European Respiratory Society
Antibiotics and the lung

To serve its primary function of gas exchange, the lung is the organ with the largest epithelial surface area in continuous contact with the external environment. The upper and lower airways of humans are repeatedly exposed to airborne particles and microorganisms. Infectious respiratory disorders are therefore an important part of our daily activities as practising physicians. Furthermore, the management of these infectious diseases continues to evolve. Physicians are continuously confronted with new challenges in the cost-effective management of these infectious diseases. Antibiotic treatment is a key factor in the treatment schedules of these diseases. However, the efficacy of antibiotics traditionally used in the treatment of respiratory infections is increasingly compromised by the emergence of resistant bacteria. This issue of the Monograph covers basic knowledge about treatment with antibiotics, state-of-the-art information about a variety of different classes of antibiotics, economic aspects of antibiotic treatment and the epidemiological consequences of antibiotic use in the community.

  • European Respiratory Society Monographs
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    Correspondence: G.W. Amsden, Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326, USA.,

    Although the concepts of using an antibiotic's pharmacokinetics and pharmacodynamics to adjust dosing and using the susceptibility of a pathogen to a specific drug have been in the literature for >40 yrs, it has not been until the last 10–15 yrs that great strides have been made using these theories. A variety of dosing concepts have been derived that when applied are thought to help ensure more optimal clinical and bacteriological outcomes in patients. While some of these have started to be applied prospectively in daily practice such as using higher doses of β‐lactams against pneumococci with decreased susceptibility to penicillin, others may only represent a starting point for more research. This is especially true when attempts are made to apply these serum concentration-based concepts to drugs whose infection site concentrations are not in equilibrium with corresponding serum concentrations, as is seen with fluoroquinolones and macrolides. Along with additional research, to hone some of these dosing optimisation concepts, logistic issues may in the end limit these concepts to being applied in a population-based manner rather than as a true individualsed one.

  4. Page 13
    Correspondence: M. Cazzola, Via del Parco Margherita 24, 80121 Naples, Italy.,

    The efficacy of antibiotic treatment in bacterial lower respiratory tract infections (LRTIs) is partly dependent on the levels reached by the drug and on the length of stay at the site of infection. The place where the infection develops inevitably influences the clinical presentation. Unfortunately, the in vivo determination of antimicrobial concentrations at these sites is plagued with several methodological difficulties. Moreover, a severe obstacle is also encountered when attempting to compare pulmonary pharmacokinetics of different antimicrobials using data present in literature as different studies conducted on a single therapeutic agent differ in terms of methods used, dosage, therapeutic interval, and route of administration. Although the presence of a correlation between antibiotic levels at the site of infection and their clinical efficacy in LRTIs has not been clearly demonstrated due to these difficulties, drugs with higher intrapulmonary concentrations would have greater clinical efficacy.

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    Correspondence: M.T. Labro, NSERM U479, CHU X. Bichat, 16 rue Henri Huchard, Paris, 75018, France.

    The respiratory tract is constantly confronted with a multitude of noxious agents that abound in the environment, including a variety of microbial pathogens. To cope with permanent aggressions, the lung maintains a highly sophisticated defence system. However, excessive or inappropriate inflammatory responses may have a role in the pathogenesis of a number of pulmonary diseases including asthma, diffuse panbronchiolitis, cystic fibrosis and chronic obstructive pulmonary disease, particularly emphysema. Outside their antibacterial activity, it is obvious that antibacterials can display immunomodulating properties that can have therapeutic importance. The modulation of immune functions is receiving major attention, particularly in the field of inflammatory diseases. Two nonmutually exclusive hypotheses are forwarded to explain the anti-inflammatory activity of various antibiotics. Firstly that inflammation is triggered by a latent/chronic infection due to a pathogen susceptible to the antibiotic, which generally, resides within host cells and secondly that antibiotics modulate one (various) components of the inflammatory response. Because phagocytes by uncontrolled use of the same mechanisms as those used to destroy pathogens (i.e. oxidative species, enzymes and mediators) can have detrimental effects on the host itself, they have a fundamental role in the pathogenesis of exaggerated inflammatory responses and are critical targets for the immunomodulatory effects of antibacterial agents.

