update on the use of the macrolides for community-acquired respiratory tract infections · 2020. 7....

Future Drugs Ltd

10.1586/14750708.3.5.619 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(5), 619–650 619

REVIEW

Update on the use of the macrolides for community-acquired respiratory tract infectionsJoseph M BlondeauDepartment of Clinical Microbiology, Royal University Hospital & Saskatoon Health Region and Departments of Microbiology & Immunology & Pathology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, Saskatchewan, S7N 0W8, CanadaTel.: +1 306 655 6943Fax: +1 306 655 [email protected]

Keywords: azithromycin, erythromycin, clarithromycin, macrolides

The use of macrolides dates back more than 50 years, when erythromycin was the first of this class to be introduced into clinical practice. In the early 1990s, the so-called ‘newer’ or extended-spectrum macrolides were approved for clinical use in patients with a variety of infectious diseases. While clinically efficacious, the pharmacokinetic (frequent daily dosing) and adverse-events profile (specifically gastrointestinal) of erythromycin initially limited its use as an alternative agent for patients with allergy to β-lactam agents. Erythromycin could be characterized as being active against Gram-positive and atypical pathogens but has limited in vitro activity against Gram-negative organisms (particularly Haemophilus influenzae). The newer macrolide compounds, azithromycin and clarithromycin, were characterized has having in vitro antibacterial activity that was similar to that of erythromycin but with enhanced in vitro activity against Gram-negative respiratory tract pathogens, most notably, H. influenzae. These ‘newer’ macrolides also offered better pharmacokinetic/pharacodynamic properties with less frequent daily dosing and reduced gastrointestinal side effects. The role of atypical and/or new pathogens combined with the global escalation of acquired antimicrobial resistance continues to redefine and impact on the selection of empiric versus organism-directed therapy for respiratory infectious diseases. Macrolide compounds continue to be a valuable class of antimicrobial compounds, as evidenced by their continued prominent place in various guidelines. The key to the long-term viability of the macrolide class appears to be centered around understanding the factors that lead to the selection of macrolide resistance and the role that different macrolide compounds may have in this process.

Initial milestones in anti-infective therapyinclude the discovery of penicillin and the sub-sequent discovery and clinical use of the mac-rolide antibiotics. Early in the anti-infective era,the macrolides were a new class of agents at atime when there were few antimicrobial optionsavailable and, as such, were a major develop-ment in anti-infective therapy. Erythromycinwas derived from Streptomyces erythreus and, asthe first macrolide antibiotic, was originallymarketed in 1952 and was seen as an alternativetherapy to β-lactam antibiotics (e.g., penicillin)– especially in penicillin-allergic patients – fortreating infections caused by Gram-positivecocci, such as Staphylococcus and Streptococcusspecies, including Streptococcus pneumoniae. Thein vitro activity of erythromycin against theatypical pathogens (Mycoplasma and Chlamydiaspecies) as well as against Legionella species andpathogens associated with infection outside ofthe respiratory tract, provided a broader spec-trum of clinical use of these compounds fortreating human infections.

Despite the many years that erythromycinhas been used, and continues to be used, to treatinfection, it is far from a perfect compound.From data summarized by others, some limitingcharacteristics of erythromycin include [1–4]:

• Poor oral bioavailability

• Inactivation in acidic environment necessitatingenteric coating formulation

• Gastrointestinal (GI) side effects, such as nausea,cramping and diarrhea

• Short half-life – multiple daily dosing

• Poor activity against Haemophilus influenzaeRegardless of these less desirable features, erythro-mycin has been a mainstay of anti-infective therapyand remains widely used in clinical practice.

Compared with other classes of antimicrobialcompounds, most notably the β-lactams, advancesin macrolide development were slow. Clarithromy-cin (twice-daily formulation) and azithromycinwere approved for clinical use in 1992 (40 yearsafter erythromycin) and 1994, respectively. Theonce-daily formulation of clarithromycin was

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approved for clinical use in 2003. Several othermacrolide compounds have been developed; how-ever, none have been approved or used extensivelyin North America. Some of the major characteris-tics of newer macrolide compounds, including azi-thromycin and clarithromycin, that wereimprovements over erythromycin include [1–4]:

• Expanded spectrums of activity to includefastitidious Gram-negative bacilli, such asH. influenzae and Neisseria species, as well asother Gram-negative bacilli (Table 1)

• Improved pharmacokinetics allowing foronce- or twice-daily dosing

• Marked reduction in GI side effects

Infectious diseases are an ever-evolving field withadvances that improve the clinical and laboratorydiagnosis of infection and the understanding ofdisease transmission and pathogenesis. Suchadvances ultimately impact on study design andrefine our knowledge of the association of variouspathogens with an infectious process. Someadvances over the past 20–30 years have involvedthe recognition or appreciation of a greater prev-alence of atypical pathogens (Mycoplasma spp.,Chlamydia spp.) associated with community-acquired pneumonia (CAP) and, more recently,

with acute bacterial exacerbations of chronicbronchitis [5]. Have we witnessed a true increasein the prevalence of atypical pathogens in respira-tory tract infections (RTIs), or merely definedwhat has always been by advances in diagnostictechnology? Perhaps it is a little of both but, froma practical point of view, it doesn’t really mattersince this information results in better patientmanagement by selecting a more appropriateantimicrobial compound – that is, β-lactam com-pounds are not active against Mycoplasma spp.and Chlamydia spp., whereas macrolides andfluoroquinolone compounds are. While redefin-ing organism prevalence in patient populations isimportant for clinical management, it has alsobecome increasingly important to continue todefine the prevalence of increasing antimicrobialresistance and its clinical impact. Antimicrobialresistance has been recognized for decades – sincethe initial release of penicillin in the 1940s andthe subsequent discovery of penicillinase-produc-ing strains of S. aureus within a few years; how-ever, the dramatic increase in drug resistantpathogens over the past 15–20 years has beenastounding. Antimicrobial drug resistance hasnow been described for virtually every bug–drugcombination, with few exceptions.

Table 1. Comparative in vitro activity of macrolides against selected pathogens.

Macrolides MIC90 (mg/ml)

Azithromycin Clarithromycin Erythromycin

Haemophilus influenzae 0.5–4.0 8–16 4–16

β-lactam positive 1–4 8–16 4–16

β-lactam negative 1–4 8–16 4–18

Moraxella catarrhalis 0.06 0.25 0.25

β-lactam positive 2 0.19 0.25

β-lactam negative 0.094–2.0 0.125 0.25

Streptococcus pneumoniae 0.12–4.0 0.015–16.0 0.25

Penicillin susceptible 0.12–4.0 0.06 0.06–4.0

Penicillin intermediate 16–>32.0 16–>32 8–>32.0

Penicillin resistant 16–>32.0 8–>32 8–>32.0

Klebsiella pneumoniae 16–64 0 0–>64.0

Staphylococcus aureus

Methicillin susceptible 1–8 0.05–>8.7 1–>10

Methicillin resistant >27.3–128 >59.9 ?64–>100

Streptococcus pyogenes 0.12–0.5 0.015–0.16 0.03–0.18

Legionella pneumophilia 0.5–1.2 0.06–0.22 0.46–0.5

Chlamydia pneumoniae 0.25–0.33 0.11–0.25 0.19–0.5

Chlamydia trachomatis

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Macrolides for community-acquired respiratory tract infections – REVIEW

How do we interpret antimicrobial resistanceand the clinical impact? Is the level of in vitroresistance paralleled by similar levels of clinicalfailures? This is doubtful given that serum drugconcentrations, upon which susceptibility break-points are established, are substantially lower thanpulmonary or urinary drug concentrations, anobservation likely to be important for respiratoryor urinary tract infections, respectively.

Macrolides have been used successfully forthe treatment of infections involving the upperand lower respiratory tract, as well as infectionsat other anatomical locations and against patho-gens for which the compounds have appropriatein vitro activity. This review will only focus onRTIs and highlight the microbiological, phar-macological, clinical and safety data associatedwith the macrolides, with a greater emphasis onazithromycin and clarithromycin. A discussionon the position of the macrolides in the pneu-monia and bronchitis guidelines will also be pre-sented. Readers are referred to other reviews fordata on macrolide use outside of the respiratorytract and against uncommon or unconventionalpathogens [6,7].

Macrolide developmentStructurally, erythromycin and clarithromycin are14-membered macrolide antibiotics, whereas azi-thromycin has a nitrogen addition to the 14-mem-bered ring, resulting in a 15-memberedcompound that is more accurately referred to as anazalide antimicrobial agent. Specifically, the basicmacrolide structure has a methyl-substitutednitrogen in place of the carbonyl at the 9a positionof the glycone ring. This modification is thoughtto enhance the Gram-negative activity when com-pared with erythromycin [8–10]. Azithromycin isprotected against acid degradation, has higher tis-sue penetration (compared with erythromycin)and a longer elimination half-life as a result of itsstructural modifications [10–12]. Clarithromycinhas a methylated hydroxyl group at position 6,resulting in protection from acid degradation andimproved bioavailability, as well as reduced GI sideeffects [1,13]. Azithromycin has a longer half-lifethan clarithromycin (68 vs 6 h for the twice-dailyformulation, respectively). The once-daily formu-lation of clarithromycin has a half-life slightlylonger than the twice-daily formulation; however,the modified formulation results in both immedi-ate and delayed release of the drug over the dosinginterval of 24 h. The chemical structures of azi-thromycin, clarithromycin and erythromycin areshown in Figure 1.

