Abstract
Macrolide antimicrobials are commonly prescribed, specifically for the treatment of respiratory tract infections. Although still effective, the development of widespread macrolide resistance has limited their use. Aside from their antimicrobial effects, macrolides are also known to possess immune-modulatory properties which may confer a survival benefit in both acute and chronic inflammatory states. This review discusses the efficacy, potential mechanisms, and adverse effects of macrolide therapy specifically in community-acquired pneumonia in outpatients, hospitalized ward patients, and those requiring intensive care unit admission. Challenges for ongoing research in this field are discussed and treatment recommendations offered.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Macrolides are used in clinical medicine for the treatment of a variety of infections but most commonly respiratory tract infections. Aside from their antimicrobial effects, macrolides are also known to possess immune-modulatory properties—although the clinical significance of these properties, particularly in acute infection, is largely unknown.
Given their relative safety and convenience, macrolides have been used liberally, resulting in the development of widespread antimicrobial resistance. Fortunately, North America has been less affected compared with other parts of the world. As a result, macrolides still remain an attractive option as both empiric and targeted therapies in respiratory infections.
The objective of this review is to discuss the efficacy of macrolides, specifically in community-acquired pneumonia (CAP). We will discuss outpatients, hospitalized ward patients, and those requiring intensive care unit (ICU) admission for severe CAP separately. A thorough literature review was undertaken to identify contemporary papers published in this subject area.
Mechanisms of Action and Antimicrobial Spectrum
Macrolides are bacteriostatic antimicrobials acting through interruption of bacterial protein synthesis. Macrolides reversibly bind to the 23S ribosomal RNA of the 50S bacterial ribosome subunit, inhibiting RNA-dependent protein synthesis. Peptide elongation is inhibited and incomplete peptide chains detach prematurely [1]. Unfortunately, point mutations in the 23S rRNA binding site can confer class-wide resistance [2].
Traditionally, macrolides have been used for broad Gram-positive coverage including Streptococcus pneumoniae, other streptococcal species, and anaerobic Gram-positive bacteria (e.g., Prevotella, non-difficile Clostridia). Macrolides have limited Gram-negative antimicrobial effect but exhibit activity against many miscellaneous microorganisms such as mycobacteria, spirochetes, Bordetella, Coxiella, and atypicals such as Legionella pneumophila, Mycoplasma, and Chlamydia [3, 4]. The advanced macrolides, such as azithromycin, have extended spectra including greater Gram-negative activity against Enterobacteriaceae, Neisseria gonorrhoeae, and important CAP pathogens such as Haemophilus influenzae and Moraxella catarrhalis [3, 5].
Ketolides, a subclass of macrolides, bind to the ribosome with greater affinity and provide even broader antimicrobial coverage. Ketolides confer more reliable coverage of S. pneumoniae, H. influenzae, and M. catarrhalis, as they are less vulnerable to the development of resistance [6]. Cethromycin was rejected by the FDA in 2009 based on insufficient evidence for efficacy in CAP, and potentially fatal hepatotoxicity led to a black box warning for telithromycin in 2010; however, two new ketolides are in advanced phase clinical trials [6, 7].
Antimicrobial Resistance
Macrolide resistance varies by region but has been steadily increasing worldwide, with S. pneumoniae resistance rates as high as 96 % in Asia [8], approximately 30–40 % in the USA [9, 10], and 16 % in Canada [11]. Mycoplasma pneumoniae resistance is also becoming more prevalent with resistance rates greater than 80 % in one Chinese study [12]. US estimates of macrolide resistance in M. pneumoniae are substantially lower—approximately 10 % [13]. Resistance rates in H. influenzae and M. catarrhalis are even lower, as US data from 2008–2010 reports 1.3 and 0.5 % resistance for each pathogen, respectively [10].
Many risk factors for S. pneumoniae macrolide resistance have been described. The most consistently reported are recent macrolide use as well as exposure to other classes of antibiotics [14–16]. One recent study found macrolide resistance was associated with older age, antibiotic use in the previous 30 days, and chronic obstructive pulmonary disease (COPD) [15]. Young age (less than 5 years), daycare attendance, and recurrent otitis media have been identified as risk factors in the paediatric population [17–19]. Additionally, patients with comorbidities such as chronic heart, lung, liver or renal disease, malignancy, immune suppression, or alcoholism are at higher risk of developing macrolide resistance [20]. Interestingly, macrolide use can also predispose to penicillin resistance in S. pneumoniae [21].
Common mechanisms of macrolide resistance include efflux pumps mediated by mefA/E (the so-called M phenotype) and ermA-M genes encoding for methylation of the 23s RNA thereby blocking macrolide binding. The ermA-M mutation also confers resistance to lincosamides (clindamycin) and streptogramin B antibiotics, earning the name ‘MLS phenotype’ [22, 23], and is associated with high-level macrolide resistance (minimum inhibitory concentration [MIC] >64 μg/mL) [16]. Fortunately, the predominant mechanism of resistance in S. pneumoniae in North America is the M phenotype, resulting in lower-level resistance; however, this may be changing [24].