    The most important family of antibacterial agents of recognised value in this context are cyclines, ansamycins and macrolides.

  6. Page 64
    Correspondence: T.T. Bauer, University Hospital-Bergmannesheil, Medical Clinic III, D-44789, Bochum, Germany.

    Antibiotic and especially β‐lactams are frequently used in the treatment of pulmonary infections, ranging from exacerbation of chronic obstructive pulmonary disease to severe cases of nosocomial pneumonia. The comprise of three major groups, penicillins, cephalosporins and carbapenems agents with broad spectrum antimicrobial activity. This article is comprised of the major features associated with the three groups of β‐lactams and points out special capabilities of the most frequently used drugs. Indications of β‐lactam use in infective lung disease is rehearsed and selected clinical trials in this field are referenced.

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    Correspondence: J. Dorca, Pneumology Dept, Bellvitge University Hospital, Feixa llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.

    During recent decades the macrolides have occupied a central position in the management of different types of lower respiratory tract infections. This is due in some part to their excellent activity and safety both in the adult and in the paediatric population. Recently, however, the development of pneumococcal macrolide antibiotic resistance in some geographical locations, in combination with the introduction of new antibiotics displaying higher activity against certain specific pathogens, has challenged this role.

    In acute bronchitis, where antibiotics are not systematically needed, macrolides have the potential to be the alternative choice in selected cases, considering the different pathogens involved, due to its simplistic dosage regimen and relative safety. Considering the acute exhacerbations of chronic bronchitis, azithromycin and clarithromycin may be useful in patients with mild to moderate chronic obstructive pulmonary disease (COPD). Other alternatives such as amoxicillin/clavulanate or quinolones, which are more active against Haemophilus influenzae, should be preferred for the treatment of bronchial infection in the group of COPD patients with the poorest lung function, more debilitated in their general condition and presenting frequent episodes of infectious exacerbation.

    Owing to their combined activity against the pneumococcus and the atypical bacteria, the macrolides have been the cornerstone for the management of community-acquired pneumonia (CAP). Today, the macrolides remain as a basic alternative for mild-to-moderate CAP managed in an outpatient context in areas where high level macrolide resistance is low. However, the ketolides and new quinolones should be preferred in countries where this type of resistance is important. In the more severe CAP, more studies are needed comparing the classical association β‐lactam plus macrolide against monotherapy with a parenteral new quinolone.

    Finally, in addition to its antimicrobial activity, the macrolides display some unique anti-inflammatory properties that could be of practical use in the management of chronic bronchial infections affecting cystic fibrosis and bronchiectasis.

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    Correspondence: H. Lode, Dept of Chest and Infectious Diseases, City Hospital Emil Behring, Affil. Free University of Berlin, Zum Heckeshorn 33, 14109 Berlin, Germany.

    The newer fluoroquinolones levofloxacin, gatifloxacin, moxifloxacin and gemifloxacin offer major therapeutic advances compared with previous antibacterial agents in the treatment of lower respiratory tract infections (LRTIs). They provide a broad antibacterial spectrum combined with pharmacokinetic advantages that include excellent penetration into respiratory tissue and high bioavailability with oral therapy. In overall they can be considered safe and well tolerated. Therefore current treatment guidelines for management of community-acquired LRTIs recommend these agents for empirical therapy in several clinical situations. In guidelines for management of hospital-acquired pneumonia (HAP) only ciprofloxacin is recommend, although efficacy of levofloxacin has been recently evaluated in one clinical trial. However the use of the newer fluoroquinolones will be restricted in severe (HAP) due to limited efficacy against Gram-negative bacteria and methicillin-resistant Staphylococcus aureus.

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    Correspondence: R. Cosentini, Emergency Medicine Department, IRCCS Ospedale Maggiore di Milano, Via F. Sforza 35, 20122 Milan, Italy.