Mechanism of action Macrolides and azalides have the same mechanismof action: they reversibly bind to the 50S ribos-omal subunit of susceptible organisms and inhibitthe mRNA-directed protein synthesis – a bacteri-ostatic effect. However, bactericidal activity mayoccur under certain conditions or against specificmicro-organisms [13,14]. The clinical significanceor benefit of a bactericidal versus bacteriostaticeffect in patients with mild-to-moderate RTIremains unclear [15]. Recently, Blondeau and col-leagues demonstrated a bactericidal effect for azi-thromycin and clarithromycin when high-densitybacterial inocula of S. pneumoniae were exposed toeach agent and killing was increased in vitro [194].Erythromycin stimulates the dissociation of pepti-dyl–tRNA during translocation, thus suppressingRNA-dependent protein synthesis and inhibitingbacterial growth [16–19].

In vitro activityThe in vitro activities of azithromycin, clarithro-mycin and erythromycin are shown in Table 1. Ingeneral terms, macrolides are more active in vitroagainst Gram-positive and atypical agents thanagainst Gram-negative pathogens, and have littleor no intrinsic activity against enteric Gram-nega-tive bacilli or Pseudomonas aeruginosa and otherafermentative Gram-negative bacilli. For clarithro-mycin, MIC90 values are based on the testing ofthe parent compound and not that of the 14-OHmetabolite that has been previously shown to haveantimicrobial activity. Macrolide susceptibilitytesting is influenced by a number of factors, suchas pH, the addition of serum and/or incubation ina CO2 environment, and these variables mayeither increase or decrease the in vitro susceptibil-ity measurements [20]. As with other classes ofcompounds, the in vitro activity of the macrolidesis not uniform against all respiratory pathogens.For example, the MIC90 values for clarithromycinagainst Gram-positive organisms are lower thanthose for azithromycin and erythromycin, suggest-ing better in vitro activity for clarithromycinagainst these Gram-positive organisms. Despitethe higher MICs for azithromycin against Gram-positive organisms, they are still within clinicallyachievable therapeutic levels. Methicillin-resistantstaphylococci and Enterococcus species are notwithin the spectrum of the macrolides. Unfortu-nately, macrolide resistance appears to be a classeffect and, as such, Gram-positive organismsresistant to erythromycin are also cross-resistant toazithromycin and clarithromycin. However, recentdata suggest differences in drug-specific resistance

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within the macrolide class, indicating a differentpropensity of various compounds to select forresistance. The unfortunate consequences of thisphenomenon is that a resistant organism selectedby one macrolide is generally resistant to othercompounds in the class. As such, a compound thatselects for resistance more frequently than othersmay compromise the entire class. Macrolides aregenerally active against clinical isolates ofS. pneumoniae that are susceptible to penicillin;however, significant co- or cross-resistance occursfor strains that are highly resistant to penicillin(i.e., penicillin MICs > 2 µg/ml).

Azithromycin and clarithromycin are moreactive in vitro against H. influenzae than erythro-mycin and azithromycin tends to have lower MICvalues. However, susceptibility testing with clari-thromycin must take into account the 14-OHmetabolite to fully appreciate the true level of sus-ceptibility for this pathogen. Clarithromycindemonstrates lower MIC values against Legionellapneumophila and Chlamdyia pneumoniae than azi-thromycin and erythromycin. However, MIC val-ues tend to be lower for azithromycin than for theother two agents against Moraxella catarrhalis andMycoplasma pneumoniae.

A summary of MIC90 values for azithromy-cin, clarithromycin and erythromycin againstrespiratory pathogens are listed in Table 1.

Antimicrobial resistanceTwo mechanisms of resistance to macrolides arealtered target binding site and efflux. Macrolide,lincosamide and streptogramin B resistance occursas a result of the synthesis of ribosomal RNAmethylases that cause methylation of an adenineresidue in the 23S ribosomal RNA of the 50S sub-unit [21]. This is encoded by the erythromycinribosomal methylase (erm) B gene (also referred toas ermAB) and pneumococcal strains possessingthis gene usually express high-level macrolideresistance (MIC90 ≥ 64 µg/ml) [22]. Genes encod-ing for macrolide resistance may be plasmid basedor chromosomally located, inducable or expressedconstitutively, and induced by both older andnewer macrolides [19,23,24].

Efflux (the ability of organisms to pump anti-microbial agents out of the bacterial cells) is animportant mechanism of macrolide resistance thatis encoded by the mefE gene [22,25]. Efflux resultsin an insufficient concentration of drug within thecell to inhibit protein synthesis and, as such, the

Figure 1. Chemical structures of erythromycin, clarithromycin and azithromycin.

O

OH

O O

O

OH

O

O

OH

O

OH

O

N

OH

O

OH

O O

O

OH

O

O

O

OH

O

N

OH

O

N

O

OH

O O

O

OH

O

O

OH

O

N

OH

OH

Erythromycin

Clarithromycin

Azithromycin



organism is resistant. Pneumococcal strains pos-sessing the mefA gene usually express low-levelresistance (MIC90 ≥ 4 µg/ml) to the macrolides;however, cross-resistance to lincosamides andstreptogramin B does not usually occur [26].

Epidemiological surveys of resistanceIt has been previously suggested by Carbon andPoole that the prevalence of resistance to macro-lides is related closely to the extent to whichthese agents were used, most notable for S. pneu-moniae and S. pyogenes [188]. Macrolide resistancein M. catarrhalis, M. pneumoniae, C. pneumoniaeand L. pneumophila has not yet developed.

A substantial number of investigators havedocumented the prevalence of drug-resistantrespiratory pathogens globally [26–33]. Amongstthe respiratory pathogens, multidrug-resistantS. pneumoniae is a concern, especially the obser-vation that prevalence rates have risen dramati-cally throughout the 1990s, and continue tothis day. From data summarized from the Alex-ander Project, mean prevalence rates of mac-rolide-resistant pneumococcus was 22%,varying from 78% in Hong Kong to 2% in theCzech Republic, and macrolide resistance wasfound to be higher against penicillin-resistantstrains. Resistance was also problematic withpenicillin-susceptible strains, such that mac-rolide-resistance rates were higher than penicil-lin-resistance rates for 11 out of the18 countries participating in the AlexanderProject in 1997 [34].

Several recent reports have documented theprevalence of macrolide susceptibility of respira-tory pathogens in North America (Canada andthe USA). Doern and colleagues reported thatapproximately 25.2–25.7% of 1531 clinical iso-lates of S. pneumoniae collected and tested inthe USA were macrolide nonsusceptible and,for isolates highly resistant to penicillin, cross-resistance to the macrolides was 77–78% [35].More recently, Doern and colleagues reportedon the in vitro susceptibility of 1817 S. pneumo-niae isolates from 44 US medical centers andreported that approximately 27–28% of strainswere macrolide resistant [36]. Doern also notedthat, while the prevalence of macrolide resist-ance has increased since 1999–2000, the rate ofincreasing resistance has slowed since this time,suggestive perhaps of a plateau period. Doernalso noted that clarithromycin MICs were con-sistently twofold lower that those for erythro-mycin which, in turn, were twofold lower thanthe MIC values for azithromycin.

Hoban and colleagues recently reported onmacrolide-resistant S. pneumoniae in Canada andfound that 215 out of 2688 (8%) strains wereresistant [26]. These 215 macrolide-resistant strainswere characterized and 48.8% were PCR-positivefor mefA (efflux) and 46.5% were PCR-positive forermB (target site), suggesting that both mechanismsof resistance are prevalent in Canada.

Shortridge and colleagues studied 60 clinicalpneumococcal isolates from four New York City(NY, USA) medical centers [37]. The isolates dem-onstrated varying degrees of penicillin resistance.The ermB gene was present in 22% of isolateswith intermediate resistance to penicillin com-pared with 38% for isolates with high-level peni-cillin resistance. By contrast, efflux was present in8, 11 and 19% of the pneumococcal isolates thatwere sensitive, intermediate- or high-level penicil-lin resistant, respectively. Marchese and colleaguesstudied pneumococcal isolates from central andnorthern Italy and reported that 82.6% of themacrolide-resistant strains possessed the ermBgene, while the remaining isolates were macrolide-resistant due to efflux [38]. Tonoli and colleaguesexamined 117 penicillin-susceptible macrolide-resistant S. pneumoniae isolates and found that88% expressed the ermB gene and 12% wereresistant due to efflux [39].

Studies characterizing the prevalence rates ofantimicrobial-resistant organisms are necessaryfor the appropriate use of antimicrobial agents inany one geographical area. Similarly, document-ing the prevalence of the different mechanismsof macrolide resistance (ermB and mefA) inS. pneumoniae is also essential given the differentlevels of resistance (higher and lower MICs) andthe potential impact on appropriate clinical use.

Such observations might suggest that the mereuse of a macrolide would be problematic from aresistance perspective; however, more recent datasuggest a differential or drug-specific impact ofthe various macrolide compounds on the selec-tion of macrolide-resistant S. pneumoniae. Mac-rolide resistance does not always translate intoclinical failure [22]. Surveillance studies docu-menting the prevalence of resistance are neces-sary; however, studies specifically investigatingthe clinical activity of macrolides against organ-isms demonstrating various levels of resistance tothese drugs have not been performed.

