REVIEW 10.1111/j.1469-0691.2005.01217.x Antimicrobial therapy for pulmonary pathogenic colonisation and infection by Pseudomonas aeruginosa in cystic fibrosis patients R. Cantón1, N. Cobos2, J. de Gracia2, F. Baquero1, J. Honorato3, S. Gartner2, A. Alvarez2, A. Salcedo4, A. Oliver5 and E. Garcı́a-Quetglas3 on behalf of the Spanish Consensus Group for Antimicrobial Therapy in the Cystic Fibrosis Patient* 1 Servicio de Microbiologı́a, Hospital Universitario Ramón y Cajal, Madrid, 2Unidad de Fibrosis Quı́stica, Hospital Vall d’Hebron, Barcelona, 3Servicio de Farmacologı́a Clı́nica, Clı́nica Universitaria, Pamplona, 4Sección de Neumologı́a Pediátrica, Hospital Materno Infantil Universitario Gregorio Marañón, Madrid and 5Servicio de Microbiologı́a, Hospital Son Dureta, Palma de Mallorca, Spain ABSTRACT Pseudomonas aeruginosa colonisation has a negative effect on pulmonary function in cystic fibrosis patients. The organism can only be eradicated in the early stage of colonisation, while reduction of bacterial density is desirable during chronic colonisation or exacerbations. Monthly, or at least 3-monthly, microbiological culture is advisable for patients without previous evidence of P. aeruginosa colonisation. Cultures should be performed at least every 2–3 months in patients with well-established colonisation, and always during exacerbations or hospitalisations. Treatment of patients following the first isolation of P. aeruginosa, but with no clinical signs of colonisation, should be with oral ciprofloxacin (15–20 mg ⁄ kg twice-daily for 3–4 weeks) plus inhaled tobramycin or colistin (intravenous treatment with or without inhaled treatment can be used as an alternative), while patients with acute infection should be treated for 14–21 days with high doses of two intravenous antimicrobial agents, with or without an inhaled treatment during or at the end of the intravenous treatment. Maintenance treatment after development of chronic P. aeruginosa infection ⁄ colonisation (pathogenic colonisation) in stable patients (aged > 6 years) should be with inhaled tobramycin (300 mg twice-daily) in 28-day cycles (on–off) or, as an alternative, colistin (1–3 million units twice-daily). Colistin is also a possible choice for patients aged < 6 years. Treatment can be completed with oral ciprofloxacin (3–4 weeks every 3–4 months) for patients with mild pulmonary symptoms, or intravenously (every 3–4 months) for those with severe symptoms or isolates with ciprofloxacin resistance. Moderate and serious exacerbations can be treated with intravenous ceftazidime (50–70 mg ⁄ kg threetimes-daily) or cefepime (50 mg ⁄ kg three-times-daily) plus tobramycin (5–10 mg ⁄ kg every 24 h) or amikacin (20–30 mg ⁄ kg every 24 h) for 2–3 weeks. Oral ciprofloxacin is recommended for patients with mild pulmonary disease. If multiresistant P. aeruginosa is isolated, antimicrobial agents that retain activity are recommended and epidemiological control measures should be established. Keywords Colonisation, cystic fibrosis, Pseudomonas aeruginosa, pulmonary colonisation, review, therapy Accepted: 7 April 2005 Clin Microbiol Infect 2005; 11: 690–703 Corresponding author and reprint requests: R. Cantón, Servicio de Microbiologı́a, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain E-mail: rcanton.hrc@salud.madrid.org *Grupo Español de Consenso del Tratamiento Antimicrobiano del Paciente con Fibrosis Quı́stica, con participación de la Sociedad Española de Fibrosis Quı́stica (SEFQ): J. Dapena, L. Máiz, C. Vázquez; Sociedad Española de Neumologı́a Pediátrica (SENP): C. Antelo, N. Cobos, S. Gartner, A. Salcedo; Sociedad Española de Enfermedades Infecciosas y Microbiologı́a Clı́nica (SEIMC): R. Cantón, L. Martı́nez-Martı́nez and A. Oliver; Sociedad Española de Quimioterapia (SEQ): F. Baquero, E. Garcı́a-Quetglas, J. Honorato; Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR): A. Álvarez, L. Borderı́as, J. de Gracia, M. Vendrell. INTRODUCTION The quality of life and life-expectancy of cystic fibrosis (CF) patients have improved considerably as a result of the control of bronchopulmonary bacterial colonisations and exacerbations [1–3]. Pseudomonas aeruginosa is the most prevalent organism in the airway colonisation of CF patients. Up to 30% of patients aged < 2 years can have positive P. aeruginosa cultures, and this figure rises to 80% in patients aged > 18 years [4]. P. aeruginosa colonisation, generally with
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 691 environmental isolates, occurs in a large number of patients before the age of 3 years [5]. The antibody response to this pathogen can be detected before cultures from respiratory tract samples are positive for this organism [6]. Colonisation occurs initially with low bacterial density nonmucoid morphotypes, which are usually susceptible to antimicrobial agents [6–9]. Later, and for a variable period of time, cultures tend to provide intermittent positive and negative results. P. aeruginosa colonisation clearly has a negative effect on pulmonary function [2,9–13]. Initially, colonisation is associated with a slight reduction in pulmonary function [14] but, as colonisation progresses, the cell density and the collective growth pattern of P. aeruginosa change and its capacity for survival improves. There is a tendency for it to form complex multicellular mucosa-attached aggregates (biofilms), and the organism generates a large quantity of alginate (mucoid phenotype), which results in an impediment to antimicrobial treatment and the phagocytic process [15]. Under these conditions, pulmonary colonisation by P. aeruginosa becomes chronic, with eradication becoming almost impossible. Thus, this pathogen can be eliminated only in the early stages [9]. A single basic P. aeruginosa genotype usually persists throughout the lifespan of a CF patient [16,17]. Despite this, there is genetic diversification in the different pulmonary compartments, with the appearance of multiple colony morphotypes, auxotypes and sensitivity profiles for antimicrobial agents [16]. A high bacterial load, and the change from a non-mucoid to a mucoid morphotype, correlate with the production of antibodies, accompanied by changes in pulmonary function parameters and a higher