Diego Viasus , Carolina Garcia-Vidal , and Jordi Carratala
Purpose of review
Community-acquired pneumonia (CAP) is a major public health problem all over the world. The increasingnumber of antibiotic-resistant bacteria is a matter of concern for physicians when choosing antibiotictreatment in patients with CAP. This review focuses on the current recommendations of antibiotic treatment,recent information concerning antibiotic resistance of pathogens, and the advances in antibiotic therapy inthe field of CAP.
Recent findings
A significant increase in the frequency of resistance to the antibiotics commonly used against causativepathogens of CAP, such as b-lactams or macrolides, has been reported in recent years. At present, theprevalence of fluoroquinolone resistance in Streptococcus pneumoniae remains low. Community-acquiredmethicillin-resistant Staphylococcus aureus and influenza A(H1N1)pdm09 have been reported as causes ofsevere CAP. Several newly-developed antibiotics, including cepholosporins, ketolides and quinolones,present marked activity in vitro against the main causative pathogens of CAP. Many randomized controlledtrials have demonstrated equivalent efficacy of the newer antibiotics compared with conventionalantimicrobial therapy in mild-to-moderate CAP.
Summary
An increase of resistance to the antibiotics used in CAP has been documented over the years. Several newantibiotics have been developed for treating CAP, with promising results. However, data regarding theirefficacy and safety in patients with severe CAP are lacking.
aDepartment of Infectious Diseases, Hospital Universitari de Bellvitge,Bellvitge Biomedical Research Institute (IDIBELL) and bDepartment ofClinical Sciences, University of Barcelona, Barcelona, Spain
Correspondence to Professor Jordi Carratala, Department of InfectiousDiseases, Hospital Universitari de Bellvitge. Feixa Llarga s/n, 08907,L’Hospitalet de Llobregat, Barcelona, Spain. Tel: +349 326 076 25; fax:+349 326 076 37; e-mail: [email protected]
Curr Opin Pulm Med 2013, 19:209–215
DOI:10.1097/MCP.0b013e32835f1c0b
INTRODUCTION
Community-acquired pneumonia (CAP) is one ofthe leading causes of death worldwide and is associ-ated with a high economic burden [1]. Although themortality rate in patients with CAP was dramaticallyreduced by the introduction of antibiotics in the1950s, it has not decreased greatly since that time.Recent studies have shown overall mortality rates of8–15% [2,3]; however, mortality in patients withCAP who require ICU admission can reach 30% [4].
Current CAP guidelines recommend stratifyingpatients into risk groups and selecting appropriateempirical antimicrobial therapy depending on thepresence of specific factors [5–7]. In previous studies,guideline-concordant therapy for CAP has been associ-ated with improved health outcomes and reductionsin resource use [8,9]. Nonetheless, treatment failurespersist and in some cases may be due to the emer-gence of antimicrobial resistance or new pathogenscausing CAP [10]. In this context, the lack of newantibiotics constitutes a major cause for concern.
illiams & Wilkins. Unaut
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This review will focus on the current recommen-dations for antibiotic treatment, recent findingsregarding antibiotic resistance among respiratorypathogens, and advances in antibiotic therapy inthe field of CAP.
CURRENT RECOMMENDATIONS FORANTIBIOTIC TREATMENT
Treatment guidelines for the management of CAPhave been endorsed by various organizations. The
horized reproduction of this article is prohibited.
� An increase of resistance to the antibiotics used in CAPhas been documented during the last years.
� Several new antibiotics have been developed fortreating CAP, including cephalosporins, ketolides, andquinolones, with promising results.
� Data regarding efficacy and safety of newer developedantibiotics in patients with severe CAP are lacking.
Infectious diseases
most representative are the consensus guidelinesof the Infectious Diseases Society of America andthe American Thoracic Society (IDSA/ATS) [5], theBritish Thoracic Society [7], and the EuropeanRespiratory Society and European Society forClinical Microbiology and Infectious Diseases [6].These guidelines state that the selection of anti-microbial regimens for empirical therapy in CAPshould be based on risk group stratification andthe most likely causative pathogens. Other factorsin the choice of antimicrobial agents in CAPare pharmacokinetics/pharmacodynamics, allergy,intolerance, previous use of antibiotics, compliance,cost, potential adverse events and knowledge oflocal pathogen susceptibility. Guideline recommen-dations are generally for a class of antibiotic ratherthan a specific drug. The goals of antimicrobialtreatment are to reduce or eradicate the bacterialload in order to achieve clinical success, reduceassociated morbidity and mortality, and minimizethe potential for development of resistance [11].