Immune Modulation
Macrolide antibiotics have been shown to possess immune-modulating properties independent of their antimicrobial activity [25]. Their beneficial effect in chronic inflammatory lung diseases such as diffuse panbronchiolitis [26], cystic fibrosis [27], bronchiectasis [28], bronchiolitis obliterans syndrome [29], asthma [30], and COPD [31] are well documented. However, their benefit in the setting of acute pulmonary inflammation, as in CAP, is not as well established.
Proposed mechanisms of immune modulation are broad. They include suppression of pro-inflammatory cytokines [32], such as bacterial endotoxin-induced secretion of IL-8 [33] and IL-6 [34], decreased polymorphonuclear (PMN) cell recruitment [34], attenuation of reactive oxygen species production [35], and modulation of key transcription factors such as activator protein-1 (AP-1) and nuclear factor kappa B (NFkB) [36]. In addition, macrolides can promote apoptosis [37], decrease airway mucus production [38], and affect cell-signalling pathways [39].
The best clinical evidence to date on the non-antibiotic effects of macrolides in pneumonia was demonstrated in a randomized, placebo-controlled trial in patients with sepsis and ventilator-associated pneumonia (VAP) [40]. Patients were treated with clarithromycin for 3 days versus placebo in addition to standard antimicrobial therapy for VAP. The authors found that the addition of clarithromycin resulted in accelerated resolution of VAP and weaning from mechanical ventilation, and delayed death in those who died of sepsis.
In addition, the authors measured markers of inflammation (serum IL-10, TNF-alpha, as well as the expression of various cytokines in stimulation assays) and apoptosis at baseline and for 6 days following treatment [41]. They found that treatment with clarithromycin restored the balance between pro-inflammatory versus anti-inflammatory mediators, resulted in more efficient antigen presentation, and increased apoptosis. These effects were more pronounced in patients with septic shock and multi-organ dysfunction.
Further study on the role of macrolides as anti-inflammatory agents, particularly in CAP, is required. However, given our knowledge to date, this research area seems promising to say the least.
Outpatient CAP
Outpatient populations are those least likely to benefit from the non-antimicrobial effects of macrolides, as mild disease generally produces less inflammation and immune dysfunction. The more important question in this group is whether or not macrolide monotherapy provides sufficient antimicrobial coverage for CAP. Macrolides are ideal for the treatment of atypical pathogens; however, increasing S. pneumoniae resistance [9, 15, 42] may result in treatment failures with macrolide monotherapy.
The largest study published to date examining the use of macrolides in the treatment of outpatients with CAP is a prospective cohort of almost 3000 patients [43]. The authors found that compared with respiratory fluoroquinolone monotherapy, macrolide monotherapy decreased 30-day mortality (adjusted odds ratio [aOR] 0.28; 95 % CI 0.09–0.86, p = 0.03), as well as the composite outcome of 30-day mortality and hospitalization. Although the authors adjusted for pneumonia severity index (PSI), the macrolide group was significantly younger and had fewer comorbidities.
Skalsky et al. [44] performed a systematic review and meta-analysis of randomized controlled trials (RCTs) for CAP, comparing macrolides to respiratory fluoroquinolones. Both were most often used as monotherapy. In a subgroup analysis of mostly outpatients, there was no difference in mortality (relative risk [RR] 0.96; 95 % CI 0.53–1.72). Another systematic review and meta-analysis of RCTs in outpatients with CAP [45] was limited by trial number. However, macrolide therapy was not associated with increased clinical cure when compared to respiratory fluoroquinolones in any of the analyses.
Finally, a systematic review and meta-analysis of RCTs and quasi-RCTs evaluating the treatment of lower respiratory tract infections (LRTIs) with azithromycin versus amoxicillin or amoxicillin-clavulanic acid was recently published [46]. LRTI included acute bronchitis, acute exacerbation of COPD, and CAP. There was no difference in clinical failure rates between treatment groups in the combined LRTI population, although the acute bronchitis subgroup had fewer clinical failures with azithromycin (RR 0.63; 95 % CI 0.45–0.88). We postulate this might have been due (at least in part) to the anti-inflammatory properties of macrolides, as acute bronchitis is commonly non-bacterial in aetiology [47–49].
Based on this data, macrolide monotherapy in outpatient CAP is still an excellent option in patients without risk factors for pneumococcal resistance. Even with increasing resistance rates, however, there is evidence that low-grade efflux pump-mediated resistance might not be clinically relevant [50].
Inpatient, Non-severe CAP
The overall association between macrolide-containing regimens and improved outcomes in ward patients with CAP is based predominantly on observational data.
The Infectious Diseases Society of America (IDSA) guidelines for CAP [20] recommend a beta-lactam/macrolide combination or respiratory fluoroquinolone monotherapy in hospitalized patients with CAP not requiring intensive care. This is based on retrospective data [51–54] suggesting increased mortality with beta-lactam monotherapy. The European guidelines for lower respiratory tract infections [55] differ, however, as they do endorse beta-lactam monotherapy, despite the lack of atypical coverage.
