficient?

Absolutely! Besides HIV infection which should be excluded in all patients with recurrent bouts of bacterial pneumonia irrespective of age, “selective polysaccharide antibody deficiency”, also known as “specific antibody deficiency” or SAD, should also be excluded (1-3). SAD in adults with recurrent pneumonia is not rare, having been reported in about ~8% of such patients (4).  

Think of SAD when your adult patient presents with recurrent bouts of bacterial pneumonia  despite having normal serum total immunoglobulin (IgG, IgA, and IgM) levels and IgG subtypes (1-3).  These patients have a normal response to tetanus toxoid (a protein) but cannot mount adequate antibody response against polysaccharide antigens of pathogens such as pneumococcus.  

One way to diagnose SAD in a suspected patient is through vaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV23).  In patients with low baseline antibody titers to many of the capsular types of pneumococcus included in the PPSV23,  a suboptimal response (defined by the lab) 4 weeks after vaccination with PPSV23 is suggestive of SAD. Remember that if your patient has already been vaccinated with the 13 valent pneumococcal conjugate vaccine (PCV13), you can only evaluate for the response to serotypes included in the  PPSV23 only.

Although there are no randomized-controlled studies and treatment should be individualized, immunoglobulin replacement may reduce the risk of future bouts of pneumonia in SAD (2-3). 

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References

1. Cohn JA, Skorpinski E, Cohn JR. Prevention of pneumococcal infection in a patient with normal immunoglobulin levels but impaired polysaccharide antibody production. Ann Allergy Asthma Immunol 2006;97:603-5. https://www.ncbi.nlm.nih.gov/pubmed/17165266

2. Cheng YK, Kecker PA, O’Byrne MM, Weiler CR. Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome. Ann Alergy Asthma Immunol 2006;97:306-311. https://www.ncbi.nlm.nih.gov/pubmed/17042135

3. Perez E, Bonilla FA, Orange JS, et al. Specific antibody deficiency: controversies in diagnosis and management. Front Immunol 207;8:586. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439175/pdf/fimmu-08-00586.pdf

4. Ekdahl K, Braconier JH, Svanborg C. Immunoglobulin deficiencies and impaired immune response to polysaccharide antigens in adult patients with recurrent community acquired pneumonia. Scand J Infect Dis 1997;29:401-7. https://www.ncbi.nlm.nih.gov/pubmed/9360257

 

My 65 year old patient has had several bouts of bacterial pneumonia in the past 2 years. Her total serum immunoglobulins are within normal range. Could she still be immunodeficient?