Although CAP may be caused by numerouspathogens, a limited number of agents areresponsible for most cases. Streptococcus pneumoniaeremains the most common cause of CAP acrossall severities. Haemophilus influenzae and atypicalagents such as Mycoplasma pneumoniae and Chlami-dophila pneumoniae are usually associated with CAPnot requiring ICU admission, whereas CAP dueto Staphylococcus aureus, Gram-negative pathogens,and Legionella species is more likely to require ICUadmission [5–7]. Recently, community-acquiredmethicillin-resistant S. aureus (CA-MRSA) andinfluenza A(H1N1)pdm09 have been reported tobe significant causes of severe CAP [12,13].
Based on guideline recommendations [5–7] forhospitalized patients in the general medical ward,monotherapy with a respiratory fluoroquinoloneor combination therapy with a b-lactam and amacrolide is generally recommended. For severecases requiring ICU admission, antimicrobial selec-tion will depend on the presence of risk factors forPseudomonas or CA-MRSA infections. Combination
Resistance to antibiotics that are commonly usedin CAP poses a major problem when choosingempirical therapy. Resistance patterns presentlarge geographical variations. Therefore, antibioticrecommendations must be modified on the basis oflocal susceptibility patterns.
Streptococcus pneumoniae
Changes in antimicrobial use, the introductionof the pneumococcal conjugate vaccine, or otherconfounding variables may have markedly alteredS. pneumoniae resistance patterns [14]. Between1998 and 2009, 14 934 S. pneumoniae isolates werecollected from medical centers across the UnitedStates as part of the SENTRY Program [14].Seventy-two percent of the isolates were collectedfrom upper and lower respiratory tract infectionsand the majority of the others were derived frombacteremias. That article reports striking falls(P<0.05) in susceptibility rates for b-lactams (from2004 to 2009, susceptibility rates decreased from93.8 to 82.7%, 94.7 to 84.1%, and 97.4 to 87.5%for amoxicillin/clavulanate, penicillin, and ceftria-xone, respectively). Macrolide (erythromycin) andclindamycin susceptibility rates also fell markedlyfrom 82.2 to 60.8% and from 96.2 to 79.1%,respectively. Regarding macrolides, in a Europeanstudy high frequencies of resistance (>20%) wererecorded in Belgium, Bulgaria, Cyprus, Finland,France, Hungary, Italy, Poland, Portugal, Romaniaand Spain; low frequencies (<5%) were reported inDenmark, Norway, Sweden, and United Kingdom[15].
Data from the AWARE Ceftaroline SurveillanceProgram (2008–2010) [16] showed that, among3329 isolates of S. pneumoniae from nine US Censusregions (71 medical centers), the frequenciesof resistance were 1.7 and 21.1% for parenteraland oral penicillin (nonmeningitis), respectively.Slight increases in resistance to erythromycin(38.4 to 41.7%) and levofloxacin (0.6 to 1.09%) weredocumented.
Reports in some countries have suggestedthat fluoroquinolone resistance in S. pneumoniaemay be increasing [17]. Among 1349 S. pneumoniaeinvasive isolates during 2007–2009 in Madrid,Spain, 45 levofloxacin-resistant strains [3.3%,all showing a levofloxacin minimum inhibitory
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concentration (MIC) of �32 mg/ml] were detected.Levofloxacin resistance in that study was limitedto a few serotypes and was due mainly to aclonal spread of serotype 8 ST63 (Sweden 15A-25).These isolates were fully susceptible to penicillinand resistant to erythromycin and clindamycin.In contrast, fluoroquinolone activity, measuredby levofloxacin susceptibility, ranged from 98.7(2002) to 99.8% (1998) with an overall decreasein susceptibility of only 0.6% in the 12 yearsmonitored in the SENTRY Program in theUnited States. However, as a measure of possiblesingle-step mutational resistance, the proportion ofisolates with ciprofloxacin MIC results �4 mg/mlwas relatively stable (range: 1.5–4.9%) [14].Recently, the CAPNETZ Study Group documentedlow prevalence of fluoroquinolone-resistant strainsand resistance precursor strains in S. pneumoniaefrom patients with CAP in Germany [18]. None ofthe isolates exhibited fluoroquinolone resistance,1.2% of the isolates contained a first step mutation,and 6.7% exhibited an efflux phenotype.