The European statement is justified by evidence from two large meta-analyses [56, 57] of randomized data, including a Cochrane review. Both showed no mortality difference between beta-lactam monotherapy and antimicrobial regimens including atypical coverage. An updated review [58] continues to support this. However, macrolide monotherapy was included as a comparator to beta-lactam monotherapy in this analysis, which is problematic. This regimen is guideline discordant and therefore should not be used in comparison to beta-lactam monotherapy. Luckily, new studies are able to provide further insight.
Beta-lactam monotherapy and beta-lactam/macrolide therapies were recently compared in a large meta-analysis of observational studies by Nie et al. [59], demonstrating decreased mortality with beta-lactam/macrolide therapies compared to beta-lactam monotherapy (OR 0.67; 95 % CI 0.61–0.73, p < 0.001, I 2 = 3 %). This meta-analysis included almost 43,000 inpatients from 16 studies and demonstrated only low to moderate heterogeneity. Results were robust to multiple sensitivity analyses.
Subsequently, Postma et al. [60] performed a cluster-randomized crossover trial to test the non-inferiority of a beta-lactam monotherapy strategy compared to beta-lactam/macrolide or respiratory fluoroquinolone therapies in inpatients with non-severe CAP. In their primary analysis of 90-day mortality, the beta-lactam monotherapy strategy was non-inferior to either alternate strategy. Though these results are certainly noteworthy, preadmission antibiotic exposure and/or deviation from the assigned strategy in up to one quarter of patients limits the validity of the results. As well, microbiological data was lacking.
Lastly, in another trial [61], the authors were unable to demonstrate non-inferiority of beta-lactam monotherapy compared with beta-lactam/macrolide therapy for clinical stability at 7 days. In this open-label, randomized controlled trial of 580 non-severe CAP inpatients, 7.6 % fewer patients in the beta-lactam monotherapy arm reached clinical stability at 7 days. There were no differences in 90-day mortality.
Though the weight of observational data still sits clearly in favour of beta-lactam/macrolide therapy over beta-lactam monotherapy for non-severe inpatient CAP [59], the new randomized data certainly challenges this conclusion, particularly with regard to mortality. We would comment that if clinicians increasingly decide to prescribe beta-lactam monotherapy in hospitalized patients with CAP, this may result in the secondary benefit of decreased population-level macrolide resistance.
Next, the discussion of inpatient CAP requires a comparison of the relative efficacies and safety of guideline-concordant therapies—beta-lactam/macrolide combination therapy versus respiratory fluoroquinolone monotherapy. These therapies are recommended in CAP guidelines based primarily on retrospective observational data. Without taking into account local susceptibilities, the two regimens are largely equivalent in antimicrobial spectra.
A large prospective study by Asadi et al. [62] examined mortality in non-ICU inpatients with CAP. In an adjusted analysis, there was no difference in mortality between beta-lactam/macrolide and respiratory fluoroquinolone groups; however, the beta-lactam/macrolide strategy had a greater risk of ICU admission as well as the composite outcome of ICU admission and death, suggesting they might have been sicker comparatively.
A subsequent systematic review and meta-analysis of observational studies and RCTs comparing macrolide versus non-macrolide-containing regimens [63] demonstrated decreased mortality with the use of macrolides (RR 0.78; 95 % CI 0.64–0.95, p = 0.01, I 2 = 85 %). However, this effect was lost when the analysis was limited to RCTs and when observational trials of large administrative databases were excluded. Perhaps more importantly, a pre-defined subgroup analysis of guideline-concordant beta-lactam/macrolide versus respiratory fluoroquinolone therapies revealed no difference in mortality (5.3 % for beta-lactam/macrolide versus 5.8 % for respiratory fluoroquinolones, p = 0.22).
Finally, a systematic review and meta-analysis by Skalsky et al. [44], including only RCTs, examined both inpatients and outpatients with CAP. Macrolides, either alone or in combination, were compared with respiratory fluoroquinolones. There was no mortality difference between the groups, including when inpatient and outpatient groups were analysed separately.
In summary, these data suggest macrolides—when used in combination—may be associated with decreased mortality in ward patients with CAP. Of course, most of the studies suggesting a benefit are retrospective and inherently subject to confounding. Although randomized trial data is limited, the available evidence suggests that for non-severe inpatient CAP, beta-lactam/macrolide versus respiratory fluoroquinolone regimens are equivalent. This supports 2007 IDSA guidelines. Additionally, this data suggests that adherence to guidelines may be more important than the specific antimicrobial choice. Therefore, we would suggest that therapy in inpatient CAP not only be guideline concordant but also guided by recent antibiotic use and individual patient characteristics [20].
Inpatient, Severe CAP
The study of severe CAP is inherently difficult. Most data are observational and the complexity of this heterogeneous group makes statistical adjustment challenging. When attempted, adjustments often do not include markers of illness severity such as the Acute Physiology and Chronic Health Evaluation (APACHE) II score, or important confounders such as glucocorticoid use. In addition, varied definitions of severe CAP (by PSI, IDSA criteria, or ICU admission) and a wide range of subpopulations in this group (such as those requiring mechanical ventilation or presenting in septic shock) make combining and comparing studies difficult.