Drug half-livesIt has long been suggested that macrolide use pre-cedes macrolide resistance and the use of long-act-ing macrolides are more likely to correlate with

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resistance development, whereas short-actingcompounds were not [40]. When compared witherythromycin with a relatively short half-life (2 h),both azithromycin and clarithromycin would beconsidered longer-acting agents due to the pro-longed half-life. However, for azithromycin, thehalf-life is ten-times longer than that of clarithro-mycin (60–70 vs 6 h). Is there any evidence tosuggest that, despite the relatively extended half-lives of both compounds, the likelihood of select-ing macrolide resistant organisms is greater withazithromycin than it is with clarithromycin? Theanswer to this question appears to be yes! Severalrecent lines of evidence suggest that there may bea differential impact on macrolide resistance whenorganisms are exposed to azithromycin and clari-thromycin, with the former being more likely tobe associated with resistance [41].

Minimum inhibitory & mutant-prevention concentration testingBlondeau and colleagues applied MIC and mutant-prevention concentration (MPC) testing to morethan 170 randomly collected unique clinical iso-lates of S. pneumoniae and found that 14–16% ofstrains had MICs of greater than 1 µg/ml to azi-thromycin, clarithromycin and erythromycin – afinding consistent with current levels of macrolidenonsusceptibility in Canada [42–45]. When testedby MPC, the percentage of strains with MPCsgreater than 1 µg/ml increased to 73% in thepresence of azithromycin, 23% in the presence ofclarithromycin (p > 0.0001 compared with azi-thromycin) and 33% in the presence of erythro-mycin (p > 0.0001 compared with azithromycin;p = 0.03 compared with clarithromycin). TheMPC approach tests more than 109 colony-form-ing units (cfu) of bacteria on agar plates contain-ing drug – an inoculum most likely to containresistant subpopulations, if present, and also abacterial burden present during various humaninfectious diseases [46–49]. For MIC testing,105 cfu/ml are tested as recommended by theClinical and Laboratory Standards Institute(CLSI, formerly the National Committee forClinical Laboratory Standards [NCCLS]).

In a more recent report, Blondeau and col-leagues tested 191 clinical isolates of S. pneumo-niae by MPC testing against azithromycin,clarithromycin and erythromycin [50]. For all buttwo strains, MICs were less than 0.25 µg/ml to allcompounds and a substantial number of strainshad MICs to all three drugs less than 0.12 µg/ml.By MPC testing, azithromycin was statisticallymore likely to select for bacterial subpopulations

with MPCs greater than 1, 2, 4 and 8 µg/ml thanclarithromycin (p > 0.004–



Risk factors for infection with TMP/SMX-resistantS. pneumoniae were:

• Absence of chronic organ system disease(OR: 1.64; p < 0.001)

• Previous use of penicillin (OR: 1.71;p < 0.03)

• Previous use of TMP/SMX (OR: 4.73;p < 0.001)

• Previous use of azithromycin (OR: 3.49;p < 0.001)

Risk factors for infection with macrolide-resistantS. pneumoniae were:

• Previous use of penicillin (OR: 1.77;p < 0.03)

• Previous use of TMP/SMX (OR: 2.07;p < 0.04)

• Previous use of clarithromycin (OR: 3.93;p < 0.001)

• Previous use of azithromycin (OR: 9.93;p < 0.001)

Risk factors for infection with fluoroquinolone-resistant S. pneumoniae were:

• Previous use of fluoroquinolones (OR: 12.1;p < 0.001)

• Current residence in a nursing home(OR: 12.9; p < 0.001)

• Nosocomial acquisition of pneumococcalinfection (OR: 9.94; p < 0.003)

In this study, some 24 patients had received eryth-romycin therapy compared with 67 that receivedclarithromycin and 37 that received azithromycin.According to the authors, azithromycin was asso-ciated consistently with an increased risk of resist-ance to agents from all classes except thefluoroquinolones. As such, they concluded thatmacrolides were not homogeneous with respect totheir association with antimicrobial resistance. Forexample, erythromycin use was not associatedwith infecting organisms that were resistant to anyantimicrobial class. Clarithromycin use was associ-ated with an increased likelihood of erythromycinresistance. Azithromycin use was associated withan increased risk of resistance to macrolides, peni-cillin and TMP/SMX in infecting strains. Indeed,greater than 50% of isolates recovered frompatients with invasive pneumococcal strains whohad received azithromycin during the 3-monthperiod prior to infection were resistant to erythro-mycin. As some data have suggested that this asso-ciation may be related to a long half-life leading tosub-MIC blood and pulmonary drug levels (espe-cially in the epithelial lining fluid), the selective

pressure for resistance may be reduced if shorter-acting macrolides are used preferentially or thosethat attain higher drug concentrations [52–55].

Kastner and Guggenbichler studied the impactthat various macrolides had on the promotion ofresistance in the oral flora of children [56]. Childrenwere randomly assigned to receive azithromycin,clarithromycin, erythromycin, roxithromycin andjosamycin for RTI. Throat swabs were collectedfor culture prior to treatment and weekly thereaf-ter, for 6 weeks. At 1 week post-treatment, 90% ofchildren harbored macrolide-resistant strains intheir oral flora. With the exception of azithromy-cin, the percentage of patients colonized by resist-ant organisms decreased to 17% forclarithromycin, erythromycin and josamycin andto 33% for roxithromycin-treated patients after6 weeks. For the azithromycin group, 85% ofpatients remained colonized by macrolide-resist-ant organisms after 6 weeks and 11.6% sufferedfrom reinfection. The authors argued that the longelimination half-life of azithromycin allows forsubinhibitory serum and epithelial lining fluiddrug concentrations over a period of several weekspost-treatment, and this may impact on the emer-gence of resistance. From the study, they con-cluded that azithromycin therapy appears to putselective pressure on the infective and native floraof children, thereby, promoting the carriage ofmacrolide-resistant strains.

Macrolide resistance/consumptionDavidson and colleagues reported on macrolide-resistant S. pneumoniae in Canada and correlatedthe findings (by province) with azithromycin,clarithromycin and erythromycin use [57]. Thestudy was conducted by collecting pneumococ-cal isolates from across Canada, and followingstandardized susceptibility testing, macrolide-resistant strains were genetically characterized todetect the presence of the erm or mef genes. Sus-ceptibility data was correlated with macrolideusage that was normalized for population.

According to the data summarized, the inci-dence of macrolide resistance with S. pneumo-niae varied considerably throughout Canada in2002, however, despite this, three distinct trendswere recognized:

• Coastal provinces had macrolide resistancerates approximating 5%

• Prairie provinces and Ontario had macrolide-resistance rates between 9 and 14%

• Quebec and the Maritime provinces hadmacrolide-resistance rates exceeding 20%

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The following points regarding azithromycinconsumption were summarized:

• Azithromycin consumption in the coastalprovinces remained low at less than 20% ofprescribed macrolides

• Azithromycin accounted for greater than 44%of all macrolide use in the three provinceswith the highest macrolide-resistance rates

• Azithromycin accounted for 25–32% ofmacrolide use in the prairie provinces

There was no statistically significant correlationidentified between total macrolide consumptionand the regional differences in macrolide resist-ance. According to the data of Davidson and col-leagues, regions with the lowest rates of macrolideresistance used significantly less azithromycincompared with other macrolides [58]. The prov-inces with the highest macrolide resistance ratesused more azithromycin compared with othermacrolide compounds. Davidson and colleaguesconcluded that their data suggested azithromycinmay have a greater propensity to select for macro-lide-resistant S. pneumoniae compared withclarithromycin and erythromycin.

Doern commented on antimicrobial use and theemergence of antimicrobial resistance with S. pneu-moniae in the USA [59]. One point in his argu-ments was that “the more potent an antimicrobialagent, the less likely it is to select for resist-ance...Within each class, potencies differ.” Regard-ing macrolides, Doern indicated that azithromycinis consistently three- to fourfold less active thanclarithromycin for the pneumococcus, based onin vitro MIC measurements. Additionally, peakserum drug levels of azithromycin followingadministration of standard dosages are approxi-mately a tenth of those achieved with clarithromy-cin. Doern argued that serum levels are appropriatefor pharmacodynamic analysis and, as such, azi-thromycin was inferior to clarithromycin in termsof in vitro activity and pharmacokinetics. To sup-port his position, Doern cited studies by Diekemaand colleagues [60] and Leach and colleagues [61]indicating that azithromycin use was more likely toselect for macrolide resistance than clarithromycin.In 2002, Edelstein responded to the arguments ofDoern by indicating that the studies cited do notcontain any data regarding the relative emergencerates for azithromycin and clarithromycin and thatserum drug levels may not be the correct parameterto assess the pharmacodynamic behavior of azi-thromycin (in pneumonia) as it ignores good evi-dence regarding the delivery of azithromycin to theinfection site by drug-containing neutrophils [62].

In a subsequent rebuttal to the points raised byEdelstein, Doern [63] cited studies by Ghaffar andcolleagues [64] and Gray and colleagues [65] show-ing the emergence of macrolide resistance inS. pneumoniae isolates following exposure ofinfected persons to azithromycin. However, asthese studies were noncomparative, there was noattempt to assess the affect of clarithromycinexposure on the emergence of macrolide-resistantS. pneumonia. From studies published by Hydeand colleagues and Garcia-Rey and colleagues,associations were made between macrolide useand macrolide-resistant S. pneumoniae [66,67].Doern indicated that these two studies suggestthe higher probability of macrolide resistancefollowing azithromycin therapy since, in theUSA, the vast majority of macrolide use in pedi-atric patients is azithromycin and, for the studyconducted in Spain, the once-daily adminis-tered macrolide was presumably azithromycin.In the Spanish study, the once-daily adminis-tered macrolide had a 1.5-times greater statisti-cal association with the emergence of macrolide-resistant S. pneumoniae than macrolides thatwere administered two- to three-times each day.