number of exacerbations [18–20]. In contrast, pulmonary function remains relatively stable in patients without mucoid morphotype conversion [21]. Hyper-mutability is one of the factors that characterises P. aeruginosa isolates from the lung of the CF patient [22]. This property accelerates the adaptation of this organism to the lung environment, which facilitates the chronicity of the process. Hyper-mutability also promotes the early emergence of variants with a mucoid morphotype and a modified antigenic structure [23,24], as well as the emergence of antimicrobialresistant mutants that can be selected during treatment, particularly in patients in an advanced stage of CF [11,25]. In such circumstances, the possibility of controlling colonisation with antimicrobial agents is severely hampered; thus, it is critical to stop the progression of the initial colonisation in order to avoid or delay the development of a chronic infection. MICROBIOLOGICAL ASSESSMENT OF P. AERUGINOSA BRONCHOPULMONARY COLONISATION ⁄ INFECTION Microbiological studies are generally performed using sputum samples. In the absence of sputum, retropharyngeal samples or bronchial aspirates should be obtained. However, the diagnostic value of the latter samples are inferior to that of sputum. Bronchoalveolar lavage should be reserved for assessing new treatments, or for investigating patients who fail to respond to treatment and have a poor evolution [26,27]. In patients with an early diagnosis of CF, it is essential to undertake continuous microbiological monitoring that will permit early detection of the initial P. aeruginosa colonisation. In these patients, the aggressive use of antimicrobial agents can prevent the persistence of colonisation and delay the establishment of chronic infection [9,28]. Mucoid morphotype P. aeruginosa is usually detected, as a marker, at the start of chronic infection [3]. This stage requires treatment for maintenance and ⁄ or exacerbations [2,29]. Although there is some controversy, microbiological monitoring in the chronic phase is essential for monitoring the colonisation pattern and for determining the susceptibilities of the different morphotypes [30]. In general, antimicrobial treatment of exacerbation is based on the findings of the most recent microbiological culture [31]. The practical ⁄ optimal frequency for performing a microbiological sputum culture is controversial [25,30–32]. A monthly, or at least 3-monthly, culture is advisable for patients without evidence of P. aeruginosa colonisation, in order to detect the initial colonisation event and initiate early treatment. Cultures should be taken from other patients whenever exacerbations present, or at least every 2–3 months in periods without exacerbations [26,31,32]. Gramstains of sputum are not generally recommended, as they give no relevant information for
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 692 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005 the CF patient [33]. The sputum sample must be liquefied and homogenised before plating. Microbial culture must include selective and differential media for isolating Staphylococcus aureus, Haemophilus influenzae and Burkholderia cepacia, as well as general and differential media for Gram-negative bacilli. Quantitative counting of the different pathogens is recommended whenever possible, particularly with exacerbations or when it is necessary to record treatment effectiveness [34]. All P. aeruginosa morphotypes identified in the culture should be tested for susceptibility to antimicrobial agents [34,35]. The precise susceptibility testing method remains a matter of debate, although there is consensus that incubation of susceptibility tests should be for at least 24 h to facilitate growth of mucoid and small-colony variants. Methods must permit calculation of the MIC. Microdilution is considered to be the standard, although not all automated systems incorporating the microdilution technique have demonstrated their accuracy for testing P. aeruginosa CF isolates [6,36,37]. The difficulty of testing the susceptibility of hyper-mutable strains has been described recently [38]. The high frequency at which spontaneous resistant mutants are generated makes it difficult to distinguish true resistance (produced by selection during previous exposure to the antimicrobial agent) from that produced by mutant selection during the susceptibility testing procedure, particularly when using the microdilution technique. Etest and diskdiffusion techniques are useful for detecting hyper-mutable strains and can differentiate between these two effects [39]. The accuracy of classical routine methods, which always use planktonic bacteria and not those forming biofilm growth, has also been debated [31,40,41]. At the same time, the criteria used in the antibiogram interpretation for defining the clinical categories (susceptible, intermediate and resistant) have been questioned, particularly for patients receiving inhaled antibiotherapy. MICROBIOLOGICAL PATTERNS OF P. AERUGINOSA PULMONARY COLONISATION ⁄ INFECTION The interaction between P. aeruginosa and the CF patient (summarised in Fig. 1) is described normally as colonisation ⁄ infection, indicating the pathogenic ambivalence of this organism in these patients. ‘Colonisation’ usually refers to bacterial development on a surface, often without a harmful effect [3]. In contrast, the term ‘infection’ indicates a pathogenic effect resulting from microbial invasion of the tissues, although this is rare in CF patients [8], where it indicates a pathogenic effect resulting from the mere presence of the organism. Thus, ‘infection’ should be considered as colonisation with pathogenic effects, resulting from the biological exploitation of a large mucosal surface by a bacterial population with a very high cell density (> 1010 cells ⁄ g in the adult) [3,34]. Even without an active virulent process, such heavy epi-mucosal (external to the host tissues) colonisation is expected to produce a passive pathogenic effect [3,42,43], and can be termed ‘pathogenic colonisation’. A population of this size facilitates the appearance of bacterial variants, some of which develop antimicrobial resistance or hyper-express virulence factors (active pathogenesis). It is obvious that reduction of the bacterial mass should be beneficial for the host. Initial colonisation (primary colonisation or pioneer colonisation) The term ‘initial colonisation’ corresponds to the first documented contact between P. aeruginosa and the host (first positive culture), but with neither clinical evidence of infection nor appearance of specific antibodies (Table 1). Initial colonisation is usually with non-mucoid strains, and there is no diversity in colonial morphotypes or antimicrobial resistance, which is generally of minor importance [7,8]. A positive culture indicates that colonisation has reached a sufficient level for detection, although the counts are usually still low. A negative culture after the first positive culture can indicate: (1) an aborted initial colonisation that has been spontaneously eliminated, as not all P. aeruginosa strains have the same colonising capacity [43]; (2) a cryptic colonisation, which could indicate that secretions from the colonised pulmonary areas are not represented in the sample or that the bacteria are so scarce that they are not recovered in the culture [9]; or (3) eradication of P. aeruginosa after treatment. The reappearance of a positive culture after 1 year of negative cultures following completion of antimicrobial treatment should be managed as a new initial colonisation event.
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 693 Absence of colonisation 1) 2) Initial colonisation l Fig. 1. Summary of the sequence of colonisation and infection events involving Pseudomonas aeruginosa in cystic fibrosis patients, and the theoretical objectives of antimicrobial treatment at each stage. 3) 4) 5) Sporadic colonisation Chronic Infection/ colonisation Exacerbation Theoretical aims of antimicrobial treatment at each stage 1 2 3 4 5 Prevention of initial colonisation (prophylaxis treatment) Eradication of initial colonisation Clearance and tentative eradication of sporadic colonisation Clearance of bacterial density in chronic infection/colonisation Clearance of bacterial mass during exacerbations Table 1. Microbiological patterns and criteria in pulmonary Pseudomonas aeruginosa colonisation ⁄ infection in cystic fibrosis patients Infection ⁄ colonisation Definition I: Initial colonisation (first colonisation event or pioneer colonisation) First positive P. aeruginosa culture Detection of the first positive P. aeruginosa culture in the bronchial tree. No clinical symptoms or specific immunological response II: Sporadic or intermittent colonisation Intermittent presence of positive and negative P. aeruginosa cultures in consecutive samples after initial colonisation. No signs of infection or immunological response Detection, within a period of Possible recovery of strains with mucoid 6 months of the initial colonisation, colonies and other colonial morphotypes of a positive P. aeruginosa culture among at least three cultures, with at least 1 month between each positive culture III: Colonisation with bronchopulmonary infection Initial or sporadic colonisation with presentation of clinical or immunological signs of infection As for initial or sporadic colonisation. In patients without microbiological specimens, the appearance or increase of antibodies in two successive blood samples, with at least 3 months between each sample, can be used as a diagnostic criterion IV: Chronic colonisation Persistent positive P. aeruginosa cultures without new clinical signs of infection, but with an immunological response consistent with the presence of P. aeruginosa Detection within a period of 6 months of a minimum of three positive P. aeruginosa cultures, with at least 1 month between the positive cultures Usually produced by strains with mucoid colonies and other colonial morphotypes. This is the common pattern during advanced periods of the disease As for chronic colonisation In patients with microbiological specimens, an increase of antibodies in two successive blood samples can be used as a diagnostic criterion V: Chronic bronchopulmonary Presentation of clinical signs of infection (exacerbation) infection and an increased immunological response during the course of a chronic colonisation Microbiological criteria Sporadic or intermittent colonisation Sporadic or intermittent colonisation occurs after an initial P. aeruginosa colonisation event and is indicated by intermittent positive and negative cultures [25], albeit still in the absence of apparent signs of infection or immunological response. This stage can be defined microbiologically as a 6-month period following initial colonisation, during which only one positive culture is obtained from a minimum of three cultures taken at least 1 month apart (Table 1). Note that one negative culture during a sporadic colonisation phase should not be considered to indicate true Comments A positive culture following 1 year of negative cultures after finishing treatment is considered as a new initial colonisation. The strains are usually non-mucoid colonies, with little diversity in morphotypes or antimicrobial susceptibilities elimination, since it generally reflects a low-grade colonisation that cannot be detected in the culture, or is a sampling effect derived from the heterogeneity of the samples cultured, some of which might represent material from pulmonary areas still free of colonisation. It is quite common in this period to obtain mucoid strains and variability in colony morphotypes [9]. Colonisation with bronchopulmonary infection In this case, the initial or sporadic colonisation stages are associated with clinical or immunological signs of infection. For the reasons mentioned