Other limitations when studying severe CAP include highly variable antimicrobial regimens and the use of historical cohorts that may not reflect contemporary outcomes. Lastly, data on microbial aetiology is often not available, making it difficult to know if empiric therapies were effective. Clearly inappropriate empiric antimicrobial therapy has been associated with poor outcomes in a number of studies [64–66].
A systematic review and meta-analysis of patients admitted to the intensive care with CAP provides the most comprehensive data on macrolide therapy and mortality [67]. This review included 28 observational studies and almost 10,000 critically ill patients with CAP. In an adjusted analysis of macrolide versus non-macrolide-containing regimens, a significant mortality benefit was observed (RR 0.75; 95 % CI 0.58–0.96, p = 0.02, I 2= 57 %). The major limitation of this meta-analysis was the sole inclusion of observational data.
A recent, large prospective cohort [68] study examining the association between adequate initial antibiotic coverage and survival in severe CAP patients demonstrated no difference in mortality between beta-lactam/macrolide and beta-lactam/respiratory fluoroquinolone groups at 60 days. Adjustment for multiple factors including Simplified Acute Physiology Score (SAPS) II, receipt of mechanical ventilation, presence of septic shock, and use of glucocorticoids was rigorously performed.
In a prospective cohort study [69] including only intubated CAP patients, a mortality benefit was observed with beta-lactam/macrolide therapy compared with beta-lactam/respiratory fluoroquinolone therapy (aHR 0.48; 95 % CI 0.23–0.97, p = 0.04). Notably, patients in both groups received guideline-concordant therapies. Groups were equivalent in terms of age, major comorbidities, incidence of bacteremia, and illness severity scoring. However, the beta-lactam/respiratory fluoroquinolone group received piperacillin-tazobactam or a carbapenum more often than the beta-lactam/macrolide group (48 vs. 6.5 %). The choice of broader-spectrum therapy may reflect unfavourable clinical features in the beta-lactam/respiratory fluoroquinolone group despite seeming similar by recorded characteristics.
For those with CAP and severe sepsis, retrospective observational data [70] also suggests decreased 30-day mortality with macrolide-containing regimens compared with non-macrolide therapies (aHR 0.3; 95 % CI 0.2–0.7). However, several important comorbidities were significantly less frequent in the macrolide group and not adjusted for in the analysis beyond inclusion in the PSI score.
Lastly, macrolides have also been associated with decreased in-hospital and 30-day mortality in a retrospective study of bacteremic CAP [71]. As well, in patients with pneumococcal bacteremic CAP, a mortality benefit was observed with the addition of a macrolide [72]. Despite adequate treatment with a beta-lactam, patients who did not receive macrolides experienced higher adjusted mortality. This potentially suggests a non-antimicrobial, immune-modulatory mechanism of effect as discussed previously.
Although randomized trial data in severe CAP is limited, a meta-analysis of RCTs by Vardakas et al. [73] compared respiratory fluoroquinolone therapy to beta-lactam/macrolide combination, or beta-lactam or macrolide monotherapies. In the severe CAP subgroup, treatment success was highest in the respiratory fluoroquinolone group versus all other comparator regimens, although at least some of the comparators were guideline discordant [74–76]. In addition, most trials were unblinded and some lacked intention-to-treat analyses.
In summary, there is a paucity of randomized trial data examining the association between macrolide therapies and mortality in patients with severe CAP. Most of the available data is observational in nature and therefore subject to confounding; however, it does suggest a mortality benefit with macrolide use. The mechanism by which a mortality benefit may be conferred is also unclear. The antimicrobial effect of macrolides on atypical pathogens is one possibility. Second, macrolides may attenuate the inflammatory response in critically ill patients who are at higher risk of systemic inflammatory response syndrome (SIRS) compared to non-ICU cohorts. In fact, studies demonstrate increased markers of inflammation in this population [77], and animal models of pneumonia have demonstrated a reduction in inflammatory markers as well as improved histopathology of lung tissue with macrolide therapy [78].
Unfortunately, the design of a randomized trial that is needed to compare optimal antibiotic regimens in severe CAP—specifically macrolide vs. non-macrolide-based therapies—offers a unique set of challenges. Most important would be a treatment arm with a regimen that is concordant with the IDSA guidelines and a very large number of patients required to detect a mortality benefit if one truly exists, necessitating multicenter, and likely multinational, collaboration to complete such an effort. Until such a study is completed, we support current IDSA guidelines in the treatment of severe CAP.
Adverse Effects
The most serious adverse event associated with macrolide therapy is cardiotoxicity, specifically fatal arrhythmias. However, several reviews suggest that the absolute risk of this event is actually very low [79, 80]. Azithromycin is felt to have the least cardiotoxicity [81] within the macrolide class and is generally preferred. A recent systematic review examining the association between azithromycin and cardiovascular death [82] found only six case reports of QT prolongation and three cases of fatal arrhythmia reported in the literature between 1946 and 2013. Notably, all patients had underlying cardiac disease and other potentially confounding risk factors or medications.