Doern suggested that the relative potency of azi-thromycin compared with clarithromycin againstS. pneumoniae may be related to the differentialimpact observed between azithromycin and clari-thromycin on the selection of S. pneumoniae resist-ance to macrolides [63]. Edelstein argued thatalveolar lining fluid drug concentrations maynot be the correct parameter to assess azithromy-cin pharmacodynamics owing to high drug con-centrations delivered by drug-containingneutrophils. To this point, Doern argued that,for extracellular pathogens, such as the pneumo-coccus, epithelial lining fluid drug concentra-tions are likely more relevant than intracellulardrug concentrations. Comparing clarithromycinwith that of azithromycin suggests that epithelialcell lining fluid levels of clarithromycin areapproximately 30-fold higher than those of azi-thromycin [68–71]. Thus, one can imagine that ifdrug concentrations within an infected compart-ment do not achieve or exceed the minimumamounts required to inhibit the growth of theinfecting pathogen, antimicrobial resistance couldensue if subinhibitory drug concentrations (per-haps within the MSW) promoted the selectionand amplification of resistant bacterial subpopula-tions – particularly those likely to exist in high-density populations. Such a point has previouslybeen argued from our laboratory based on theMPC approach and the suggestion that the drug



concentration shown to be therapeutic may, infact, be the same drug concentrations that allowthe selective amplification of resistant subpopula-tions when the concentration is insufficient toinhibit the growth of resistant cells [44].

Subsequently, Gordon and Blumer argued infavor of single-dose, shorter-course therapy withazithromycin. Their arguments in support ofthis strategy were based on the observations thatazithromycin has a long elimination half-life(>50 h), is concentrated within phagocytic cellsand tissues and the drug achieves targeted deliv-ery by the cells to the site of infection (Trojanhorse phenomenon) – data supported by in vitroand in vivo models according to the authors [72].Clearly, this debate remains unresolved.

What does the data summarized above suggestand how should it be used? From in vitro, clinicaland drug-usage data, it suggests that there appearsto be a differential impact of various macrolidesfor their propensity to select for macrolide resist-ance. Each study identifies azithromycin as beingmore frequently associated with macrolide resist-ance. In its simplest terms, macrolide resistancewould refer to any organism requiring more drugthan the susceptibility breakpoint for inhibition.Despite these observations, the subcellularmechanism(s) of this differential impact remainundefined. Also, the arguments above are forS. pneumoniae only and it may be that, for differ-ent pathogens where azithromycin activity isgreater than for other macrolides, that resistancewould be selected less often for particular patho-gen. However, as mentioned previously, resist-ance has been slower to develop to macrolides forother respiratory pathogens and, therefore,emphasis on the differential impact of the vari-ous macrolides on S. pneumoniae resistance isnecessary, appropriate and justified.

Pharmacological properties Pharmacokinetics & pharmacology of azithromycinThe following characteristics are associated withazithromycin and its 15-member macrolide ringstructure (Table 2): increased acid stability, a longerelimination half-life and an increased tissue pene-tration compared with erythromycin [10–12]. Azi-thromycin is also well absorbed and has a lowserum concentration in the presence of protractedserum and tissue half-lives [68,73,74], and fooddecreases the bioavailability of azithromycin by upto 50%. Each dose of azithromycin should betaken at least 1 h before or 2 h after meals.

The mean peak plasma or serum concentrationof azithromycin is approximately 0.45 mg/l and isattained approximately 2.5 h after administration[68,75] of a 500 mg single oral dose and, followingadministration of the 500 mg intravenous dose,higher serum concentrations (3.6 ± 1.60 µg/mlwith 2-h trough levels of approximately0.20 ± 0.15 µg/ml) have been observed [76].Another characteristic of azithromycin relates tothe high affinity for cells and tissues. Drug levelsin leukocytes, macrophages, fibroblasts and vari-ous tissues are ten- to 100-times higher thanserum drug concentrations [77]. Excretion of azi-thromycin is primarily in feces and bile, and only6 and 12% (approximately) of the oral and intra-venous dose of azithromycin, respectively, isrecovered from urine [9,68,75,78]. Dosage adjust-ments do not appear necessary in patients withhepatic and/or renal dysfunction. A unique obser-vation with azithromycin is the unusually longhalf-life of approximately 68 h [73].

Several animal and human studies have demon-strated the high affinity of azithromycin for cellsand tissues and have shown that the uptake intocell types is rapid and dependent on extracellular

Table 2. Properties of macrolides [188].

Agent Dosage, extent of dosing (mg)

Cmax

(µg/ml)t½* (h) Urinary

recovery (%)

Bronchial mucosa (mg/kg body weight)

Epithelial lining fluid (µg/ml)

Alveolar macrophages (µg/ml)

Azithromycin 500‡ 0.62 ~48 h 4.5–12.2

Clarithromycin 250§ 1.1 6.8 26.1 ± 7.0 222 ± 816#

Erythromycin 250¶ 2.9 ± 0.8 1.5–3.0

*Values represent the mean and are generally for administration of a single dose of the oral agent.‡500 mg (2 × 250 mg) day 1, then 250 mg daily for 5 days.§250 mg twice daily for 7 days.¶250 mg 6-hourly for 5 days.#8 h after last dose.Cmax: Maximum drug concentration; t½: Half-life.

REVIEW – Blondeau

628 Therapy (2006) 3(5)

drug concentration, pH, viability of the cell andconcomitant administration of cytokines [77,79].Intracellular drug concentrations for azithromycinin human and mouse polymorphonuclear (PMN)leukocytes, human fibroblasts, murine peritonealmacrophages and mouse and rat alveolar macro-phages may be up to 226-times the extracellularconcentrations [77,80]. The intracellular accumula-tion of azithromycin within human PMN leuko-cytes is prolonged and may last up to 24 hcompared with 30 min with erythromycin [80].Finally, after 72-h incubation, human fibroblastsaccumulated 21-fold more azithromycin thanerythromycin [77] and it has been suggested thatazithromycin-loaded fibroblasts may serve as adrug reservoir, allowing the slow release of thedrug into the circulation [77].

Pharmacokinetics & pharmacology of clarithromycinThe methylation at position 6 of clarithromy-cin allows for the improved bioavailability, pro-tection from acid degradation, excellent tissuepenetration, high intracellular drug concentra-tions and fewer GI side effects compared witherythromycin [1,8,13,81].

Clarithromycin has a higher bioavailabilitythan azithromycin (37 vs 55%, respectively) andfood increases the rate of absorption of clarithro-mycin but does not affect overall bioavailability.Clarithromycin can be taken with or withoutmeals [68,82]. Following oral dosages of 250 and500 mg twice daily, the mean peak steady-stateserum concentrations are 1 and 2–3 µg/ml,respectively [83]. The serum half-life of clarithro-mycin is 3–4 h following a 250-mg dose and5–7 h following a 500-mg dose, and theextended half-life permits twice-daily dosingwith steady-state serum concentrations usuallyachieved following five doses [81,84,85].

Clarithromycin has been formulated foronce- and twice-daily dosing. Pharmacokinet-ics of the once-daily formulation, at dosages of500 mg and 2 × 500 mg, were evaluated andcompared with those of the twice-daily formu-lation, at equal dosages of 250 and 500 mg.Absorption, as assessed by the steady state areaunder the curve (AUCSS), was equivalentbetween the two formulations and comparativebetween dosages. Relative bioavailability forthe 500-mg total daily dose was 96.3 and95.3% for the parent compound and the14-OH metabolite, respectively, and compara-ble results were observed at the 1000-mg totaldaily dosage: relative bioavailability of 97.4 and

111.7% for the parent compound and 14-OHmetabolite, respectively. The relative increasein the formation of the active 14-OH metabo-lite with the once-daily formulation appears tobe related to the longer Tmax and may beimportant for coverage of H. influenzae. Thekinetics for clarithromycin were similar forboth formulations, as observed in their serumhalf-lives of approximately 5–6 h at time pointsbeyond the Cmax [86].

The 14-OH-clarithromycin active metaboliteis somewhat unique and offers the followingcharacteristics: it is formed within 3 h of admin-istration and has a half-life of up to 7 h [81]; is asactive as clarithromycin against a variety ofGram-positive and -negative bacteria; and ismore active in vitro and in vivo than clarithro-mycin against H. influenzae, M. catarrhalis,Legionella species and some streptococci andstaphylococci [87]. Up to 40% of clarithromycinis recovered in urine. Patients with creatinineclearance of less than 30 ml/min may requiredosage adjustments [88]; however, dosage adjust-ments are not usually necessary in patients withnormal renal function but moderate to severehepatic dysfunction [89].

Clarithromycin, as with azithromycin, isextensively distributed in cells and body tissues,achieving drug concentrations that are two- tosixfold higher than in serum. In comparativedistribution studies in animals, clarithromycinwas shown to achieve higher concentrations inorgans and tissues than erythromycin, especiallyin the lungs [90–93]. Patel and colleagues pro-vided evidence suggesting that the levels of clar-ithromycin achieved in the epithelial liningfluid and alveolar macrophages are higher thanthose of azithromycin [69]. This observation mayhave important consequences for the selectionof antimicrobial resistance during drug therapy(as discussed above). From their study in 41healthy volunteers administered clarithromycin(500 mg twice-daily for nine doses) or azithro-mycin (500 mg initial dose and 250 mg once-daily for the remaining four doses), Patel andcolleagues reported the absolute clarithromycinconcentrations in epithelial lining fluid andalveolar macrophages were higher than those ofazithromycin for up to 8 and 12 h, respectively,following the last dose [69].