    Over the past 20 yrs resistance has steadily compromised standard therapy of bacterial lower respiratory tract infections. The spread of methicillin-resistant staphylococci, and penicillin/macrolide-resistant pneumococci, the emergence of glycopeptide-resistant staphylococci, and the increasing emergence of erythromycin-resistant strains of Streptococcus pyogenes underline the need for therapeutic alternatives. There is an urgent need to reduce antibiotic pressure on the multiresistant Gram-positive bacteria and prevent their dissemination. Nonetheless, such strategies may simply delay the emergence of fully resistant organisms, so that the development of new, effective drug therapy is also a priority. Recent efforts have focused both on the development of derivatives based on previously existing compounds, and the more complex creation of innovative antibiotic classes. However, difficulties in developing truly innovative drugs are a major problem. Currently, oxazolidinones, novel glycopeptides, streptogramins, glycylcyclines, and lipopetides hold promises for the development of a new armamentarium of highly effective compound towards multiresistant Gram-positive bacteria.

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    Correspondence: G.C. Schito, Institute of Microbiology, University of Genoa, Genoa, Italy.

    In recent years one of the more alarming aspects in the field of clinical microbiology has been the dramatic increase in the incidence of resistance to antibacterial agents among pathogens causing nosocomial as well as community-acquired infections. Profound geographical differences exist in the incidence of resistance among pathogens causing community-acquired lower respiratory tract infections, only some of which can be explained by the local use of antibiotics. In some cases increased resistance has been shown to be caused by the spread of one or more resistant clone.

    Streptococcus pneumoniae, one of the main organisms implicated in respiratory tract infections, has developed multiple resistance mechanisms to fight the effect of the most commonly used antibiotics. Insusceptibility to both penicillin and macrolides among strains of S. pneumoniae is seen worldwide but is highly variable from country to country, with the eastern countries usually more affected. Increasing antibiotic resistance has been reported for other major respiratory tract pathogens, including Haemophilus influenzae and Moraxella catarrhalis. A high percentage of M. catarrhalis strains (>90%) produces β‐lactamase, while β‐lactamase production among strains of H. influenzae rarely reaches more than 30% around the world.

    In contrast to the extraordinary number of microbiological studies documenting the patterns of antimicrobial drug susceptibility, very few studies have analysed the clinical relevance of antibiotic resistance and the extent of the challenge presented by this phenomenon remains unclear. Further research is required to establish the clinical impact of antibiotic resistance in respiratory pathogens.

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    Correspondence: L.A. Mandell, Henderson Hospital, 5th Floor 40 Wing, 711 Concession Street, Hamilton Ontario, L8VIC3, Canada.

    This chapter deals with community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and acute exacerbations of chronic bronchitis (AECB). It first considers those situations which require the use of antibiotics before briefly discussing the various issues surrounding the streamlining, de-escalation and shortening of treatment as well as situations that do not require the use of antibiotics. Situations that require antibiotics the need for streamlining, de-escalation and shortening of treatment as well as situations that do not require antibiotic use will be discussed in different degrees of details.

    CAP can be treated either with directed therapy or using empirical therapy. The former involves use of a narrow spectrum antibiotic directed against a known pathogen whereas the latter essentially is an educated guess involving broader spectrum agents directed against a variety of pathogens in the hope that the correct one will be eradicated. While there is no question that the former is more desirable the latter is almost always the one used.

    Various treatment guidelines are currently available including those from the Infectious Diseases Society of America (IDSA), the American Thoracic Society (ATS) and the Canadian Infectious Disease Society/Canadian Thoracic Society (CIDS/CTS). The Canadian Guidelines are presented in tabular format.

    Antimicrobial resistance has become a legitimate concern over the past 1–2 decades and this issue is discussed in some detail. Hospital-acquired pneumonia (HAP) is the second most common nosocomial infection and ventilator-associated pneumonia (VAP) represents a subset of HAP. Here too, a large number of potential pathogens may be encountered but a “core group” are felt to be the most likely pathogen in most cases.

