There hasn’t been an update to the IDSA/ATS guidelines for CAP (community acquired pneumonia) since 2007 (I keep hearing they will be out soon). These guidelines recommend a macrolide antibiotic as first-line therapy for previously healthy patients who have no risk factors for drug-resistant S. pneumonia (SPN) infection (strong recommendation) and a combination of a macrolide and a beta-lactam for patients who require hospitalization but not in the ICU 1. In the last few years, concerns for macrolide resistance have been discussed (I’m looking at you EM-RAP). Paradoxically no real affects on clinical outcomes have been shown. Referred to as the aptly named in vivo-in vitro paradox2 there are divergent findings of macrolide resistance and clinical outcome. Lets talk amongst ourselves, shall we?
Macrolide resistance is a thing! But the clinical studies don’t yet support the concerns of the in vitro findings of resistance. The IDSA/ATS guidelines have not been updated since 2009 and its still OK to use macrolide monotherapy when high levels of strep pneumo resistance are unlikely. So what to do? If I’m worried about compliance I’ll still prescribe OUTPATIENT azithromycin alone (especially if I feel atypicals are the cause and at least until new IDSA guidelines come out). If I am at all “worried” I will add in a beta-lactam. For HOSPITALIZED PATIENTS OR SEVERE DISEASE NEVER USE AZITHROMYCIN ALONE. RESISTANCE MAY BE ANNOYING BUT ITS NOT YET FUTILE
I’m not disagreeing with macrolide resistance in general, I just don’t think it’s futile to use these even as monotherapy in CAP. Typically Azithromycin resistance is defined as an MIC >2 μg/mL) and sometimes very high resistance levels are seen. However there seems to be disparate results between MIC’s and clinical cure rates. I think the misperception is best seen in Zhanel’s article 3on clinical cure rates. This study looked at community acquired respiratory infections (CARTI) and azithromycin resistance in streptococcus pneumoniae. Overall if you look at the study there was about a 10% difference in clinical cure rate in those treated with azithromycin for ALL respiratory tract infections. HOWEVER, in this group they included the following as CARTI: acute otitis media (sometimes air comes out of my ear when I sneeze but I don’t think its part of the respiratory tract!), CAP, acute bacterial exacerbations of chronic bronchitis and acute bacterial sinusitis. They found 1127 patients with CARTI of which they found 29% (112/388) of subjects with SPN had AZ-R. Overall, clinical cure rates in CARTI subjects treated with azithromycin were higher for in AZ-S (89.4%) versus AZ-R (78.6%; P=0.003). BUT if you look at CAP alone for AZ-S vs AZ-R the failure rates were 3/52 vs 2/27 (p=0.986) and the cure rates were 49/52 (94%) vs 25/27 (93%), respectively. These are small numbers true so lets look at some more studies.
In this study by Yanagihara4 they looked at a 3 (Three??? Yes three) day course of azithromycin in adults with mild to moderately severe CAP, and to determine whether in vitro macrolide resistance in of SPNis related to clinical failure. A good clinical response was defined as improvement of 3 of the 4 following outcomes: 1) resolution of fever 2) resolution of wbc’s, 3) improvement of CRP and 4) improvement of CXR findings. They found a good response in 13/17 (76%) and an ineffective response in 4/17 (23%). Strangely, 6 of 7 patients in whom high-level resistance was documented (MICs >256 μg/mL) showed good clinical responses. If you look at CAP alone for AZ-S vs. AZ-R the failure rates were 0/2 vs. 4/12 and the cure rates were 2/2 vs. 8/12, respectively.
In this study, Kohno5 looked at moderate-to-severe community-acquired pneumonia. They found that despite mostly having AZ-R strains in Japan, clinical efficacy and bacterial eradication were achieved in 10 of 11 patients. If we combine these 3 studies (not a great meta-analysis I know…) for AZ-R then you would have 43/50 (86%) good responses and 7/50 (14%) poor responses and this is in places with the highest rates of resistance… 6
Lastly, in this study by Cilloniz7 looked at outcomes in AZ-S vs. AZ-R. They found 30-day mortality in AZ-S to be 32/493 (6%) vs. AZ-R 9/133 (7%, p=0.93) and ICU admission to be 140/493 (28%) vs. 32/133 (24%, p=0.29).