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 694 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005 above, this might include patients who, even with negative cultures, have a specific immunological response. Chronic colonisation From the microbiological viewpoint, chronic colonisation is considered to be established when at least three cultures are positive for P. aeruginosa among samples taken at least 1 month apart during a 6-month period (Table 1). The immunological response in this phase is generally consistent with P. aeruginosa colonisation, and mucoid colonies and a great variety of other morphotypes are usually found [16,25]. Most frequently, chronic colonisation is the result of the progressive adaptation of a bacterial clonal population to the ecological niches of the lung, and leads to a large bacterial mass that induces the pathogenic consequences of colonisation. Exacerbations, in which the presentation of more virulent variants cannot be excluded, usually coincide with increases in the bacterial mass or with the emergence of antigenic variants [3,44]. Chronic bronchopulmonary infection Chronic bronchopulmonary infection is characterised by presentation with clinical signs of infection, or by an increase in antibody titres, during the course of a chronic colonisation. Cultures have the same characteristics as during chronic colonisation. Antibody detection in successive blood samples can be used as a diagnostic criterion for patients without microbiological cultures. BACTERIAL ERADICATION AND BACTERIAL CLEARANCE IN CF PATIENTS CF antimicrobial treatment is directed ideally at the elimination of P. aeruginosa [2,29,45–47]. Microbiologically, presumptive eradication means at least three consecutive negative cultures during the year after treatment, with each one separated by a minimum interval of 1 month (Table 1). In most cases, bacterial eradication in cases of pathogenic chronic colonisation is unobtainable, as it would imply the elimination of all the ‘germ nuclei’, including those established in areas with higher nutritional resources. Cell multiplication probably occurs preferentially in particular advantageous juxtamucosal sites, so that an important part of the intraluminal bacterial cells represent the product of multiplication in these ‘germ nuclei’. Eradication seems to be possible only during initial colonisation, and the likelihood is inversely proportional to the microbial mass present in the lung [9]. If there is an important intraluminal population, elimination of the bacteria from the ‘germ nuclei’ will result in their immediate replacement by intraluminal bacterial cells. Moreover, a high bacterial inoculum is difficult to eradicate with antimicrobial agents, as the appearance of resistant mutants is also proportional to the bacterial cell density, which is particularly the case for hyper-mutators and monotherapy. Also, when the inoculum is raised, a part of the bacterial population exposed to an antimicrobial agent becomes refractory to its killing effect—a state of ‘phenotypic tolerance’—and can therefore survive the treatment [48]. The presence of large microbial masses usually coincides with advanced stages of CF, anatomical alterations and compartmentalisation of the colonised space, without an adequate interaction between the antimicrobial agent and all the microbial cells [41]. Negative cultures during or after antimicrobial treatment, particularly inhaled treatment, do not necessarily indicate true eradication. Such negativity can reflect reduced bacterial counts or carryover of antimicrobial agents in the sample obtained. Even molecular methods can give false indications of eradication [17]. The term ‘bacterial clearance’ delimits the objective obtainable with antimicrobial treatment during chronic colonisation, including periods of exacerbation. A significant clearance of bacterial load is defined as a reduction of at least two logs in P. aeruginosa bacterial counts when comparing cultures taken immediately before and after treatment [17,49,50]. A reduction in density and, more rarely, negativity can be observed in non-quantitative cultures. USE OF ANTIMICROBIAL AGENTS IN P. AERUGINOSA LUNG COLONISATION ⁄ INFECTION Preferably, bactericidal drugs should be used to reduce the bacterial cellular mass in cases of CF, and they should, if possible, be fast-acting to avoid the selection of resistant mutants and prevent phenotypic tolerance. Bacterial death with some antimicrobial agents, such as b-lactams, is
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 695 obtained only after prolonged contact with the bacteria, independent of the concentration used, but with others, such as aminoglycosides, is fast and proportional to the dose [51]. The bactericidal activity of fluoroquinolones is somewhat slower, and is also proportional to the dose, but paradoxically, very high doses can be less efficient [52,53]. With colistin, the bactericidal activity is not quite as rapid, but the lethal effect is proportional to the dose [54]. As a general rule, in bactericidal drug combinations, the effects of the individual drugs are additive or synergic. The antimicrobial agents must reach an adequate active concentration in the bacterial environment to give an efficient reduction in the bacterial mass. Normally, a significant proportion of the antimicrobial agent administered never reaches its bacterial target, or its effect is reduced because of the local physico-chemical conditions in the endobronchial environment. Reduction of the bacterial mass is usually achieved only after the use of high doses and a number of successive, correctly spaced exposures to the bactericidal agents. As stated above, part of the bacterial population may not be in full contact with the antimicrobial agent, or may enter a state of phenotypic tolerance. At this stage, and in the absence of antimicrobial agents during dose intervals or between cycles, the bacterial population reacquires the capacity for death. Different situations for use of antimicrobial agents in CF patients can be distinguished, each of which requires a different therapeutic approach. • Prophylactic treatment. These protocols, established initially to prevent S. aureus colonisation, do not constitute recommended routine practice, as they have been associated with acquisition of P. aeruginosa in a high percentage of patients [55]. Antimicrobial agents have only been used occasionally with the intention of delaying the initial P. aeruginosa colonisation event, and their benefits have not been assessed properly [47]. • Treatment of initial colonisation. Aggressive initial treatment can eradicate P. aeruginosa, with cultures remaining negative for several years after therapy [9,13,17,56,57]. Previous strategies using intravenous