Haemophilus influenzae
Among 1545 isolates of H. influenzae in theAWARE Ceftaroline Surveillance Program (2009–2010) [16], 26.3% were nonsusceptible to ampicil-lin. Slight increases in resistance to azithromycin(0.8–1.4%) and trimethoprim/sulfamethoxazole(19.4 vs. 24.4%) were reported during thestudy period. Moreover, according to the BritishSociety for Antimicrobial Chemotherapy (BSAC)Working Parties on Resistance Surveillance in theUnited Kingdom [19], over 90% of the H. influenzaeisolates were susceptible to most of the anti-microbials tested, the exceptions being ampicillin(84.6% susceptible), trimethoprim (84.0%), cefuro-xime (82.9%), amoxicillin (77.2%) and cefaclor(11.7%).
Mycoplasma pneumoniae
M. pneumoniae showing resistance to macrolideshas been increasingly isolated in clinical samplesfrom pediatric and adult patients with CAP. Theemergence of macrolide-resistant isolates has beenreported in Japan, France, United States, Denmark,and China (rates of >40% in Japan, 80–90% inChina, and 3–10% in Europe and the United States)[20,21]. In a recent study, macrolide-resistantM. pneumoniae genotypes were not found in114 M. pneumoniae-positive specimens obtainedfrom a collection of 4390 samples in patients withacute respiratory tract infections in the Netherlands[22].
CA-MRSA strains are primarily associated with skinand soft tissue infections. Increasingly, however,they are being recognized as a cause of more invasiveinfections including severe CAP. Until very recently,most data on CAP caused by MRSA were provided bycase series. Studies conducted in the United Statesand Europe have reported mortality rates more than50% [13,23].
In a retrospective Australian study of 16 caseswith CA-MRSA and CAP [24] and age range11 months to 86 years, the most common radio-logical presentation included multilobar consolida-tion, necrotizing consolidation and empyema.There was a delay in initiation of appropriateantimicrobial treatment (range: 18 h to 11 days)after presentation. Seven patients required ICUsupport and three patients died of complicationsfrom pneumonia, all within 72 h of presentation.Moreover, Moran et al. [25] performed a prospectiveobservational study to determine prevalence andclinical features, and to identify factors associatedwith MRSA-related CAP in adult patients. MRSA wasidentified in 14 patients (2.4%; range by site: 0–5%)and in 5% of patients admitted to the ICU.Two (14%) MRSA pneumonia patients died. Featuressignificantly associated with isolation of MRSA(as compared with any other or no pathogen)included patient history of MRSA, nursing homeadmission in the previous year, close contactin the previous month with someone with a skininfection, multiple infiltrates or cavities on chestradiograph, and comatose state, intubation,receipt of pressors, or death in the emergencydepartment.
In a multicenter, prospective study of 885 epi-sodes of CAP, a single case of MRSA pneumoniawas detected, along with 10 methicillin-sensitiveS. aureus cases (MSSA) [26]. More recently, a Spanishstudy found 11 cases of MRSA out of 3523 patientswho presented with CAP [27].
Other pathogens
Among 456 isolates of Moraxella catarrhalis inthe AWARE Ceftaroline Surveillance Program(2009–2010) [16], 96.4% were nonsusceptible topenicillin. Other antibiotics showed low resistancefrequencies (<2.5%). According to the BSAC Work-ing Parties on Resistance Surveillance in the UnitedKingdom, for M. catarrhalis, resistance was solelydue to b-lactamase (prevalence over 91%) reducingsusceptibility to penicillins only [19]. Isolates weresusceptible to b-lactamase inhibitors, macrolides,and tetracyclines.