    Just as with CAP, empirical therapy is often caused in HAP as well. The reasons for this are that HAP/VAP may be associated with significant morbidity and mortality and there are good data to show that inappropriate initial therapy or delayed appropriate therapy are associated with increased mortality. The treatment recommendations for HAP and VAP represent slight modification of the original CIDS and ATS recommendations.

    Again various resistance issues are discussed particularly as they relate to Gram-negative pathogens. For AECB the definition and classification is discussed and major and minor criteria are proposed. The major criteria are: 1) increased cough and volume of sputum; 2) increased purulence of sputum; and 3) increased dyspnoea while the minor criteria include: wheeze, sore throat, cough and symptoms such as nasal congestion or discharge. The presence of two major symptoms or one major and one minor for at least 2 consecutive days define an acute exacerbation. A variety of pathogens may be responsible for flare ups but it has become fairly clear that the aetiological agent will vary depending upon pulmonary function.

    A number of treatment schemes have stratified patients according to severity of underlying disease and risk of failure with antibacterial therapy. British, German and Canadian Guidelines have been proposed based upon such a stratification scheme. The Canadian Guidelines are presented in one of the papers.

    Initial regimens are often, by necessity, more broad spectrum than may be required. They may be streamlined or de-escalated allowing a narrowing of the spectrum of activity thereby reducing antibiotic selection pressure and hopefully minimizing resistance without compromising patient care. A variety of approaches including antibiotic practice guidelines, critical pathways and protocols have been helpful. Also automated and partially nonautomated approaches have also been of use.

    The use of shorter course treatment is being looked at very carefully in CAP, HAP and AECB and data already exists showing that treatment may be shortened in all three of these disease entities.

    Finally some situations which do not require antibiotic use were also considered. These include Type III AECB and acute bronchitis. The former consists of only one of the cardinal manifestations and the latter is typically of viral aetiology.

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    Correspondence: T. Welte, Dept of Pneumology and Intensive Care Medicine, University of Magdeburg, Leipziger 44 Street, 39120 Magdeburg, Germany.

    Respiratory infections are among the most frequent reasons for prescribing antibiotics. Despite the widely accepted consensus that antibiotic therapy is not appropriate for the treatment of most cases of acute bronchitis, sinusitis and pharyngitis, ∼50 % of patients diagnosed with upper respiratory tract infections are treated with these drugs. Several studies strongly support the hypothesis that the excessive use of antibiotics in such patients has contributed to the emergence and spreading of antibiotic resistance. Countries with the highest per capita antibiotic consumption have the highest frequency and patterns of resistance. The emergence of penicillin-resistant Streptococcus pneumoniae is related to the consumption of penicillin, cephalosporinines and macrolides. Macrolid prescription correlates significantly with the level of macrolid resistance of group A streptococci. Oral cephalosporin use might be associated with the increase of β‐lactamase producing strains of Moxarella catarrhalis and Haemophilus influenzae. This resulted in progressive use of fluorchinolones in outpatients, which is associated with resistance in S. pneumoniae, Escherichia. coli and other Gram-negative bacteria. Paediatric bacterial isolates are more often resistant to various antimicrobial agents than isolates from adult patients. This might be due to more frequent use of antibiotics in children and extensive child-to-child transmission.

    The three major reasons for the rise in microbial resistance rates which include: 1) the widespread application of antibiotics in animals; 2) the growing use of antibiotics in all developed countries; and 3) the fast spread of resistances due to travelling and globalisation, are discussed in this chapter. The increasing use of antibiotics reflects a shift in the attitude of the communities towards disorders and diseases. Prevention programs have to be multimodal and integrative. Infections of the respiratory tract play an important role for further developments, since they have an enormous medical and economical impact. Therefore pulmonologists should be integrated in the further conception of such programmes.

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    Correspondence: G. DiMaria, Dept di Medicina Interna e Medicina Specialistica, Sezione Malattie Respiratorie, University of Catania, Italy.