antimicrobial agents for 2 weeks [55] or a sole oral (ciprofloxacin) [58] or nebulised (colistin or tobramycin) antimicrobial agent [2,59,60] have now been replaced by combined oral and inhaled treatment [2,28,61]. The duration of this strategy is not standardised, and varies from 3–4 weeks to 6–12 months. • Treatment of chronic colonisation (maintenance or chronic suppressive therapy). Maintenance therapy aims to minimise the harmful effects produced by the presence of heavy P. aeruginosa colonisation even in the absence of exacerbations [30]. It is directed towards a decrease in the bacterial load, passive release of proinflammatory substances, and a reduction in the consequent inflammatory response. This approach not only avoids deterioration in pulmonary function, but also helps in its recovery [62]. There are differences of opinion regarding the options, and even as to whether antibiotics should be administered. Some CF units have promoted the regular use of intravenous b-lactams every 3–4 months, regardless of the respiratory symptoms [63]. The results, although promising, have not formed part of controlled clinical trials [64]. Although continuous colistin (1–3 million units ⁄ 12 h) or tobramycin (80 mg ⁄ 12 h) inhalation seems to produce a beneficial effect in the evolution of the chronic infection [65,66], the inhaled nonphenol tobramycin formulation (300 mg ⁄ 12 h) in 28-day cycles (on–off cycles) has been shown to give a clear improvement in pulmonary function, and a consistent decrease in P. aeruginosa density in the sputum [67]. • Treatment of acute respiratory exacerbations. It is accepted generally that if the patient has two or more of the symptoms or signs included in Table 2, then antimicrobial therapy should be started to avoid further deterioration of pulmonary function [31]. Treatment of acute exacerbations is aimed at immediate reduction of the bacterial inoculum, which is frequently higher than the average colonisation levels [46]. The recommended drugs are anti-pseudomonal penicillins (piperacillin, ticarcillin) or cephalosporins (ceftazidime, cefepime), a monobactam (aztreonam) or a carbapenem (imipenem, meropenem, but not ertapenem), in combination with an aminoglycoside (usually tobramycin) for 2–3 weeks [47,68]. The treatment should be intravenous, except for mild exacerbations, when oral drugs are indicated [29]. In this case, there should be an interval of at least 3 months between the cycles to reduce the possibility of resistance becoming established. For chronic P. aeruginosa colonisation, inhaled antimicrobial agents should be maintained if they are already being used [69].
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 696 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005 Table 2. Symptoms and signs used to define exacerbations in cystic fibrosis patients Symptoms Increased cough Increased sputum production and ⁄ or change in colour Increased respiratory difficulty and decreased tolerance of physical activity Haemoptisis Anorexia, tiredness and loss of weight Increased sensation of ‘thoracic congestion’ Signs Fever ‡ 38C on more than one occasion in the previous week Deterioration of FEV1 of > 10% (spirometry) with respect to basal volumes obtained in the last 3 months Deterioration of haemoglobin saturation of > 10% (oximetry) with respect to basal values of the last 3 months Changes in pulmonary auscultation Increased trapped air or presentation of new radiological infiltrates Modification or increase in antibodies against P. aeruginosa the clinical viewpoint, the beneficial effect on pulmonary function is maintained during the rest periods. Such dosing intervals are also microbiologically justified, as the rest periods facilitate overgrowth of the susceptible and non-hypermutable populations, which tend to grow better than the resistant and hyper-mutable populations in the absence of antibiotic selection, thus reducing their displacement by resistant populations. ANTIMICROBIAL TREATMENT IN PRACTICE: PROTOCOLS TO CONTROL P. AERUGINOSA COLONISATION ⁄ INFECTION FEV1, forced expiratory volume in 1 s. There is scarce experience with inhaled administration during acute exacerbations. The risk of developing resistance must be considered in the choice of therapy. In CF patients chronically colonised with P. aeruginosa, there is no single antimicrobial agent for monotherapy that is capable of preventing the development of resistance, particularly when administered systemically. This fact is even more evident in bacterial populations that include hyper-mutators [38]. As a result, the use of combinations is recommended strongly, whenever possible, to avoid a greater development of resistance and to obtain a synergic effect. Possible exceptions may be inhaled antimicrobial agents, such as tobramycin, as the concentrations reached in the respiratory airway are up to 100-fold higher than those reached with systemic administration, and are usually higher than the mutant prevention concentration for most P. aeruginosa strains [70]. However, generalised use for prolonged periods can, in some cases, result in a gradual increase in the MIC to > 128 mg ⁄ L, which is the cut-off value of resistance proposed for nebulised tobramycin [49,62,71,72]. The first evidence that maintenance therapy in CF patients with chronic P. aeruginosa colonisation reduces progressive pulmonary deterioration was found when comparing patients receiving intravenous antimicrobial agents in three or four programmed yearly cycles with patients receiving them only during exacerbations [63]. There have been many studies with inhaled formulations, particularly tobramycin, that have obtained good short- and long-term results [62,73]. The recommended regimen includes alternate 4-weekly cycles of treatment and no treatment [62]. From Treatment of patients following the first isolation of P. aeruginosa The aim of treatment is the eradication of P. aeruginosa in order to delay chronic colonisation [9,28,61,74]. There are two possible situations, depending on the clinical state of the patient (Table 3). Stable patient with or without mild respiratory symptoms Treatment should be initiated with oral ciprofloxacin (30–40 mg ⁄ kg ⁄ day) divided into two doses (maximum 2 