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Recently, severe CAP was documented as acomplication of influenza A(H1N1)pdm09 duringpandemic and postpandemic periods [12,28,29].Influenza A(H1N1)pdm09 is resistant to amanta-dine and rimantadine. Experience from pros-pective and retrospective cohorts suggested thatneuraminidase inhibitors were useful for improvingthe prognosis of patients admitted to hospitals,especially in those with more severe disease[30–32]. Oseltamivir resistance has remained lowduring postpandemic periods [33,34].
NEWLY DEVELOPED ANTIBIOTICS
Recently, several new antibiotics have been devel-oped with promising results in treating CAP.
Cephalosporins
Treatment with cephalosporins has been recom-mended as first-line empirical therapy for CAP.In last years, novel cephalosporins have beenevaluated for treating patients with CAP.
Ceftaroline
Ceftaroline is a fifth-generation parenteral cephalo-sporin that binds to penicillin-binding proteinsand prevents the synthesis of bacterial cell wall.It has activity against a broad spectrum of Gram-positive and Gram-negative pathogens, and is thefirst approved cephalosporin with in-vitro activityagainst MRSA [35]. The efficacy and safety ofintravenous ceftaroline (600 mg twice daily) forthe treatment for CAP has been evaluated in severalstudies. The randomized, double-blind, multicenter,phase III trials – FOCUS 1 and 2 [36
&&
,37&&
] –demonstrated high clinical cure (>82%) andnoninferiority of ceftaroline to ceftriaxone amongnon-ICU hospitalized adults with CAP [PneumoniaSeverity Index (PSI) risk classes III–IV]. Clinical curewas defined as total resolution or improvement ofall signs and symptoms of pneumonia to the extentthat no further antimicrobial therapy was necessary.Patients were also required to have absence of feverfor 24 h. However, patients with PSI risk classes I, IIand V were excluded, as were patients with severerenal impairment, immunosuppression, known orsuspected infection caused by atypical agents, riskfactors for MRSA or resistant pathogens, and thoseadmitted directly to the ICU. Thus, data regardingthe efficacy of ceftaroline for CAP in thesepopulations are lacking. Finally, these studies foundthat ceftaroline was well tolerated, with a safetyprofile similar to that of ceftriaxone and othercephalosporins.
The novel broad-spectrum parenteral cephalosporinceftobiprole has a microbiological activity againstmost typical bacterial pathogens causing CAP,including MRSA. The results of a multicenter,double-blind study in which 706 hospitalized adultswith severe CAP were randomized to ceftobiprole(500 mg by infusion over 120 min every 8 h) or toceftriaxone (with or without linezolid) were recentlypublished [38
&&
]. Patients who had received anti-microbial therapy for more than 24 h in the previous3 days and those with suspected or confirmedpneumonia due to atypical agents or aspirationwere excluded. No significant differences in base-line characteristics were found between thetreatment groups. However, approximately 22% ofpatients had a PSI score more than 90 in bothgroups. Regarding end points, ceftobiprole wasnot inferior to the comparator in terms ofclinical cure and microbiological eradication rates.Nevertheless, the incidence of treatment-relatedadverse events was higher in the ceftobiprole group(36 vs. 26%), mainly due to nausea and vomiting.There was no difference between the groupsregarding treatment discontinuation due to anadverse event.
Ketolides
The ketolides are a subclass of macrolides,which were designed specifically to overcomemacrolide-resistant respiratory pathogens. Recently,new ketolides have been developed for treatingCAP.
Cethromycin
Two phase III, double-blind, randomized, parallel-group, multicenter studies have been performedto evaluate the efficacy and safety of cethromycin,a novel oral ketolide agent, in patients with mild-to-moderate CAP [39
&&
]. In vitro, cethromycin hasmarked activity against the main causative patho-gens of CAP and has the ability to overcome bothefflux and methylation mechanisms of macrolide-resistance in S. pneumoniae. Patients were randomlyassigned in a 1 : 1 ratio to receive oral cethromycin(300 mg daily for 7 days) or clarithromycin (250 mgtwice daily for 7 days). In comparison withclarithromycin, these two noninferiority studiesdemonstrated the efficacy and safety of cethro-mycin in CAP patients. Importantly, the studypopulation only included ambulatory adults withCAP. Clinical cure and bacterial eradication rates didnot differ significantly between study groups in thetwo studies. Although cethromycin appeared to be
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more effective at treating S. pneumoniae bacteremicpatients, the low number of patients limits any firmconclusion regarding this issue. The most commonadverse events experienced in both treatmentgroups were diarrhea, nausea, dysgeusia, and head-ache. However, dysgeusia (metallic aftertaste) wassignificantly more frequent in the cethromycingroup. No patient met the criteria for Hy’s Law, apredictor of liver toxicity.