Indeed there is some thought that macrolide antibiotics have additional properties than just their bacteriostatic/bacteriocidal properties. Some studies8 suggest that macrolides have anti-inflammatory properties and prevent the production of pro-inflammatory mediators and cytokines. This recent study of lowered mortality in CAP would agree with a reduction of all cause in hospital mortality and a 10% difference (not statistically significant) in 30-day mortality. Here, Arnold et al.9 looked at 549 patients with CAP and bacteremia where 247 (45%) were treated with a macrolide and 302 (55%) were not. The unadjusted 30-day mortality was 18.4% in the macrolide group, and 29.6% in the non-macrolide group (RR=0.81, CI 0.50–1.33; P = 0.41). Unadjusted in-hospital all-cause mortality was 7.3% in the macrolide group, and 18.9% in the non-macrolide group (RR= 0.54, CI 0.30–0.98; P = 0.043).
There are two major mechanisms mediating resistance to macrolides. The ermB gene encodes a methyltransferase that causes ribosomal methylation resulting in a phenotype that reduces susceptibility to macrolides (and lincosamide FYI). This mechanism results in the highest macrolide resistance. The second mechanisms is the mefA gene which codes for an antibiotic efflux pump removing the drug from the SPN. Macrolides are concentrated intra-cellularly, and this is thought to result in increased drug delivery to the site of infection, and exposure to high concentrations of drug following phagocytosis, which may overcome low level resistance6 . Possibly high-level resistance may be clinically relevant , however that was not exactly the case in the above Yanagihara study.
So in summary, macrolide resistance is definitely real. However, there really does not seem to be a huge affect clinically when azithromycin resistance is encountered. Furthermore, Azithromycin resistance is probably more likely in its uses other than CAP, like otitis media and sinusitis (and other infections I don’t treat with antibiotics). So how do we use this information? Well I would NEVER use macrolides alone for hospitalized patients. I still believe that for hospitalized patients macrolides and beta-lactams are the way to go. In fact, I like to add azithromycin to even my ICU patients just in case there is something magical about the macrolides. For outpatient management of mild CAP I think there is still a role for macrolide monotherapy. We all know that compliance is not great with patients and I feel in mild disease I’d rather they take 1 once a day antibiotic rather than have to add in a beta-lactam and have them not take it.
- Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2, S27-72.
- Bishai W. The in vivo-in vitro paradox in pneumococcal respiratory tract infections. J Antimicrob Chemother 2002; 49, 433-436.
- Zhanel GG, Wolter KD, Calciu C et al. Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin-resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data. J Antimicrob Chemother 2014; 69, 2835-2840.
- Yanagihara K, Izumikawa K, Higa F et al. Efficacy of Azithromycin in the Treatment of Community-acquired Pneumonia, Including Patients with Macrolide-Resistant Streptococcus pneumoniae Infection. Internal Medicine 2009; 48, 527-535.
- Kohno S, Tateda K, Kadota J et al. Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. J Infect Chemother 2014; 20, 199-207.
- Cheng AC, Jenney AWJ. Macrolide resistance in pneumococci-is it relevant. Pneumonia (Nathan) 2016; 8, 10.
- Cilloniz C, Albert RK, Liapikou A et al. The Effect of Macrolide Resistance on the Presentation and Outcome of Patients Hospitalized for Streptococcus pneumoniae Pneumonia. Am J Respir Crit Care Med 2015; 191, 1265-1272.
- Ianaro A, Ialenti A, Maffia P et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000; 292, 156-163.
- Arnold FW, Lopardo G, Wiemken TL et al. Macrolide therapy is associated with lower mortality in community-acquired bacteraemic pneumonia. Respir Med 2018; 140, 115-121.