g ⁄ day) for 3–4 weeks, regardless of the age of the patient, combined with inhaled tobramycin or colistin [28,60,61,75]. Intravenous treatment can be used as an alternative, with or without inhaled treatment [17]. A sputum culture should be performed 1 month after the start of treatment; if this culture is negative, the inhaled treatment should be maintained for at least 6–12 months to avoid early reoccurrence, whereas, if the culture is positive, the treatment cycle should be repeated. When colistin is used, the dose should be increased, as should the frequency of administration. A new sputum culture should be performed at the end of the second cycle and, if this is still positive, the protocol for chronic colonisation should be applied. An antibiogram should be determined for positive P. aeruginosa cultures and, if resistance is detected, the antimicrobial treatment should be adapted accordingly. Patient with acute infection The cycle should be initiated with high doses of two intravenous antimicrobial agents, a b-lactam
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 697 Table 3. Antimicrobial treatment for Pseudomonas aeruginosa colonisation and infection Clinical situation Preferred treatment First positive P. aeruginosa culture Without clinical signs Oral ciprofloxacin, 30–40 mg ⁄ kg ⁄ day, 3–4 weeks + Inhaled tobramycin, > 6 years: 300 mg ⁄ 12 h < 6 years: 80 mg ⁄ 12 h or Inhaled colistin, 1–3 million U ⁄ 12 h Acute infection Comments IV treatmenta ± inhaled treatmentb A culture should be taken after treatment for 1 month: if negative, inhaled treatment should be maintained for 6–12 months while negative cultures persist; if positive, a new oral and inhaled therapeutic cycle should be started, or IV treatmenta ± inhaled treatment. A new culture should then be performed and, if still positive, the patient should be treated as for chronic colonisation IVa treatment, 14–21 days ± Inhaled treatmentb Chronic P. aeruginosa colonisation Stable clinical situation > 6 years: Inhaled tobramycin, 300 mg ⁄ 12 h with alternate cycles (on–off, 28 days) < 6 years: Inhaled tobramycin, 80 mg ⁄ 12 h without alternate cycles or inhaled colistin, 1–3 million U ⁄ 12 h Exacerbation stage Alternative Commence inhaled treatment during or at the end of IV treatmenta For multiresistant strains, treatment should be adapted for the susceptibility profile After clinical post-treatment remission, another culture should be taken and criteria applied as above Inhaled colistin, 1–3 million U ⁄ 12 h ± Oral ciprofloxacin, 2–4 weeks every 3–4 months IV ceftazidime, 50–70 mg ⁄ kg ⁄ 8 h or IV cefepime, 50 mg ⁄ kg ⁄ 8 h, 2–3 weeks + IV tobramycin, 5–10 mg ⁄ kg ⁄ 24 h or amikacin, 20–30 mg ⁄ kg ⁄ 24 h, 2–3 weeks Maintain inhaled regimen while the risk ⁄ benefit ratio is favourable For cases of moderate pulmonary involvement, oral ciprofloxacin can be added for 3–4 weeks every 3–4 months For cases of severe pulmonary involvement or ciprofloxacin resistance, change to an IV treatmenta regimen (cycles every 3–4 months). IV treatmenta can be used in any state of chronic colonisation Maintain inhaled regimen if previously established Prolong IV treatment if no improvement or severe involvement For mild exacerbation, oral ciprofloxacin should be administered 30–40 mg ⁄ kg ⁄ day, 2–3 weeks For multiresistant isolates, treatment should be adapted to the susceptibility profile a Treatment as in exacerbation. b Tobramycin or colistin. IV, intravenous. (ceftazidime or cefepime) and an aminoglycoside (tobramycin or amikacin), for 14–21 days, depending on the clinical response [17,76,77]. An inhaled treatment can be given during or at the end of the intravenous treatment. The duration is as mentioned above. The aminoglycosides should be administered in a single daily dose [78]. If multiresistant P. aeruginosa is isolated, antimicrobial agents retaining activity in the antibiogram should be used. In such cases, intravenous colistin is an alternative, despite its potential nephrotoxic and neurotoxic risks. Ciprofloxacin should be reserved for oral administration. The intravenous antimicrobial cycle must be repeated if the first culture after treatment is positive for P. aeruginosa. If the culture is negative, inhaled treatment must be maintained for at least 6– 12 months to avoid early reoccurrence. Maintenance treatment after development of chronic P. aeruginosa infection ⁄ colonisation Stable patient The aim of the maintenance treatment in such cases is to avoid respiratory exacerbations and delay progression of the pulmonary disease [93]. The patients usually have few clinical respiratory symptoms. Treatment with inhaled tobramycin (300 mg ⁄ 12 h) in 28-day cycles with rest periods of 28 days is advised [62], or as an alternative, colistin (1–3 million units ⁄ 12 h) [49,79,80] (Table 3). Colistin is also a possible choice for patients aged < 6 years. The length of inhaled treatment is not defined clearly, and treatment should be maintained while the risk ⁄ benefit ratio is favourable. Treatment can be completed in cases with moderate pulmonary symptoms with the oral
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 698 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005 administration of ciprofloxacin for 3–4 weeks every 3–4 months [2,58], or with an intravenous programme every 3–4 months when the effects are severe or ciprofloxacin resistance is detected [81]. Treatment of patients with exacerbations The aim of treatment in such cases is a return to the basal situation presented by the patient before the exacerbation, coupled with a decrease in the inoculum (clearance) of P. aeruginosa in the sputum [29,46,82,83]. Moderate and serious exacerbations must be treated with intravenous antimicrobial agents [3,31,68], while oral antimicrobial agents (ciprofloxacin at the same dose and duration as for first isolations) are recommended for patients with mild pulmonary disease. The choice of intravenous antimicrobial agents is usually based on the most recent set of microbiological results obtained before the exacerbation. The combined use of two antimicrobial agents for 2–3 weeks is usually recommended (Table 3), although this can be prolonged in special cases (e.g., severe exacerbation without