Solithromycin
Solithromycin exhibited favorable in-vitro potencyand a spectrum of activity against the bacterialpathogens most frequently isolated in CAP and skinstructure infections in 10 670 nonduplicated clinicalisolates from 52 medical centers in the United Statesand Europe [40]. In a recent safety data summary of aphase 1 report (171 healthy controls) and a phase 2report (64 CAP patients), no significant safetyconcerns were documented [41].
Quinolones
Quinolones play an important role in the manage-ment of CAP. Their use has been increasing over thelast decades in patients with CAP.
Nemonoxacin
Nemonoxacin, a novel nonfluorinated quinolone,exhibits potent in-vitro and in-vivo activityagainst CAP pathogens, including multidrug-resist-ant S. pneumoniae. In a randomized, double-blind,multicenter study that compared the safety andefficacy of nemonoxacin with levofloxacin inadult patients with mild-to-moderate CAP, a totalof 265 patients were included [42]. About 80–85% ofcases were PSI risk classes I–II. Oral nemonoxacin(750 mg and 500 mg) administered for 7 daysshowed clinical and bacteriological success rates ashigh as those of levofloxacin therapy. No significantdifference was noted in drug-related treatmentadverse events between the study groups. Amongthe adverse events, diarrhea, dizziness, and head-ache were the most frequently reported amongnemonoxacin-treated patients.
Zabofloxacin
A phase 2, double-blind, three-arm study performedin the United States to evaluate the safety andefficacy of two dosing regimens of zabofloxacin(a fluoroquinolone antibiotic) compared withlevofloxacin in CAP was recently completed andthe results are yet to be published [43]. In thepreliminary results of a double-blind, randomized,multicenter study in South Korea, zabofloxacin had
1070-5287 � 2013 Wolters Kluwer Health | Lippincott Williams & Wilk
the same clinical and microbiological cure ratesas moxifloxacin in adult patients with mild-to-moderate CAP [44].
JNJ-Q2
JNJ-Q2 is a novel, fluorinated 4-quinolone thatis being developed for the treatment of bacterialpathogens responsible for acute bacterial skininfections as well as respiratory infections, includ-ing CAP. In a recent study, JNJ-Q2 showedactivity against bacterial causative pathogens ofCAP [45].
KPI-10
Another antibiotic under evaluation and develop-ment is KPI-10, a new fluoroquinolone. In isolatescollected from medical centers in North America,Europe, Latin America, and Asia-Pacific between2008 and 2010, KPI-10 demonstrated potent activityagainst bacteria that are commonly the cause ofCAP, including CA-MRSA [46].
Other antibiotics
BC-3781 is an investigational semi-syntheticpleuromutilin antibiotic, which recently finisheda clinical phase 2 trial in acute bacterial skin andskin structure infections. BC-3781 was very activeagainst respiratory pathogens and its activity wasnot negatively influenced by resistance to otherantimicrobials [47].
CONCLUSION
In recent years, a significant increase in thefrequency of resistance to the antibiotics that arecommonly used to treat CAP has been documented.CA-MRSA and influenza A(H1N1)pdm09 have beenidentified as causes of severe CAP in the last years.Several new antibiotics, including cephalosporins,ketolides, and quinolones have been developed fortreating CAP, with promising results. Most of thecurrent randomized controlled trials have demon-strated the equivalent efficacy of newer antibioticswith regard to conventional antimicrobial therapy,mainly among patients with mild-to-moderate CAP.However, data regarding their efficacy and safety inpatients with severe CAP are lacking.
Acknowledgements
D.V. is the recipient of a research grant from the SpanishNetwork Research of Infectious Diseases (REIPI) (RD06/0008/0022). C.G.-V. is the recipient of a Juan de laCierva research grant from the Instituto de SaludCarlos III, Madrid, Spain.
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Conflicts of interest
There are no conflicts of interest.
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