    Lower respiratory tract infections (LRTIs), including community-acquired pneumonia and acute exacerbation of chronic bronchitis are common infectious diseases of human beings and represent a major cause of morbidity and mortality worldwide. Key pathogens associated with community-acquired LRTIs, include Streptococcus pneumoniae and other significant pathogens, such as Hemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa. Rates of antimicrobial use for the treatment of LRTIs have increased substantially during the past few decades and important progress in controlling LRTIs has been made. This progress is mostly explained by the introduction of a variety of classes of powerful antibiotics with improved pharmacokinetic and broad-spectrum activity against many common microbial pathogens.

    However, despite the development of novel antibiotic agents and the proliferation of guidelines and treatment recommendations, the management of bacterial LRTIs still represents a difficult task and an important challenge in clinical practice. This is partly due to the heterogeneity of this condition on both the etiological and clinical site. Major issues in the choice of antibiotic regimens for LRTIs include the identification of the pathogen, the occurrence of antibiotic resistance, the presence of specific risk factors and the severity of the condition.

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    Correspondence: F. Blasi, Institute of Respiratory Diseases, University of Milan, IRCCS Ospedale Maggiore Milan, Milan, Italy.

    Atypical pathogens are increasingly being implicated in the aetiology of lower respiratory tract infections (LRTIs) in both adults and children. The lack of simple, standardised diagnostic tests and the difficulty in differentiating infections due to atypical pathogens on clinical or radiological evidence alone, leads to under-recognition and potentially ineffective empirical treatment of these infections.

    A wide range of figures for the prevalence of Chlamydia pneumoniae and Mycoplasma pneumoniae in acute exacerbations of chronic bronchitis (AECB) have been reported in a number of publications. There is now a considerable weight of evidence for the pathogenic role of C. pneumoniae in AECB. Legionella spp. is not a common cause of AECB.

    chronic carriage of C. pneumoniae in patients with chronic obstructive pulmonary disorder, is associated with a higher rate of airway microbial colonisation, more severe functional impairment, and a greater propensity for the development of acute exacerbations. C. pneumoniae infection has been found to be common in chronic bronchitis and could contribute to the disease progression through its toxic effect on bronchial epithelial cells, with ciliostasis and increasing chronic inflammation through pro-inflammatory cytokine production.

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    Correspondence: M. Niederman, 222 Station Plaza N, Suite 509, Mineola, New York, 11501, US.

    Pneumonia is a cost-intensive illness, especially if managed in the hospital rather than in the outpatient setting. In order to treat this illness in a cost–effective fashion, a variety of interventions are necessary. One approach is to reduce the number of patients admitted to the hospital, however, the optimal way to do this has not yet been defined. Alternatively, other aspects of care can be targeted. These include providing initial intravenous therapy in a timely fashion, which can reduce disease-associated mortality and the length of stay in hospital. Early attention to the social and non-pneumonia medical needs of patients can help facilitate a safe and early discharge. The use of adequate therapies that are consistent with the existing guidelines, along with the provision of adequate cover for atypical bacterial pathogens, can improve outcomes and reduce costs. For selected patients, monotherapy with a macrolide or a selected quinolone can lead to a more cost-effective outcome. Finally, a focus on rapid switch from intravenous to oral therapy, along with efforts at minimising the duration of therapy, can reduce the cost, length of stay and some of the complications of pneumonia.

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    Correspondence: A. de Roux, Pneumologie I, Dept of Infectious Diseases and Immunology, Chest City Hospital Heckeshorn, Zentralklinikum Emil von Behring, Zum Heckeshorn 33, 14109, Berlin, Germany.