improvement, or patients with severe pulmonary effects in a basal situation). The patient can be treated in hospital or at home [47,62,68]. Hospital treatment is necessary for patients with severe exacerbation, haemoptysis or an incapacity to undertake domiciliary treatment, or for patients who require intensive physiotherapy or other supportive therapies. Domiciliary intravenous therapy is becoming more common, as it reduces the number of hospital admissions and allows the patient a better quality of life [84–86]. Patients suitable for domiciliary treatment are those with moderate exacerbations, normal renal function, no requirement for any other type of therapeutic support, no adverse reactions and good vein status. The first dose should be administered in hospital, with weekly follow-up visits recommended. Patients receiving inhaled antimicrobial treatment should usually maintain this regimen during intravenous treatment, and renal function must be monitored [62]. Administration of inhaled antimicrobial agents is contraindicated in patients with haemoptysis. Use of antimicrobial agents with immunomodulating activity Use of azithromycin, 250 or 500 mg three-timesweekly, has been recommended for patients with chronic P. aeruginosa colonisation [87], as use of this agent has been shown to result in a decrease in the number of exacerbations and improvement in pulmonary function. As neither a bacteriostatic nor a bactericidal effect of macrolides against P. aeruginosa has been reported, it has been suggested that an anti-inflammatory effect is responsible for the observed improvement in CF patients [88,89]. Moreover, it has been shown that macrolides may limit the quorum-sensing interbacterial signals that affect the pathogenicity of P. aeruginosa and its capacity to form biofilms [90]. It has also been suggested that the combination of macrolides with anti-pseudomonal antimicrobial agents may have a synergic effect. Combination of P. aeruginosa with B. cepacia or other Gram-negative bacteria Antimicrobial treatment is more difficult when there is co-infection with P. aeruginosa and B. cepacia because of the inherent multiresistance of the latter organism. A combination of three drugs, including a b-lactam (meropenem or ceftazidime), ciprofloxacin, chloramphenicol, minocycline or rifampicin, can be beneficial for some patients. B. cepacia is not susceptible to colistin, and rarely to aminoglycosides, although the use of amikacin in combination with two other antimicrobial agents has been recommended on some occasions [80]. In many cases, in-vitro susceptibility or resistance does not guarantee clinical success or failure. Stenotrophomonas maltophilia and Achromobacter xylosoxidans are also resistant to most antimicrobial agents, but are usually susceptible to trimethoprim–sulphamethoxazole, which is considered to be the drug of choice. The use of minocycline, doxycycline, moxifloxacin, levofloxacin and ticarcillin–clavulanic acid has also been recommended. Different combinations are recommended for A. xylosoxidans, including piperacillin–tazobactam, an aminoglycoside and a fluoroquinolone [91]. ASSESSMENT AND EPIDEMIOLOGICAL CONTROL MEASURES FOR THE CF PATIENT WITH P. AERUGINOSA COLONISATION ⁄ INFECTION Before, during and after antimicrobial treatment Different parameters can be used to assess the response to treatment of P. aeruginosa pathogenic
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 699 colonisation. Clinical parameters are related to the subjective symptoms and signs of respiratory exacerbation, tolerance to physical activity, appetite, stature, subjective changes in the sensation of dyspnoea or the usual respiratory frequency, and new pulmonary auscultation findings. Adequate response to treatment is defined by the number of exacerbations and the need for hospital admissions and intravenous treatment. Analytical parameters are necessary in some cases, particularly serological monitoring of antibodies against P. aeruginosa. These are of great interest for neonatal screening programmes, as initial colonisation can be detected up to 6–12 months before detection of P. aeruginosa in culture [92]. Measurement of exhaled CO (an indicator of inflammation) can be useful, particularly when assessing the response to treatment [93]. Among the functional parameters, the forced expiratory volume in 1 s (FEV1) is helpful for studying the progression of pulmonary disease, and has a good correlation with mortality in CF [18,94]. The annual deterioration index of this parameter is also useful [95]. Although forced vital capacity (FVC), FEV1 and the FEV1 ⁄ FVC ratio are reproducible parameters, they are not very sensitive. To detect initial changes so that early aggressive treatment can be commenced, calculation of the forced expiratory flow rate between 25% and 75% of the vital capacity (FEF25)75) can be useful, as can other techniques for measuring effects on the small airway and pulmonary hyper-insufflation markers (residual volume ⁄ total pulmonary capacity [96]. Techniques for neonates and infants should be directed at assessing pulmonary volumes and forced expiratory flows [97]. Microbiological parameters should assess bacterial density, as well as the presence of mucoid morphotypes and strains that are multiresistant or have a high capacity for transmission [68,98]. Antimicrobial susceptibilities can be extremely helpful, although they are not always adequate for predicting the success of antibiotic therapy, as treatment response can vary independently of the in-vitro results [30,99]. The parameters in imaging tests, such as the appearance of new signs in the chest X-ray, can also be of interest. High-resolution computed tomography has been used for diagnosing incipient signs of the disease [100] and also for assessing the response to intravenous treatment [101]. Ventilation scintiscan can be a useful tool for early diagnosis, as it detects objective changes and can give a prognosis of pulmonary deterioration. Eradication controls Assessment of eradication should not be based on a single culture at the end of treatment, but rather on long-term monitoring. In general, eradication following treatment of CF patients with initial P. aeruginosa colonisation