Antibiotics and the lung

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.

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.

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.

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.

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.

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.

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.

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.