Drug interaction & drug safetyTheophylline, carbamazepine and terfenadinedrug interactions are seen with erythromycin andclarithromycin, but not with azithromycin [3,94].



In a study by Guay investigating adult patientstreated with azithromycin, approximately 45% ofadult patients that received the drug reported nosignificant interactions with warfarin, theophyl-line, carbamazepine, methylprednisolone, oralcontraceptives, terfenadine or zidovudine [95].Similarly, no major drug interactions have beenassociated with erythromycin use in combinationwith numerous other agents [96].

The safety and tolerability of azithromycin wasstudied in over 6600 patients (42% female, 58%male; 61% aged ≥ 16 years) [97]. For 15.4% ofadult patients treated with azithromycin, the fol-lowing side effects were reported: GI in 12.6% ofcases; 1.4% or less for effects on CNS and PNS,cardiovascular, skin and liver. In total, investiga-tors felt that 43% of the adverse events wererelated to azithromycin therapy compared with52% for comparator agents. There was no differ-ence in tolerability of azithromycin by elderly andyoung patients. The severity of side effects wasclassified as 64% mild, 30% moderate and 6%severe, whereas the severity profile for comparativeagents was classified as 52% mild, 36% moderateand 12% severe. Laboratory abnormalities werenot detected consistently in adults or childrentreated with azithromycin that resulted in theirwithdrawal from therapy; 2.3% or less of liverenzymes, white blood cells, hemoglobin, platelets,creatinine, blood urea nitrogen, potassium or cal-cium were found to be abnormal from1900–3800 assessments and most had abnormalpercentages of 0.7% or lower (Table 3).

Clarithromycin use may include side effectssuch as nausea, diarrhea, abdominal pain, metallictaste and headache. Similar to azithromycin, clari-thromycin is generally considered to be a nontoxicdrug (Table 3) [98] and demonstrated fewer sideeffects than erythromycin when the compoundswere used in comparative studies [99]. High-doseclarithromycin (1000 mg twice daily) administeredto elderly patients with atypical mycobacterial lung

infections was associated with more severe adversereactions, including nausea, vomiting, metallictaste, abnormal results of liver function tests andCNS toxicity [100]. Dosages of 500 mg twice dailywas better tolerated by patients and mild and tran-sient and/or isolated side effects associated withclarithromycin use have included leukopenia,abnormal liver enzyme values, pancreatitis,myasthenic syndrome, cholestatic hepatitis andfulminant hepatic failure (Table 3) [101–104].

Erythromycin is associated with drug interac-tions since it interacts with the cytochromeP450 system. Drug interactions includecoadministration of clarithromycin with car-bamazepine, theophylline, caffeine, digoxin, tri-azolin, ergotamine, cyclosporine, warfarin,astemizole, terfenadine, valproate, disopyra-mide, midazolam and nicotine [20,105–116]. Clari-thromycin may also interact with zidovudineand other antiretroviral agents [117–121].

Clinical indicationsThe macrolides are indicated for a wide range ofclinical infections, with some differences betweenthe agents with respect to specific indications.For this review, only the RTI indications will besummarized. Readers are referred to other com-prehensive reviews for other potential indicationsfor the various macrolide compounds [6,41].Review of the clinical efficacy of the macrolidesin RTIs are summarized in the following sec-tions (Tables 4–11) and include clinical and bacte-riological outcome results. As previouslysummarized by Blondeau, several points regard-ing the summary of the clinical trials data mustbe emphasized and include [7]:

• The number of patients is based on thoseevaluated for clinical efficacy;

• The number of patients evaluated for bacteri-ological outcome tends to be lower than thoseevaluated for clinical efficacy;

Table 3. Incidence of macrolide-related adverse events.

Event Azithromycin (%) Clarithromycin (%)

Nausea 2.6–5.0 3–3.4

Diarrhea 3.6–6.0 2.7–3.0

Taste perversion

REVIEW – Blondeau

630 Therapy (2006) 3(5)

• Not all trials had microbiological evaluations;

• Not all trials had follow-up data for either clini-cal efficacy, bacteriological efficacy or both;

• While drug dosages are summarized, readersshould refer to the specific studies for clarifica-

tion if the summarized data is unclear;

• Readers should make note of the number ofpatients in the studies summarized and recognizethat the calculation of percentage is profoundlyaffected by low patient number values;

Table 4. Summary of selected antimicrobial comparator trials in adults with community-acquired pneumonia.

Treatment Dosage Duration (days)

No. patients

End of Treatment Ref.

Clinical outcome

Bacteriological outcome

Azithromycin

Azithromycin 500 mg day 1 and 250 mg daily on days 2–5

5 48 92 91 [140]

Amoxicillin/clavulanate 500 mg three times a day 10 56 87 89

Azithromycin 500 mg day 1 and 250 mg daily for 2–5 days

5 191 96 88 [141]

Cefaclor 500 mg three times a day 10 81 95 88


5 100 [142]

Erythromycin 500 mg daily 10 100


5 32 94 80 [143]

Cefaclor 500 mg three times a day 10 39 100 93

Azithromycin 500 mg daily 54 81 81 [144]

Benzylpenicillin 1 mu daily 50 70 70

Azithromycin 250 mg daily 53 94 94 [143]

Cefaclor 500 mg three times a day 66 100 100

Azithromycin 2.0-g microsphere Single dose 213 89.7 90.7 [153]

Levofloxacin 500 mg OD 7 214 93.7 92.3

Clarithromycin

Clarithromycin 500 mg twice daily 10 162 88.9 [145]

Sparfloxacin 400 mg loading; 200 mg daily 10 150 89.3

Clarithromycin 250 mg twice daily 175 89 89 [145]

Sparfloxacin 200 mg daily 167 89 89

Clarithromycin 500 mg twice daily 188 95 95 [146]

Moxifloxacin 400 mg daily 194 95 95

Clarithromycin 250 mg twice daily 10 208 88.5 [147]

Grepafloxacin 600 mg daily 10 211 82.9

Clarithromycin 500 mg twice daily 7–10 156 94.2 [148]

Trovafloxacin 200 mg daily 7–10 144 95.8

Clarithromycin 250 mg twice daily 7–14 92 97 89 [149]

Erythromycin 500 mg daily 7–14 81 96 100

Clarithromycin 500 mg twice daily 7–14 103 86 91 [150]

Cefixime 400 mg daily 7–14 110 88 90

Azithromycin vs clarithromycin

Clarithromycin 250 mg twice daily 10 101 95 95 [151]

Azithromycin 500 mg daily 3 102 94 94

Azithromycin 2.0-g microsphere Single dose 202 92.6 91.8 [155]

Clarithromycin 1.0 g once daily 7 209 94.7 90.5



• Readers should always refer to the originalstudy publication in order to fully appreciatethe study designs, data evaluations and/or anyspecific modification factors that may haveinfluenced the data but may be beyond thescope for inclusion in this review article;

• Clinical trials are designed to show equiva-lency and, as such, statistical differences relat-ing to clinical efficacy are unlikely. Also, manystudies may exclude patients with a pathogenthat is resistant to either study drug;

• For some of the studies summarized in thisreview, statistical differences were observedbetween some compounds for bacterial eradica-tion. Additionally, some differences were

organism specific. Such specific data was notincluded in the tables in this report in an attemptto keep the tables simple. Readers should refer tospecific studies in order to fully appreciate howthe study was conducted, sample size, statisticalmethods and any other variables that mayinfluence the interpretation of the results.

Clinical use in childrenPharyngitis and tonsillitis in children agedbetween 5 and 15 years is usually caused byStreptococcus pyogenes (group A Streptococci).Penicillin remains the drug of choice owing toits proven efficacy and lack of clinically signifi-cant resistance. The macrolides have been

Table 5. Empirical antimicrobial selection for adult patients with community-acquired pneumonia: Canadian guidelines.

Type of patient factor(s) involved Treatment regimen

First choice Second choice

Outpatient without modifying factors

Erythromycin, azithromycin or clarithromycin Doxycycline

Outpatient with modifying factor

COLD (no recent antibiotics or oral steroids within prior 3 months)

Azithromycin or clarithromycin Doxycycline

COLD (recent antibiotics or oral steroids within prior 3 months; Haemophilus influenzae and enteric Gram-negative rods implicated)

Levofloxacin, gatifloxacin or moxifloxacin Erythromycin, azithromycin or clarithromycin plus amoxicillin/clavulanate or second-generation cephalosporin

Suspected macroaspiration oral anerobes

Amoxicillin/clavulanate macrolide Levofloxacin, gatifloxacin or moxifloxacin plus clindamycin or metronidazole

Nursing home resident

Streptococcus pneumoniae, enteric Gram-negative rods; H. influenzae implicated

Erythromycin, azithromycin or clarithromycin plus amoxicillin/clavulanate or levofloxacin, gatifloxacin or moxifloxacin monotherapy

Erythromycin, azithromycin or clarithromycin plus second-generation cephalosporin

Hospitalized Treatment identical to other hospitalized patients (see below)

Hospitalized patient or medical ward

S. pneumoniae, Legionella pneumophila, or Chlamydia pneumoniae implicated

Levofloxacin, gatifloxacin or moxifloxacin monotherapy

Erythromycin, azithromycin, or clarithromycin plus second-, third- or fourth-generation cephalosporin

Hospitalized patient in ICU

P. aeruginosa not suspected; S. pneumoniae, L. pneumophila, C. pneumoniae, or enteric Gram-negative rods implicated

Levofloxacin, gatifloxacin or moxifloxacin (i.v.) plus cefotaxime, ceftriaxone or β-lactam/β-lactamase compound

Erythomycin or azithromycin (i.v.) plus cefotaxime, ceftriaxone or β-lactam/β-lactamase compound

P. aeruginosa suspected Ciprofloxacin or another antipseudomonal fluoroquinolone plus an antipseudomonal β-lactam agent or an aminoglycoside

Triple therapy with antispeudomonal β-lactam (e.g., ceftazidime, piperacillin, tazobactam, imipenem or meropenem) plus an aminoglycoside and erythromycin, azithromycin or clarithromycin

COLD: Chronic obstructive lung disease; i.v.: Intravenous. Reproduced with permission from [138].