is demonstrated by negative cultures over a prolonged period and anti-pseudomonal antibodies that remain or become negative [56]. If P. aeruginosa reappears after its theoretical eradication, molecular typing studies are advisable to determine whether persistent colonisation has remained undetected by culture, or whether re-infection by a new strain has occurred [17]. Epidemiological control measures The environment constitutes a source of P. aeruginosa that will colonise the respiratory tract of the CF patient. It is necessary, particularly for noncolonised patients, to avoid possible contact with other colonised patients (including other CF patients or adults with chronic bronchitis and bronchiectasis), and to minimise the uptake of drinks and non-cooked foods that may be colonised by Pseudomonas (including water or milk in open containers outside a refrigerator), as well as contaminated systems or drugs used in inhalation treatment [102]. Therefore, epidemiological control should focus on the protection of CF patients by avoiding acquisition and minimising the sources and routes of transmission of P. aeruginosa. Protective measures should be applied in the daily life of the patient, during hospital admission, during management in the outpatient clinics and in domiciliary treatment. Standard precautions and epidemiological controls are also applicable to CF patients, although the following patient features, site of colonisation and the characteristics of the pathogens involved should be taken into account [102]: • All CF patients can harbour transmissible organisms in the respiratory tract, including P. aeruginosa. Standard precautions should be taken to avoid acquisition and transmission to other patients, with special attention paid to
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703 700 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005 • • • • • the airway route. Many methods have been tried in CF patients to avoid transmission of B. cepacia [102], but there is still no consensus regarding the best approach for P. aeruginosa. Nevertheless, they should be of the same level when multiresistant P. aeruginosa is isolated. Although there is no supporting evidence, epidemiological measures should be prolonged following eradication or during a course of antimicrobial therapy. In order to prevent person-to-person spread, there must be rigorous infection control practices. Hand-washing by all staff coming into contact with the patients is crucial, as are the cleanliness of the stethoscope, changing of sheets between patients, and the use of gloves in the handling of objects and devices potentially contaminated with respiratory secretions. The use of masks and caps by staff is recommended during examination procedures and monitoring of respiratory parameters. General hygiene measures should be applied (sterilisation ⁄ disinfection) [103] for equipment that comes into contact with CF patients, particularly in the respiratory tract, such as humidifiers, nebulisers and compressors. These measures should be applied in both the hospital and external environment, and should be extended to surfaces and places where respiratory function tests are performed. Management and follow-up of ambulatory patients should be undertaken according to their colonisation pattern. It is recommended that outpatient consultations and functional tests should be organised to avoid contact between patients and minimise the possibilities of transmission. In the case of P. aeruginosa colonisation, stratified appointments of patients on different days has been applied successfully [28]. Hospital inpatients colonised with multiresistant P. aeruginosa should be subjected to barrier control measures similar to those applied to patients colonised with methicillin-resistant S. aureus [102]. Moreover, segregation of patients colonised with multiresistant P. aeruginosa should be considered, similar to that applied to patients colonised with B. cepacia. Epidemiological control measures should include microbiological cultures for monitoring and follow-up of colonisation at least once every 2–3 months, whenever there are exacer- bations and when changes are noted in the clinical status or during hospitalisation. Assessing clonality in P. aeruginosa populations Clonality studies have been essential in demonstrating the high variability that exists between P. aeruginosa isolates from different patients, the persistence of the same clonal type in the same patient, and, rarely, simultaneous colonisation with different clones [5,6,44,98]. This analysis is also important for documenting the start of chronic colonisation in patients for whom eradication treatment following the first isolation of P. aeruginosa has failed, for demonstrating crosscolonisations between patients, or for identifying hyper-transmissible clones [5,17,99,102]. Techniques with high reproducibility and discriminatory power should be used, such as pulsed-field gel electrophoresis or PCR-based techniques [5,98,102]. Control of emergence of multiresistant isolates Monitoring of susceptibility profiles and the possible selection of resistant variants in chronically colonised P. aeruginosa patients should be performed at least every 3 months in cases of exacerbation, during hospital admission, or when there are doubts about the response to therapy [31,33]. This practice allows close follow-up of the patients and monitoring of the possible spread of multiresistant organisms between patients [25,71,101]. Every CF unit should record statistics, participate in national registers, and record susceptibility patterns for the various antimicrobial agents [25,71,101]. The relationship of susceptibility patterns to antimicrobial treatment protocols permits identification of the possible influence of certain regimens in the selection of antimicrobial-resistant organisms [55,57], and provides the necessary feedback to allow the design of alternative strategies for controlling pathogenic colonisation and infection of CF patients with P. aeruginosa. REFERENCES 1. Ratjen F, Doring G. Cystic fibrosis. Lancet 2003; 361: 681– 689. 2. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918–951.
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