Another recent retrospective cohort study [83] demonstrated increased risk of cardiovascular death with azithromycin compared to no antibiotic therapy, however, demonstrated no difference when compared with penicillin. A second, large retrospective cohort of outpatients [84] found a small absolute increase in cardiovascular deaths in patients treated with azithromycin compared with amoxicillin and ciprofloxacin but not when compared to levofloxacin. The risk of cardiovascular death was most pronounced among patients with a high baseline risk of cardiovascular disease. The retrospective nature of these studies, as well as derivation from large administrative databases lacking clinical information, limits reliability of their results. Most importantly, the underlying indication for antibiotic use in these studies was not controlled for.
In an attempt to further clarify this issue, Mortensen et al. [85] examined cardiovascular events and all-cause mortality in elderly patients admitted with CAP. Although they found a higher risk of myocardial infarction in those treated with azithromycin, there was no increase in risk of any cardiac event or arrhythmia. Most importantly, the overall 90-day mortality was actually lower in the azithromycin group (OR 0.73; 95 % CI 0.70–0.76, p < 0.001), demonstrating a net benefit associated with azithromycin therapy.
In summary, the absolute risk of macrolide-induced cardiotoxicity is low [79, 80, 82]. When choosing therapy for an individual patient, side effect profiles must be considered for all potential antimicrobial agents. Concurrent use of other QT-prolonging drugs may be a significant contributor to the true risk. In accordance with common clinical practice, the risks and benefits of macrolide therapy, and a review of other concurrent medications, must be performed prior to prescription in each patient.
Discussion
This review summarizes contemporary data on the use of macrolides in CAP. Macrolides are commonly used in the treatment of CAP based on various guideline recommendations. Macrolides have also been shown to improve outcomes in a number of chronic lung conditions due to their immunomodulatory effects. The mechanisms of action in acute CAP are less clear, but we postulate may be both antimicrobial and anti-inflammatory in nature.
Macrolide monotherapy for outpatient CAP is still an appropriate strategy and remains supported by guidelines. Theoretically, azithromycin offers the broadest coverage and has the most favourable side effect profile. Resistance in both S. pneumoniae and Mycoplasma is increasing globally, however, limiting the use of macrolides in patients with recent macrolide exposure [2, 4, 22, 23].
Outcome data in inpatients with non-severe CAP generally support current IDSA guidelines. A mortality benefit with macrolide-based regimens may exist, based on one large meta-analysis of observational studies [63]; however, higher quality data is needed. New data examining beta-lactam monotherapy in inpatient CAP is particularly interesting [60, 61] and also warrants further study.
Observational data also suggests macrolides may be associated with decreased mortality in severe CAP [67], including those with severe sepsis [70]. This benefit may be due to immune modulation given systemic inflammation is common in this patient population. Unfortunately, there is a paucity of randomized trial data comparing macrolide versus non-macrolide therapies and guideline-concordant regimens—in general—in severe CAP. Contradictory observational data confuses the issue further. Until further randomized trial data is available, current guideline-concordant regimens should be considered equivalent.
Finally, the need for a well-designed, randomized trial to assess CAP outcomes with current guideline-concordant regimens is essential. Without this, we have effectively reached the limit of our knowledge. Critically ill patients may have the greatest potential gain with further study, though these patients are also the most logistically challenging to study. Many outcomes other than mortality should also be examined—such as treatment failure, need for hospitalization as well as readmissions, hospital (and ICU) lengths of stay, and adverse events. In fact, these outcomes may be more appropriate (versus mortality) to study in patients with mild to moderate CAP. Meanwhile, ongoing etiologic research and surveillance of antimicrobial resistance are essential in evolving CAP treatment strategies over time.
Conclusions
In conclusion, macrolides are safe and effective therapies in CAP. Risk factors for macrolide resistance must be considered to avoid inappropriate prescriptions. The potential immune-modulatory properties of macrolides may be particularly beneficial in patients with systemic inflammatory response syndrome—specifically those with severe CAP—however further study is required. Despite the fact that observational data suggests a mortality benefit with macrolide therapies, higher quality randomized trial data is needed. Sufficient equipoise exists to warrant this large undertaking. Until then, IDSA CAP guidelines should guide empiric therapy.
References
Schlunzen F, Zarivach R, Harms J, et al. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature. 2001;413(6858):814–21. doi:10.1038/35101544.
Tenson T, Lovmar M, Ehrenberg M. The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J Mol Biol. 2003;330(5):1005–14.
Retsema J, Girard A, Schelkly W, et al. Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms. Antimicrob Agents Chemother. 1987;31(12):1939–47.
Drew RH, Gallis HA. Azithromycin—spectrum of activity, pharmacokinetics, and clinical applications. Pharmacotherapy. 1992;12(3):161–73.
Peters DH, Friedel HA, McTavish D. Azithromycin. A review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy. Drugs. 1992;44(5):750–99.
Georgopapadakou NH. The wobbly status of ketolides: where do we stand? Expert Opin Investig Drugs. 2014;23(10):1313–9. doi:10.1517/13543784.2014.954036.
Ross DB. The FDA, and the case of Ketek. N Engl J Med. 2007;356(16):1601–4.