REVIEW – Blondeau

632 Therapy (2006) 3(5)

shown to be effacious in the treatment of groupA Streptococci pharyngitis and remain a suitablealternative in patients with penicillin allergy.

Several different bacterial pathogens havebeen associated with acute and chronic otitismedia (OM) and include S. pneumoniae,H. influenzae, M. catarrhalis, S. pyogenes,S. aureus and other bacteria. Erythromycin is apoor choice for treating otitis given the preva-lence of H. influenzae and the poor activity oferythromycin against this pathogen. Both azi-thromycin and clarithromycin have shown goodin vitro activity against the pathogens causingmiddle ear infections (Table 1). A randomizedclinical trial comparing 3–5-day courses of azi-thromycin was compared with a 10-day course ofamoxicillin/clavulanate and was found to be clin-ically equivalent in the management of acute OMin the pediatric population. However, side effectswere statistically less commonly associated withazithromycin. Clinical cure in acute OM has alsobeen reported in studies comparing clarithromy-cin and amoxicillin or amoxicillin/clavulanate orcephalosporins. Recently, several studies havereported bacteriological failures with the newermacrolides. In 1996, McLinn and Williams pub-lished a report showing that 34 confirmedH. influenzae cases treated with azithromycinfailed to bacteriologically eradicate the pathogenin 71% of children; however, clinical cure rateswere similar [122]. Similar bacteriological failurehas been shown with penicillin.

A recent pediatric trial investigating the effi-cacy, safety and tolerability of a 3-day course ofazithromycin with a 10-day course of amoxicil-lin/clavulanate resulted in a cure or clinicallyimproved rate of 91 and 87%, respectively [123].Significantly more related GI adverse events werefound in the amoxicillin/clavulanate group(p = 0.01). This short-course therapy (3 days)data corroborates other clinical results observed.

More recently, three studies (Arguedas andcolleagues, Dunne and colleagues, Block and col-leagues) evaluated single-dose (30 mg/kg) azi-thromycin therapy for the treatment ofuncomplicated OM [124–126]. Comparator regi-mens in two of the studies were ceftriaxone (50mg/kg intramuscular single dose) and amoxicillinclavulanate (22.5 mg/kg twice daily, 45mg/kg/day) (Table 12). Clinical success rates in theazithromycin-treated patients ranged from64–97% compared with 57–98% and varieddepending on patients age (aged 2 years)and day(s) of the measure of clinical response(10–32 days). In all three studies, there was no

statistical differences in clinical efficacy betweentreatment groups. However, there was a statisticaldifference in compliance (p > 0.001) for patientstaking azithromycin compared with amoxicil-lin/clavulanate [126]. In a review of these threestudies, Arguedas and colleagues concluded thata single dose of azithromycin (30 mg/kg) is safeand effective for the treatment of uncomplicatedOM in children [127]. For a more comprehensiveoverview of the diagnosis and treatment of acuteOM, readers are referred to recently publishedclinical practice guidelines [128].

Clinical use in adultsLower RTIsCommunity-acquired pneumoniaFrom some of the initial pneumonia guidelinesfrom the American Thoracic Society in 1993,macrolides (azithromycin and clarithromycin)were recommended as first-line agents in thetreatment of CAP in patients aged under 60 yearsand without comorbidities, and they wereamongst the agents of choice for treating patientswith atypical pneumonia [129–132]. A review ofselected clinical trials involving macrolides fortreating CAP are summarized in Table 4.

The 2001 American Thoracic Society guide-lines, 2003 Canadian guidelines, the 2003 Infec-tious Diseases Society of America (IDSA)guidelines and the results of several comparativeclinical studies suggests that azithromycin andclarithromycin should be considered as first-lineagents in the treatment of adults with suspectedCAP and should be the agents of choice inpatients with an established or suspected diagnosisof pneumonia owing to atypical pathogens[129,131–135]. Other first-line empiric agents to beconsidered in the empiric treatment of CAPinclude the newer fluoroquinolones (gatifloxacin,gemifloxacin and moxifloxacin) and doxycycline;however, the recent withdrawal of gatifloxacin inNorth America leaves only gemifloxacin andmoxifloxacin as ‘new’ respiratory fluoroquinolo-nes. It has been recommended that hospitalizedpatients with CAP admitted to a general medicalward and intensive care unit should be empiricallytreated with a β-lactam agent with or without amacrolide or newer fluoroquinolone as a singleagent. Those with severe pneumonia admitted toan intensive care unit should be treated with aβ-lactam agent in combination with a macrolideor fluoroquinolone. The benefit of combinationtherapy included potentially lowering mortality(severe P. pneumonia [136,137]), an expandedspectrum of activity to include both typical and



atypical agents and with some combinations,the possibility of synergistic activity. Readers arereferred to the complete guideline publications

to fully appreciate the specific recommenda-tions and the rational/data used to arrive atthese recommendations [138,139].

Table 6. Initial empirical therapy for suspected bacterial CAP in immunocompetent adults.

Patient variable Preferred treatment options

Outpatient: previously healthy

No recent antibiotic therapy A macrolide* or doxycycline

Recent antibiotic therapy‡ A respiratory fluoroquinolone§ alone, an advanced macrolide¶ plus high-dose amoxicillin# or an advanced macrolide plus high-dose amoxicillin-clavulanate**

Comorbidities (chronic obstructive pulmonary disease, diabetes, renal or congestive heart failure or malignancy)

No recent antibiotic therapy An advanced macrolide¶ or a respiratory fluoroquinolone

Recent antibiotic therapy A respiratory fluoroquinolone§ alone or an advanced macrolide plus a β-lactam‡‡

Suspect aspiration with infection Amoxicillin–clavulanate or clindamycin

Influenza with bacterial superinfection A β-lactam‡‡ or a respiratory fluorouqinolone

Inpatient: medical ward

No recent antibiotic therapy A respiratory fluoroquinolone alone or an advanced macrolide plus a β-lactam§§

Recent antibiotic therapy An advanced macrolide plus a β-lactam or a respiratory fluoroquinolone alone (regimen selected will depend on nature of recent antibiotic therapy)

Intensive care unit

Pseudomonas infection is not an issue A β-lactam§§ plus either an advanced macrolide or a respiratory fluoroquinolone

Pseudomonas infection is not an issue but patient has a β-lactam allergy

A respiratory fluoroquinolone with or without clindamycin

Pseudomonas infection is an issue¶¶ Either an antipseudomonal agent## plus ciprofloxacin or an antipseudomonal agent plus an aminoglycoside*** plus a respiratory fluoroquinolone or a macrolide

Pseudomonas infection is an issue but the patient has a β-lactam allergy

Either aztreonam plus levofloxacin‡‡‡ or aztreonam plus moxifloxacin or gatifloxacin with or without an aminoglycoside

Nursing home

Receiving treatment in nursing home A respiratory fluoroquinolone alone or amoxicillin–clavulanate plus an advanced macrolide

Hospitalized Same as for medical ward and intensive care unit*Erythromycin, azithromycin or clarithromycin.‡The patient was given a course of antibiotic(s) for treatment of any infection within the past 3 months, excluding the current episode of infection. Such treatment is a risk factor for drug-resistant Streptococcus pneumoniae and possibly for infection with Gram-negative bacilli. Depending on the class of antibiotics given recently, one or other of the suggested options may be selected. Recent use of a fluoroquinolone should indicate selection of a nonfluoroquinolone regimen and vice versa.§Moxifloxacin, gatifloxacin, levofloxacin or gemifloxacin (oral gemifloxacin only, approved by the US FDA on April 4, 2003 and is the only fluoroquinolone approved for multidrug-resistant S. pneumoniae, not yet marketed).¶Azithromycin or clarithromycin.#Dosage 1 g per oral three times a day.**Dosage 2 g per oral twice daily.‡‡High-dose amoxicillin, high-dose amoxicillin–clavulanate, cefpodoxime, cefprozil and cefuroxime.§§Cefotaxime, ceftriaxone, ampicillin–sulbactam or ertapenem; ertapenem was recently approved for such use (in once-daily parenteral treatment), although there is little experience thus far.¶¶The antipseudomonal agent chosen reflect this concern. Risk factors for Pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent antibiotic therapy or stay in hospital (especially in the intensive care unit) for patients with community-acquired pneumonia (CAP) in the Intensive Care Unit, coverage for S. pneumoniae and Legionella species must always be assured. Piperacillin–tazobactam, imipenem, meropenem and cefepime are excellent β-lactams and are adequate for most S. pneumoniae and Haemophilus influenzae infections. They may be preferred when there is concern for relatively unusual CAP pathogens, such as Pseudomonas aeruginosa, Klebsiella species and other Gram-negative bacteria.##Piperacillin, piperacillin–tazobactam, imipenem, meropenem or cefepime.***Data suggest that elderly patients receiving aminoglycosides have worse outcomes.‡‡‡Dosage for hospitalized patients 750 mg once daily.Reproduced with permission from [139].