    In view of the emerging antibiotic resistance of microorganisms responsible for nosocomial pneumonia the choice of the appropriate antibiotic is a crucial issue. Although better treatment options, like new broad spectrum antibiotics are available, antimicrobial resistance is increasing worlwide. Therefore the clinician depends on guidelines to choose the appropriate antibiotic substance, as early antibiotic treatment is crucial for favourable outcome and the initial antimicrobial therapy for hospital acquired pneumonia (HAP) must always be empirical. The following aspects should be considered: 1) severity of the pneumonia; 2) time point of occurrence; and 3) specific risk factors. Further to this the selection of antimicrobial agents has to consider local microbial and resistance patterns. As regards the aetiology of HAP in general a high rate of Gram-negative bacteria like Gram-negative rods (mostly Escherichia coli, Klebsiella spp., Enterobacter spp., Serratia spp. Proteus spp.), as well as potentially multiresistant pathogens like Pseudomonas aeruginosa, Acinetobacter spp. and Stenotrophomonas spp. have been repeatedly reported and are responsible for 55–85% of HAP cases. Gram-positive bacteria as Staphylococcus aureus have increasingly gained importance being involved in 20–30% of HAP events. Two promising drugs have been investigated in nosocomial pneumonia due to Gram-positive pathogens, quinopristin/dalfopristin and linezolid. Linezolid offers some clear advantages compared to glycopeptides that have been one of the last therapeutic options for infections due to multiresistant Gram-positive microorganisms, including methicillin-resistant S. aureus.

    Some aspects of antibiotic treatment are still under controversial discussion as the duration of antibiotic treatment, the status of aminoglycosides or the role of monotherapy. However any antimicrobial treatment regimen exhibits a specific selection pressure. As a consequence past antimicrobial treatment policies lead to specific, locally differing microbial and resistance patterns. Therefore it is evident that recommendations for initial empirical antimicrobial treatment must be flexible enough to get modified according to local findings.

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    Correspondence: T. Mazzei, Dept of Preclinical Pharmacology, University of Florence, Florence, Italy.

    Antibacterial drug interactions are an important aspect of the safety profile of these drugs, though they are often forgotten or underestimated by physicians. Different antibiotics may have a potential risk of pharmacological drug interactions, which can be classified as either pharmacodynamic or pharmacokinetic. The former are rare and are mostly limited to the potentiation of neuromuscular blocking effects by aminoglycosides and to either central nervous system adverse drug reactions or cardiac QT interval prolongation, due to the combination of fluoroquinolones either with some nonsteroidal anti-inflammatory drugs or cisapride. On the contrary, the pharmacokinetic drug interactions are relatively common, may concern all the different kinetic phases, and may result in clinically relevant consequences. Drug interactions involving antibiotics may impair their pharmacokinetics or may induce major changes in the kinetic parameters of co-administered drugs. Many clinically relevant interactions of macrolides, fluoroquinolones, rifampin or rifabutin depend on modifications of the biotransformation of different compounds, involving the cytochrome P450 system. This chapter will focus on the mechanisms and clinical relevance of the most important drug interactions that involve the major classes of antibacterial agents commonly used in the treatment of lower respiratory tract infections.

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    Correspondence: E Rubinstein, Infectious diseases Unit, Sheba Medical center, Tel Hashomer, 52621, Israel.

    Community-acquired pneumonia (CAP) is a common disease with a substantial morbidity and mortality. It is believed that appropriate and timely antibiotic therapy can improve the outcome of pneumonia. Therefore, many professional societies have composed guidelines that take into account the various epidemiological microbiological features of pneumonia pathogens, demographical characteristics of the patients, pharmcokinetic and pharmacodynamic characteristics of the antibiotics to be used and the associated costs of hospitalisation and treatment. Nevertheless pneumonia pathogens are acquiring new resistances and new drugs with improved therapeutic features are on the verge of being introduced into clinical practice. Linezolid, daptomycin, quinupristin/dalfopristin, oritavancin and dalbavancin are all active against Gram-positive pathogens including methicillin resistant Staphylococcus aureus, acquired nosocomially and penicillin resistant Streptococcus pneumonia, as well as other respiratory pathogens resistant and susceptible to conventional drugs. These drugs are primarily used systemically in hospitalised individuals with moderate-severe pneumonia. Telithromycin and cethromycin are both ketolides appropriate for the therapy of S. pneumoniae and other pathogens and are primarily oral agents and aimed for community therapy of such mild-moderate infections. As the aetiology of a patient who presents with CAP is rarely known, therapy will have to rely on the clinical presentation of the patient and the epidemiological data. The exact definition of the place of each of the agents in the management of pneumonia has not yet been defined but in future years studies and epidemiological developments are expected to outline for the appropriate use of these agents.