Kim SH, Song JH, Chung DR, et al. Changing trends in antimicrobial resistance and serotypes of Streptococcus pneumoniae isolates in Asian countries: an Asian Network for Surveillance of Resistant Pathogens (ANSORP) study. Antimicrob Agents Chemother. 2012;56(3):1418–26. doi:10.1128/AAC.05658-11.
Doern GV, Richter SS, Miller A, et al. Antimicrobial resistance among Streptococcus pneumoniae in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis. 2005;41(2):139–48.
Pfaller MA, Farrell DJ, Sader HS, Jones RN. AWARE ceftaroline surveillance program (2008–2010): trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States. Clin Infect Dis. 2012;55 Suppl 3:S187–93. doi:10.1093/cid/cis561.
Adam HJ, Baxter MR, Davidson RJ, et al. Comparison of pathogens and their antimicrobial resistance patterns in paediatric, adult and elderly patients in Canadian hospitals. J Antimicrob Chemother. 2013;68 Suppl 1:i31–7. doi:10.1093/jac/dkt024.
Liu Y, Ye X, Zhang H, et al. Antimicrobial susceptibility of Mycoplasma pneumoniae isolates and molecular analysis of macrolide-resistant strains from Shanghai, China. Antimicrob Agents Chemother. 2009;53(5):2160–2. doi:10.1128/AAC.01684-08.
Diaz MH, Benitez AJ, Winchell JM. Investigations of mycoplasma pneumoniae infections in the United States: trends in molecular typing and macrolide resistance from 2006 to 2013. J Clin Microbiol. 2015;53(1):124–30. doi:10.1128/JCM.02597-14.
Vanderkooi OG, Low DE, Green K, Powis JE, McGeer A. Toronto Invasive Bacterial Disease Network. Predicting antimicrobial resistance in invasive pneumococcal infections. Clin Infect Dis. 2005;40(9):1288–97.
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(11):1265–72. doi:10.1164/rccm.201502-0212OC.
Hyde TB, Gay K, Stephens DS, et al. Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA. 2001;286(15):1857–62.
Lynch 3rd JP, Zhanel GG. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines. Curr Opin Pulm Med. 2010;16(3):217–25. doi:10.1097/MCP.0b013e3283385653.
Barnes DM, Whittier S, Gilligan PH, Soares S, Tomasz A, Henderson FW. Transmission of multidrug-resistant serotype 23F streptococcus pneumoniae in group day care: evidence suggesting capsular transformation of the resistant strain in vivo. J Infect Dis. 1995;171(4):890–6.
Lee HJ, Park JY, Jang SH, Kim JH, Kim EC, Choi KW. High incidence of resistance to multiple antimicrobials in clinical isolates of Streptococcus pneumoniae from a university hospital in Korea. Clin Infect Dis. 1995;20(4):826–35.
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. doi:10.1086/511159.
Ruhe JJ, Hasbun R. Streptococcus pneumoniae bacteremia: duration of previous antibiotic use and association with penicillin resistance. Clin Infect Dis. 2003;36(9):1132–8.
Retsema J, Fu W. Macrolides: structures and microbial targets. Int J Antimicrob Agents. 2001;18 Suppl 1:S3–10.
Sutcliffe J, Tait-Kamradt A, Wondrack L. Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system. Antimicrob Agents Chemother. 1996;40(8):1817–24.
Farrell DJ, Jenkins SG, Brown SD, Patel M, Lavin BS, Klugman KP. Emergence and spread of streptococcus pneumoniae with erm(B) and mef(A) resistance. Emerg Infect Dis. 2005;11(6):851–8. doi:10.3201/eid1106.050222.
Zarogoulidis P, Papanas N, Kioumis I, Chatzaki E, Maltezos E, Zarogoulidis K. Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. Eur J Clin Pharmacol. 2012;68(5):479–503. doi:10.1007/s00228-011-1161-x.
Kadota J, Mukae H, Ishii H, et al. Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. Respir Med. 2003;97(7):844–50.
Gaylor AS, Reilly JC. Therapy with macrolides in patients with cystic fibrosis. Pharmacotherapy. 2002;22(2):227–39.
Zhuo GY, He Q, Xiang-Lian L, Ya-Nan Y, Si-Te F. Prolonged treatment with macrolides in adult patients with non-cystic fibrosis bronchiectasis: meta-analysis of randomized controlled trials. Pulm Pharmacol Ther. 2014;29(1):80–8. doi:10.1016/j.pupt.2014.02.002.
Gottlieb J, Szangolies J, Koehnlein T, Golpon H, Simon A, Welte T. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2008;85(1):36–41. doi:10.1097/01.tp.0000295981.84633.bc.
Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322–9. doi:10.1136/thoraxjnl-2012-202698.
Ni W, Shao X, Cai X, et al. Prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary disease exacerbation: a meta-analysis. PLoS One. 2015;10(3):e0121257. doi:10.1371/journal.pone.0121257.
Rubin BK, Tamaoki J. Macrolide antibiotics as biological response modifiers. Curr Opin Investig Drugs. 2000;1(2):169–72.