REVIEW – Blondeau

634 Therapy (2006) 3(5)

Tab

le 7

. Em

pir

ical

an

tib

acte

rial

sel

ecti

on

fo

r C

AP:

ad

van

tag

es a

nd

dis

adva

nta

ges

.

Pati

ent

gro

up

, dru

g(s

)A

dva

nta

ges

Dis

adva

nta

ges

Ou

tpat

ien

t

Mac

rolid

es (a

zith

rom

ycin

, cl

arith

rom

ycin

and

ery

thro

myc

in)

Act

ive

agai

nst

mos

t co

mm

on p

atho

gens

, inc

ludi

ng a

typi

cal a

gent

sM

acro

lide

resi

stan

ce is

rep

orte

d fo

r 20

–30%

of

Stre

ptoc

occu

s pn

eum

onia

e an

d in

vitr

o re

sist

ance

has

em

erge

d du

ring

ther

apy

S. p

neum

onia

e re

sist

ance

in v

itro

may

be

dece

ptiv

e si

nce

the

M p

heno

type

may

no

t be

clin

ical

ly r

elev

ant

and

alve

olar

lini

ng f

luid

or

intr

acel

lula

r le

vels

may

be

mor

e im

port

ant

than

ser

um le

vels

use

d to

det

erm

ine

in v

itro

activ

ity

Brea

kthr

ough

pne

umoc

occa

l bac

teria

with

mac

rolid

e-re

sist

ant

stra

ins

appe

ar t

o be

mor

e co

mm

on t

han

with

β-la

ctam

s or

flu

oroq

uino

lone

s

Clin

ical

tria

l dat

a ha

ve s

how

n co

nsis

tent

ly g

ood

resu

lts, i

nclu

ding

act

ivity

ag

ains

t st

rain

s re

sist

ant

in v

itro

Eryt

hrom

ycin

is p

oorly

tol

erat

ed a

nd is

less

eff

ectiv

e ag

ains

t H

aem

ophi

lus

influ

enza

e

Azi

thro

myc

in a

nd c

larit

hrom

ycin

hav

e th

e ad

vant

age

of o

nce-

daily

the

rapy

and

ar

e w

ell t

oler

ated

Am

oxic

illin

Am

oxic

illin

is t

he p

refe

rred

dru

g fo

r or

al t

reat

men

t of

sus

cept

ible

str

ains

of

S.pn

eum

onia

eLa

cks

activ

ity a

gain

st a

typi

cal a

gent

s an

d β-

lact

amas

e-pr

oduc

ing

bact

eria

Act

ive

agai

nst

90–9

5% o

f S.

pne

umon

iae

stra

ins

whe

n us

ed a

t a

dosa

ge o

f 3–

4g/

day

Hig

h do

sage

s (3

–4 g

/day

) req

uire

d to

ach

ieve

act

ivity

aga

inst

gr

eate

r th

an 9

0% o

f S.

pne

umon

iae

Stan

dard

in m

any

Euro

pean

CA

P G

uide

lines

for

em

piric

tre

atm

ent

of

outp

atie

nts

as w

ell a

s C

DC

gui

delin

esTh

e nu

mbe

r of

rec

ent

publ

icat

ions

doc

umen

ting

effic

acy

ism

odes

t

Am

oxic

illin

-cla

vula

nate

Com

pare

d w

ith a

mox

icill

in, s

pect

rum

in v

itro

incl

udes

β-la

ctam

ase-

prod

ucin

g ba

cter

ia s

uch

as m

ost

H. i

nflu

enza

e, m

ethi

cilli

n-su

scep

tible

Sta

phyl

ococ

cus

aure

us a

nd a

nero

bes

Lack

s ac

tivity

aga

inst

aty

pica

l age

nts

Clin

ical

tria

ls r

epor

ted

to d

ocum

ent

effic

acy

Mor

e ex

pens

ive

and

mor

e ga

stro

inte

stin

al in

tole

ranc

e co

mpa

red

with

am

oxic

illin

Stan

dard

in m

any

Euro

pean

CA

P gu

idel

ines

for

em

piric

tre

atm

ent

of

outp

atie

nts

as w

ell a

s C

DC

gui

delin

esTh

e nu

mbe

r of

rec

ent

publ

icat

ions

doc

umen

ting

effic

acy

is

rela

tivel

y m

odes

t

Ora

l cep

halo

spor

ins

(cef

podo

xim

e, c

efpr

ozil

and

cefu

roxi

me

axet

il)

Act

ive

agai

nst

75–8

5% o

f S.

pne

umon

iae

and

virt

ually

all

H. i

nflu

enza

eA

ll ce

phal

ospo

rins

(and

all

β-la

ctam

s) a

re in

activ

e ag

ains

t at

ypic

alag

ents

Clin

ical

tria

l dat

a su

ppor

t ef

ficac

y in

out

patie

nts

with

CA

PA

mox

icill

in is

mor

e pr

edic

tabl

y ac

tive

agai

nst

S. p

neum

onia

e (c

efpr

ozil

and

cefp

odox

ime

are

mor

e ac

tive

than

cef

urox

ime)

Dox

ycyc

line

Act

ive

agai

nst

90–9

5% o

f st

rain

s of

S. p

neum

onia

e. A

lso

activ

e ag

ains

t H

.inf

luen

zae,

aty

pica

l age

nts

and

cate

gory

A b

acte

rial a

gent

s of

bio

terr

oris

mVe

ry li

mite

d re

cent

pub

lishe

d cl

inic

al d

ata

on C

AP

and

few

cl

inic

ians

use

it

At l

east

one

rece

nt re

port

sho

win

g go

od o

utco

mes

in h

ospi

taliz

ed p

atie

nts

with

C

AP

Fluo

roqu

inol

ones

(gat

iflox

acin

, le

voflo

xaci

n, m

oxifl

oxac

in a

nd

gem

iflox

acin

)

Act

ive

agai

nst g

reat

er th

an 9

8% o

f S. p

neum

onia

e st

rain

s in

the

USA

, inc

ludi

ng

peni

cilli

n-re

sist

ant

stra

ins

Con

cern

for

abu

se w

ith r

isk

of in

crea

sing

res

ista

nce

by

S.pn

eum

onia

e. T

his

incl

udes

clin

ical

fai

lure

s at

trib

uted

to

emer

genc

e of

resi

stan

ce d

urin

g th

erap

y an

d se

lect

ion

of re

sist

ant

stra

ins,

suc

h as

23F

, tha

t m

ay b

e pr

eval

ent

in s

elec

ted

area

s an

d ar

e us

ually

als

o re

sist

ant

to m

acro

lides

and

β-la

ctam

s

CA

P: C

om

mu

nit

y-ac

qu

ired

pn

eum

on

ia. R

epro

du

ced

wit

h p

erm

issi

on

fro

m [

139]

.



Subs

tant

ial c

ompa

rativ

e cl

inic

al t

rial d

ata

to c

onfir

m e

quiv

alen

ce o

r su

perio

rity

to a

ltern

ativ

e co

mm

only

use

d re

gim

ens

and

a m

eta-

anal

ysis

of

tria

ls

dem

onst

rate

d si

gnifi

cant

ly b

ette

r ou

tcom

es t

han

for

β-la

ctam

s or

mac

rolid

es

Expe

nsiv

e co

mpa

red

with

som

e al

tern

ativ

es, s

uch

as d

oxyc

yclin

e or

ery

thro

myc

in

Act

ive

agai

nst

H. i

nflu

enza

e, a

typi

cal a

gent

s, m

ethi

cilli

n-su

scep

tible

S. a

ureu

s an

d ca

tego

ry A

bac

teria

l age

nts

of b

iote

rror

ism

Regi

men

s ha

ve a

dvan

tage

of

once

-dai

ly a

dmin

istr

atio

n an

d ar

e w

ell t

oler

ated

Clin

dam

ycin

Act

ive

agai

nst

90%

of

S. p

neum

onia

eN

ot a

ctiv

e ag

ains

t H

. inf

luen

zae

or a

typi

cal a

gent

s

Goo

d in

vitr

o ac

tivity

and

est

ablis

hed

effic

acy

in a

nero

bic

bact

eria

l inf

ectio

ns

and

favo

red

for

toxi

c sh

ock

asso

ciat

ed w

ith p

neum

onia

due

to

grou

p A

st

rept

ococ

ci

Lim

ited

publ

ishe

d da

ta o

n us

e fo

r C

AP

Hig

h ra

tes

of d

iarr

hea

and

Clo

strid

ium

diff

icile

-ass

ocia

ted

colit

is

Mac

rolid

e pl

us

amox

icill

in–c

lavu

lana

teM

acro

lide

adds

act

ivity

aga

inst

age

nts

to s

pect

rum

of

amox

icill

in–c

lavu

lana

te

(des

crib

ed a

bove

)Li

mite

d pu

blis

hed

data

for

out

patie

nts

Requ

ires

high

dos

ages

of

amox

icill

in–c

lavu

lana

te (4

g/d

ay)

Hig

h ra

tes

of g

astr

oint

estin

al in

tole

ranc

e an

ticip

ated

Unl

ikel

y to

be

effe

ctiv

e ag

ains

t flu

oroq

uino

lone

-res

ista

nt s

trai

ns

ofS.

