How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?

AZ is a macrolide antibiotic which interferes with bacterial protein synthesis by binding to the 50S ribosomal subunit. It is often used to treat acute respiratory tract infections due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, as well as Mycoplasma, Chlamydia, and Legionella sp1. Although it has no in vitro activity against many aerobic gram-negative bacilli such as Pseudomonas aeruginosa, its chronic use has often been associated with a significant reduction in the frequency of disease exacerbations in patients with chronic bronchiectasis and colonization due to this organism, including patients with COPD or CF1-3.

Because P. aeruginosa is invariably macrolide-resistant, the beneficial effect of AZ in chronically infected or colonized patients must be due to factors other than its direct effect on bacterial replication.  Several mechanisms have been invoked including: 1. Inhibition of quorum-sensing dependent virulence factor and biofilm production 2.Blunting of host inflammatory response (eg, ↑IL-10, and ↓ IL-1ß, IL-6, IL-8, TNF-α, and ↓ chemotaxis); and 3. Enhanced antiviral response1.

The latter finding is quite unexpected but AZ appears to augment interferon response to rhinovirus in bronchial cells of COPD patients3.  With respiratory viruses (including rhinoviruses) causing 20-55% of all COPD exacerbations, perhaps this is another way AZ may help the host! Who would have thought!!

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References

  1. Vos R, Vanaudenaerde BM, Verleden SE, et al. Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection. Transplantation 2012;94:101-109.
  2. Cochrane review. Treatment with macrolide antibiotics for people with cystic fibrosis and chronic chest infection. Nov 14, 2012. http://www.cochrane.org/CD002203/CF_treatment-with-macrolide-antibiotics-for-people-with-cystic-fibrosis-and-chronic-chest-infection
  3. Menzel M, Akbarshahi H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD. Scientific Reports 2016; 6:28698. DOI:10.1038/srep 28698.

 

 

How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?

How should patients with hospital-associated pneumonia (HAP) be empirically treated under the 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society?

Although empiric selection of antibiotics should be based on the local distribution of pathogens associated with HAP and their antimicrobial susceptibilities, routine coverage of Staphylococcus aureus (not necessarily methicillin-resistant S. aureus [MRSA]) and Pseudomonas aeruginosa or other gram-negative bacilli is recommended1.

In patients not at high risk of mortality (including ventilatory support and septic shock) or risk for MRSA (i.e.prior IV antibiotic use within 90 days, hospitalization in a unit where >20% of S. aureus isolates are MRSA or the prevalence of MRSA is unknown), piperacillin-tazobactam, cefepime, levofloxacin, imipenem or meropenem alone is suggested.

In patients not at high risk of mortality but with factors that increase the likelihood of MRSA, piperacillin-tazobactam, cefepime/ceftazidime, ciprofloxacin/levofloxacin, imipenem/meropenem, or aztreonam, plus vancomycin or linezolid should be considered.

In patients at high risk of mortality or receipt of IV antibiotics during the prior 90 days vancomycin or linezolid plus 2 of the following should be used: piperacillin-tazobactam, cefepime/ceftazidime, ciprofloxacin/levofloxacin, imipenem/meropenem, amikacin/gentamicin/tobramycin, or aztreonam are recommended (avoid double β-lactams).

In patients with structural lung disease increasing the risk of gram-negative infections (ie, bronchiectasis or cystic fibrosis), double anti-pseudomonal coverage is recommended.

 

Reference

  1. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis, Advance Access published July 14, 2016.
How should patients with hospital-associated pneumonia (HAP) be empirically treated under the 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society?

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?

What new treatment options are available for my patient with cystic fibrosis (CF) who has had recurrent pulmonary exacerbations requiring frequent hospitalizations?

CF is caused by gene mutations that result in deficient or dysfunctional transmembrane conductance regulator (CFTR) protein, an anion channel that is normally present in the epithelial membrane. Two FDA- approved drugs may provide new options for at least some CF patients. Ivacaftor (Kalydeco) is a CFTR protein potentiator that increases the probability that the CFTR channels are open in vitro and improves clinical outcomes in patients ≥12 years of age with at least one copy of G551D mutation, present in ~5% of CF patients (1). 

Orkambi is a combination of ivacaftor and lumacaftor – a drug that prevents intracellular destruction of CFTR –for patients with the Phe508del CFTR mutation, present in ~50% of CF patients.   Its use has been associated with fewer pulmonary exacerbations and hospitalization in patients (≥ 6 years of age) homozygous for this gene (2). Ivacaftor and Orkambi are priced at over $300,000/year and $295,000/year, respectively (http://www.nytimes.com/2015/07/03/business/orkambi-a-new-cystic-fibrosis-drug-wins-fda-approval.html?_r=0).

1. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR Potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-1672.

2. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015;373:220-231.

Contributed by Cynthia M. Cooper, MD, Boston, MA

What new treatment options are available for my patient with cystic fibrosis (CF) who has had recurrent pulmonary exacerbations requiring frequent hospitalizations?