Suzuki H, Shimomura A, Ikeda K, Furukawa M, Oshima T, Takasaka T. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells. Laryngoscope. 1997;107(12 Pt 1):1661–6.
Khair OA, Devalia JL, Abdelaziz MM, Sapsford RJ, Davies RJ. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells. Eur Respir J. 1995;8(9):1451–7.
Anderson R, Theron AJ, Feldman C. Membrane-stabilizing, anti-inflammatory interactions of macrolides with human neutrophils. Inflammation. 1996;20(6):693–705.
Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother. 2004;48(5):1581–5.
Aoshiba K, Nagai A, Konno K. Erythromycin shortens neutrophil survival by accelerating apoptosis. Antimicrob Agents Chemother. 1995;39(4):872–7.
Shimizu T, Shimizu S, Hattori R, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. 2003;168(5):581–7. doi:10.1164/rccm.200212-1437OC.
Shinkai M, Henke MO, Rubin BK. Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action. Pharmacol Ther. 2008;117(3):393–405. doi:10.1016/j.pharmthera.2007.11.001.
Giamarellos-Bourboulis EJ, Pechere JC, Routsi C, et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis. 2008;46(8):1157–64. doi:10.1086/529439.
Spyridaki A, Raftogiannis M, Antonopoulou A, et al. Effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by gram-negative bacteria: results from a randomized clinical study. Antimicrob Agents Chemother. 2012;56(7):3819–25.
Hackel M, Lascols C, Bouchillon S, Hilton B, Morgenstern D, Purdy J. Serotype prevalence and antibiotic resistance in Streptococcus pneumoniae clinical isolates among global populations. Vaccine. 2013;31(42):4881–7. doi:10.1016/j.vaccine.2013.07.054.
Asadi L, Eurich DT, Gamble JM, Minhas-Sandhu JK, Marrie TJ, Majumdar SR. Guideline adherence and macrolides reduced mortality in outpatients with pneumonia. Respir Med. 2012;106(3):451–8.
Skalsky K, Yahav D, Lador A, Eliakim-Raz N, Leibovici L, Paul M. Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials. Clin Microbiol Infect. 2013;19(4):370–8.
Pakhale S, Mulpuru S, Verheij TJ, Kochen MM, Rohde GG, Bjerre LM. Antibiotics for community-acquired pneumonia in adult outpatients. Cochrane Database Syst Rev. 2014;10:CD002109. doi:10.1002/14651858.CD002109.pub4.
Laopaiboon M, Panpanich R, Swa Mya K. Azithromycin for acute lower respiratory tract infections. Cochrane Database Syst Rev. 2015;3:CD001954. doi:10.1002/14651858.CD001954.pub4.
Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest. 2000;117(5 Suppl 2):380S–5.
Boldy DA, Skidmore SJ, Ayres JG. Acute bronchitis in the community: clinical features, infective factors, changes in pulmonary function and bronchial reactivity to histamine. Respir Med. 1990;84(5):377–85.
Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Emerg Med. 2001;37(6):720–7.
Lynch III JP, Martinez FJ. Clinical relevance of macrolide-resistant Streptococcus pneumoniae for community-acquired pneumonia. Clin Infect Dis. 2002;34 Suppl 1:S27–46.
Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med. 1999;159(21):2562–72.
Houck PM, MacLehose RF, Niederman MS, Lowery JK. Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states: 1993, 1995, and 1997. Chest. 2001;119(5):1420–6.
Dudas V, Hopefl A, Jacobs R, Guglielmo BJ. Antimicrobial selection for hospitalized patients with presumed community-acquired pneumonia: a survey of nonteaching US community hospitals. Ann Pharmacother. 2000;34(4):446–52.
Brown RB, Iannini P, Gross P, Kunkel M. Impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: analysis of a hospital claims-made database. Chest. 2003;123(5):1503–11.
Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections—full version. Clin Microbiol Infect. 2011;17 Suppl 6:E1–59. doi:10.1111/j.1469-0691.2011.03672.x.
Shefet D, Robenshtock E, Paul M, Leibovici L. Empiric antibiotic coverage of atypical pathogens for community acquired pneumonia in hospitalized adults. Cochrane Database Syst Rev. 2005;2(2):CD004418. doi:10.1002/14651858.CD004418.pub2.
Mills GD, Oehley MR, Arrol B. Effectiveness of beta lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis. BMJ. 2005;330(7489):456.
Eliakim-Raz N, Robenshtok E, Shefet D, et al. Empiric antibiotic coverage of atypical pathogens for community-acquired pneumonia in hospitalized adults. Cochrane Database Syst Rev. 2012;9:004418.
Nie W, Li B, Xiu Q. Beta-lactam/macrolide dual therapy versus beta-lactam monotherapy for the treatment of community-acquired pneumonia in adults: a systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(6):1441–6.
Postma DF, van Werkhoven CH, van Elden LJ, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372(14):1312–23.
Garin N, Genne D, Carballo S, et al. Beta-lactam monotherapy vs beta-lactam-macrolide combination treatment in moderately severe community-acquired pneumonia: a randomized noninferiority trial. JAMA Intern Med. 2014;174(12):1894–901.