pne

umon

iae

Ho

spit

aliz

ed p

atie

nts

Fluo

roqu

inol

ones

(gat

iflox

acin

, le

voflo

xaci

n, m

oxifl

oxac

in a

nd

gem

iflox

acin

)

Broa

d sp

ectr

um o

f ac

tivity

aga

inst

like

ly a

gent

s of

CA

P (s

umm

ariz

ed a

bove

)C

once

rn f

or in

crea

sing

res

ista

nce

(sum

mar

ized

abo

ve)

Exte

nsiv

e pu

blis

hed

data

, inc

ludi

ng r

etro

spec

tive

anal

yses

of

hosp

italiz

ed

med

icar

e pa

tient

s, s

how

ing

sign

ifica

ntly

low

er m

orta

lity

than

for

mac

rolid

es

alon

e or

cep

halo

spor

ins

alon

e

Clin

ical

out

com

e at

trib

uted

to

resi

stan

t st

rain

s re

port

ed

Effic

acy

in s

erio

us in

fect

ions

, inc

ludi

ng b

acte

rem

ic P

neum

ococ

cal p

neum

onia

, es

tabl

ishe

d

Ava

ilabl

e in

ora

l and

par

ente

ral f

orm

ulat

ions

(exc

ept f

or g

emifl

oxac

in, f

or w

hich

on

ly o

ral f

orm

ulat

ions

are

ava

ilabl

e) f

acili

tatin

g in

trav

enou

s-to

-ora

l sw

itch

Mac

rolid

es (a

zith

rom

ycin

, er

ythr

omyc

in)

In v

itro

spec

trum

sum

mar

ized

abo

veRe

tros

pect

ive

anal

ysis

of 1

4,00

0 ho

spita

lized

med

icar

e re

cipi

ents

fo

r 19

98–1

999

show

s m

orta

lity

rate

for

mac

rolid

e al

one

was

si

gnifi

cant

ly g

reat

er t

han

that

for

cep

halo

spor

in p

lus

a m

acro

lide

or a

flu

oroq

uino

lone

alo

ne

Exte

nsiv

e cl

inic

al t

rail

data

and

clin

ical

exp

erie

nce

to d

ocum

ent

effic

acy

Incr

easi

ng in

vitr

o re

sist

ance

by

S. p

neum

onia

e, a

s su

mm

ariz

edab

ove

Azi

thro

myc

in is

incl

uded

as

an a

ppro

pria

te c

hoic

e in

man

y cu

rren

t C

AP

guid

elin

es, i

nclu

ding

the

gui

delin

es o

f th

e A

mer

ican

Tho

raci

c So

ciet

yBr

eakt

hrou

gh b

acte

rem

ia d

ue t

o re

sist

ant

stra

ins

of

S.pn

eum

onia

e is

unu

sual

but

app

ears

to

be m

ore

com

mon

with

m

acro

lides

tha

n w

ith o

ther

age

nts

Tab

le 7

. Em

pir

ical

an

tib

acte

rial

sel

ecti

on

fo

r C

AP:

ad

van

tag

es a

nd

dis

adva

nta

ges

(co

nt.

).

Pati

ent

gro

up

, dru

g(s

)A

dva

nta

ges

Dis

adva

nta

ges

CA

P: C

om

mu

nit

y-ac

qu

ired

pn

eum

on

ia. R

epro

du

ced

wit

h p

erm

issi

on

fro

m [

139]

.

REVIEW – Blondeau

636 Therapy (2006) 3(5)

Cep

halo

spor

ins

(cef

tria

xone

and

ce

fota

xim

e)C

onsi

dere

d th

e pa

rent

eral

dru

gs o

f ch

oice

(as

wel

l as

peni

cilli

n G

) for

CA

P ca

used

by

susc

eptib

le s

trai

ns o

f S.

pne

umon

iae

Not

act

ive

agai

nst

atyp

ical

age

nts

or c

ateg

ory

A a

gent

s of

biot

erro

rism

Act

ive

in v

itro

agai

nst

90–9

5% o

f S.

pne

umon

iae.

Als

o ac

tive

agai

nst

H.i

nflu

enza

e an

d m

ethi

cilli

n-re

sist

ant

S. a

ureu

s Re

tros

pect

ive

anal

ysis

of

14,0

00 m

edic

are

patie

nts

show

ed

high

er m

orta

lity

for

ceph

alos

porin

s al

one

than

for

ce

phal

ospo

rins

plus

mac

rolid

es o

r flu

oroq

uino

lone

s al

one

Exte

nsiv

e cl

inic

al t

rial e

xper

ienc

e to

doc

umen

t ef

ficac

yIn

crea

sing

res

ista

nce

by S

. pne

umon

iae

Fluo

roqu

inol

ones

plu

s ce

phal

ospo

rinM

ay in

crea

se a

ntim

icro

bial

act

ivity

aga

inst

S. p

neum

onia

eN

o do

cum

ente

d be

nefit

com

pare

d w

ith f

luor

oqui

nolo

ne a

lone

Mac

rolid

e pl

us c

epha

losp

orin

Cep

halo

spor

in p

rovi

des

bett

er in

vitr

o ac

tivity

aga

inst

S. p

neum

onia

e an

d m

acro

lide

adds

act

ivity

aga

inst

aty

pica

l age

nts

Dat

a su

gges

ting

that

the

mac

rolid

e–ce

phal

ospo

rin c

ombi

natio

n is

sup

erio

r to

mon

othe

rapy

in p

neum

ococ

cal b

acte

rem

ia a

re

unco

ntro

lled

and

inco

nsis

tent

Retr

ospe

ctiv

e an

alys

es d

emon

stra

te r

educ

ed m

orta

lity

for

this

com

bina

tion

com

pare

d w

ith s

ingl

e-ag

ent t

hera

py in

pat

ient

s w

ith p

neum

ococ

cal b

acte

rem

ia

and

for

empi

ric t

reat

men

t of

pne

umon

ia

Peni

cilli

n G

Pref

erre

d ag

ent

(alo

ng w

ith c

eftr

iaxo

ne, c

efot

axim

e an

d am

oxic

illin

) for

pro

ven

peni

cilli

n-su

scep

tible

str

ains

of

S. p

neum

onia

eLi

mite

d sp

ectr

um o

f ac

tivity

aga

inst

com

mon

pul

mon

ary

path

ogen

s ot

her

than

S. p

neum

onia

e

Publ

ishe

d ex

perie

nce

to d

ocum

ent

clin

ical

eff

icac

y is

ext

ensi

ve

New

ag

ents

Telit

hrom

ycin

Act

ive

in v

itro

agai

nst

mos

t S.

pne

umon

iae,

incl

udin

g m

acro

lide-

resi

stan

t st

rain

s. A

lso

activ

e ag

ains

t H

. inf

luen

zae

and

atyp

ical

age

nts

Ava

ilabl

e in

ora

l for

mul

atio

n on

ly

Favo

rabl

e ph

arm

acok

inet

ics

Clin

ical

tria

l dat

a ar

e co

nsid

ered

pre

limin

ary

Clin

ical

tria

ls in

CA

P sh

ow e

quiv

alen

ce t

o hi

gh-d

ose

amox

icill

in, m

acro

lides

and

tr

ovaf

loxa

cin,

incl

udin

g C

AP

caus

ed b

y β-

lact

am-r

esis

tsan

t st

rain

s of

S.

pneu

mon

iae

Gem

iflox

acin

Mos

t ac

tive

of t

he ‘r

espi

rato

ry f

luor

oqui

nolo

ne’ a

gain

st S

. pne

umon

iae

in v

itro

Hig

h ra

te o

f ra

sh, e

spec

ially

in w

omen

age

d un

der

40 y

ears

and

w

ith u

se f

or m

ore

than

10

days

Clin

ical

tria

l dat

a fo

r C

AP

show

goo

d re

sults

Ava

ilabl

e on

ly in

ora

l for

mul

atio

n

Erta

pene

mC

linic

al e

ffic

acy

for

empi

ric t

reat

men

t of

CA

P co

mpa

rabl

e to

cef

tria

xone

Pare

nter

al f

orm

ulat

ion

only

Onc

e-da

ily p

aren

tera

l dos

ing

Inac

tive

agai

nst

atyp

ical

age

nts

and

less

act

ive

than

imip

enem

ag

ains

t P.

aer

ugin

osa

In v

itro

activ

ity a

gain

st S

. pne

umon

iae

is s

imila

r to

cef

tria

xone

and

cef

otax

ime

Line

zolid

Act

ive

in v

itro

agai

nst

mos

t G

ram

-pos

itive

bac

teria

, inc

ludi

ng

mul

tidru

g-re

sist

ant

S. p

neum

onia

e an

d S.

aur

eus

Lack

s es

tabl

ishe

d ac

tivity

aga

inst

aty

pica

l age

nts

Effic

acy

com

para

ble

to c

eftr

iaxo

ne f

or t

reat

men

t of

P. p

neum

onia

Alte

rnat

ive

antim

icro

bial

s ha

ve m

ore

esta

blis

hed

role

in C

AP

Ora

l and

par

ente

ral f

orm

ulat

ions

Con

cern

reg

ardi

ng a

buse

, exp

ense

, dru

g–dr

ug in

tera

ctio

n an

dto

xici

ty

Tab

le 7

. Em

pir

ical

an

tib

acte

rial

sel

ecti

on

fo

r C

AP:

ad

van

tag

es a

nd

dis

update on the use of the macrolides for community-acquired respiratory tract infections · 2020. 7....

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