Asadi L, Eurich DT, Gamble JM, Minhas-Sandhu JK, Marrie TJ, Majumdar SR. Impact of guideline-concordant antibiotics and macrolide/beta-lactam combinations in 3203 patients hospitalized with pneumonia: prospective cohort study. Clin Microbiol Infect. 2013;19(3):257–64.
Asadi L, Sligl WI, Eurich DT, et al. Macrolide-based regimens and mortality in hospitalized patients with community-acquired pneumonia: a systematic review and meta-analysis. Clin Infect Dis. 2012;55(3):371–80.
Arancibia F, Ewig S, Martinez JA, et al. Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications. Am J Respir Crit Care Med. 2000;162(1):154–60. doi:10.1164/ajrccm.162.1.9907023.
Roson B, Carratala J, Fernandez-Sabe N, Tubau F, Manresa F, Gudiol F. Causes and factors associated with early failure in hospitalized patients with community-acquired pneumonia. Arch Intern Med. 2004;164(5):502–8. doi:10.1001/archinte.164.5.502.
Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115(2):462–74.
Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR. Macrolides and mortality in critically ill patients with community-acquired pneumonia: a systematic review and meta-analysis. Crit Care Med. 2014;42(2):420–32.
Adrie C, Schwebel C, Garrouste-Orgeas M, et al. Initial use of one or two antibiotics for critically ill patients with community-acquired pneumonia: impact on survival and bacterial resistance. Crit Care. 2013;17(6):R265. doi:10.1186/cc13095.
Martin-Loeches I, Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med. 2010;36(4):612–20. doi:10.1007/s00134-009-1730-y.
Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A. Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. Eur Respir J. 2009;33(1):153–9. doi:10.1183/09031936.00054108.
Metersky ML, Ma A, Houck PM, Bratzler DW. Antibiotics for bacteremic pneumonia: improved outcomes with macrolides but not fluoroquinolones. Chest. 2007;131(2):466–73. doi:10.1378/chest.06-1426.
Martinez JA, Horcajada JP, Almela M, et al. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2003;36(4):389–95.
Vardakas KZ, Siempos II, Grammatikos A, Athanassa Z, Korbila IP, Falagas ME. Respiratory fluoroquinolones for the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials. CMAJ. 2008;179(12):1269–77. doi:10.1503/cmaj.080358; 10.1503/cmaj.080358.
Lode H, File Jr TM, Mandell L, et al. Oral gemifloxacin versus sequential therapy with intravenous ceftriaxone/oral cefuroxime with or without a macrolide in the treatment of patients hospitalized with community-acquired pneumonia: a randomized, open-label, multicenter study of clinical efficacy and tolerability. Clin Ther. 2002;24(11):1915–36.
Welte T, Petermann W, Schurmann D, Bauer TT, Reimnitz P, MOXIRAPID Study Group. Treatment with sequential intravenous or oral moxifloxacin was associated with faster clinical improvement than was standard therapy for hospitalized patients with community-acquired pneumonia who received initial parenteral therapy. Clin Infect Dis. 2005;41(12):1697–705.
Leophonte P, File T, Feldman C. Gemifloxacin once daily for 7 days compared to amoxicillin/clavulanic acid thrice daily for 10 days for the treatment of community-acquired pneumonia of suspected pneumococcal origin. Respir Med. 2004;98(8):708–20.
Kellum JA, Kong L, Fink MP, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) study. Arch Intern Med. 2007;167(15):1655–63.
Kovaleva A, Remmelts HH, Rijkers GT, Hoepelman AI, Biesma DH, Oosterheert JJ. Immunomodulatory effects of macrolides during community-acquired pneumonia: a literature review. J Antimicrob Chemother. 2012;67(3):530–40.
Albert RK, Schuller JL, Clinical Research Network COPD. Macrolide antibiotics and the risk of cardiac arrhythmias. Am J Respir Crit Care Med. 2014;189(10):1173–80. doi:10.1164/rccm.201402-0385CI.
Abo-Salem E, Fowler JC, Attari M, et al. Antibiotic-induced cardiac arrhythmias. Cardiovasc Ther. 2014;32(1):19–25. doi:10.1111/1755-5922.12054.
Owens Jr RC, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis. 2006;43(12):1603–11.
Howard PA. Azithromycin-induced proarrhythmia and cardiovascular death. Ann Pharmacother. 2013;47(11):1547–51. doi:10.1177/1060028013504905.
Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368(18):1704–12. doi:10.1056/NEJMoa1300799.
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881–90. doi:10.1056/NEJMoa1003833.
Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014;311(21):2199–208.
Funding
None declared for all authors.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no competing interests.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by the authors.
Additional information
This article is part of the Topical Collection on Respiratory Infections
Rights and permissions
About this article
Cite this article
McFarlane, A., Sligl, W. The Value of Macrolide-Based Regimens for Community-Acquired Pneumonia. Curr Infect Dis Rep 17, 50 (2015). https://doi.org/10.1007/s11908-015-0507-4
Published:
DOI: https://doi.org/10.1007/s11908-015-0507-4