Impact of Multidrug-Resistant Organisms on Patients Considered for Lung Transplantation

INTRODUCTION

The long-term success of lung transplantation is limited by the development of infections and chronic rejection, otherwise known as bronchiolitis obliterans syndrome (BOS).¹ Infection with multidrug-resistant (MDR) organisms is particularly problematic in patients with cystic fibrosis (CF), which is the third most common indication for lung transplant. Understanding the clinical impact and management options for these pathogens is critical for optimizing posttransplant outcomes and maximizing the benefit of a limited supply of donor organs.

Patients with CF are increasingly colonized and infected with MDR bacteria and fungi before transplant.^1,2 Although Pseudomonas aeruginosa remains the predominant pathogen in patients with CF undergoing lung transplant evaluation, the prevalence of other species such as Stenotrophomonas maltophila, Achromobacter xylosoxidans, Pandorea, and Ralstonia has also increased over the past decade.^3–5 Outcomes in CF have greatly improved with the introduction of inhaled tobramycin and oral azithromycin, but the increasing use of these and other broad-spectrum antimicrobials has also led to changes in CF sputum microbiology.^6,7 Antibiotic use has led to a loss of diversity in respiratory flora and increases in antimicrobial resistance.^6,8,9 With regard to MDR pathogens, few data are available to guide specific therapy and predict the posttransplant outcomes for pathogens other than P aeruginosa (Table 1).¹⁰

Table 1.

Commonly used antimicrobials for MDR pathogens

Organism	1st Line Antimicrobials	Contraindication to Transplant
MDR. P aeruginosa	Carbapenem, piperacillin/tazobactam, cefepime +/− an aminoglycoside or quinolone	Rare
Pan resistant P aeruginosa	Any of above +/− colistin
B cenocepacia	Ceftazidime, tetracyclines, trimethoprim-sulfamethoxazole, carbapenem	Probable
B gladioli	Piperacillin, aminoglycosides, carbapenem, ciprofloxacin	Possible
A baumannii	Carbapenem, colistin, tigecycline, ampicillin/sulbactam	Possible
M abscessus	Clarithromycin + amikacin	Possible
	2nd line: Clarithromycin + imipenem or cefoxitin
M avium complex	Clarithromycin, ethambutol, rifampin	Rare
S apiospermum	Voriconazole +/− echinocandin	Possible
S prolificans	Voriconazole +/− echinocandin +/− terbinafine	Possible
A terreus	Voriconazole +/− echinocandin	Rare

Data from. ^62,112,113

SPECIFIC ORGANISMS

Pseudomonas aeruginosa

Microbiology and ecology

P aeruginosa is an opportunistic gram-negative aerobic bacillus found commonly in indoor and outdoor freshwater environments.¹¹ Displaying a multitude of virulence factors, P aeruginosa often manifests in 1 of 2 distinct phenotypes, a tissue-invasive pathogen causing acute pneumonia and sepsis or as a chronic colonizer in damaged airways, such as in CF.^12,13 Although P aeruginosa has a variety of virulence factors that may predispose this organism to severe acute infections, genome analysis of P aeruginosa strains in chronically infected recipients with CF has demonstrated that strains tend to display a different set of characteristics that allow the organism to persist as a chronic colonizer. These factors include

• Hyper mutability¹⁴

• Downregulation of virulence factors including toxin production, flagellum, and lipopolysaccharide O chains¹⁵

• Mucoid phenotype, characterized by production of alginate biofilm

• Evasion from and inhibition of phagocytosis^15,16

• Multiple mechanisms of antibiotic resistance

Epidemiology

Among patients being considered for lung transplantation, most pseudomonal infections are seen in chronic suppurative lung diseases, with a prevalence of P aeruginosa in up to 80% of patients with CF and bronchiectatic lung diseases.¹⁷ Pretransplant colonization is a significant risk factor for infection after transplant, increasing the risk of infection by an odds ratio of 4.7.^18,19Pseudomonas is the most common cause of pneumonia in the first month after transplant and accounts for one-third of posttransplant pneumonias.^20,21 This organism is particularly problematic in patients with CF.²² Posttransplant airway colonization with P aeruginosa has also been associated with BOS, which is the primary cause of mortality in lung transplant recipients. It is not clear whether the risk of BOS is seen only in patients with de novo infection or whether this extends to patients who were colonized before transplant.^23,24 The posttransplant survival of patients colonized with pan-resistant P aeruginosa before transplant is similar to those with sensitive bacteria at 1 year (88% vs 96%), but worse at 3 years (63.2% vs 90.7%).²⁵ However, the average mortality with pan-resistant bacteria is comparable with that of the entire lung transplant population and thus patients should not be denied transplant candidacy because of pan-resistant P aeruginosa.¹⁰

MDR P aeruginosa, defined as resistance to greater than 3 or more classes of antibiotics, is common in patients with CF, with prevalence rates ranging from 10% to 45%.^26–28 Cutting-edge sequencing techniques have provided new insights into the longitudinal effects of antibiotic treatment on the bacterial ecosystem in these patients.^8,9 Findings from these recent studies by Zhao and colleagues⁸ and Fodor and colleagues⁹ suggest that use of antibiotics seemed to be the primary driver of the loss of diversity in respiratory flora, as opposed to age or lung function. A comparison between 1996 and 2008 demonstrated increased resistance to tobramycin in P aeruginosa isolates (11.8% vs 30.4%, P<.001), and increased carbapenem-resistant, aztreonam-resistant, and MDR P aeruginosa in patients who were exposed to intravenous carbapenems.⁶

Pretransplant management

CF Foundation guidelines recommend chronic use of inhaled antibiotics, such as tobramycin or aztreonam, reserving systemic antibiotics for symptomatic exacerbations. Antibiotics are typically selected based on local susceptibility testing; typical classes of antibiotics with antipseudomonal activity include extended spectrum cephalosporins, β-lactam/anti-β-lactamase, carbapenems, quinolones, and aminoglycosides. The increase in MDR P aeruginosa over the past 2 decades had led to interest in assessment of synergy with antibiotics, using either the checkerboard dilution assay or the multiple combination bactericidal assay (MCBT).^29,30 Synergy is defined as those combinations with demonstrable bactericidal activity. In studies from 1990 to 2006, combinations containing meropenem had the most bactericidal activity, showing in vitro efficacy in greater than 60% of strains.²⁹ Studies of the clinical efficacy of synergy testing have shown mixed results. In a randomized trial of patients with CF with respiratory exacerbations, antibiotic therapy guided by MCBT therapy did not improve the time interval between exacerbations, lung function, or end-of-treatment bacterial density before transplant.³¹

Posttransplant treatment

Most centers treat recipients with a history of P aeruginosa with 2-drug antipseudomonal therapy for 2 to 3 weeks postoperatively to reduce the risk of pneumonia and allograft colonization, based on previous susceptibilities.^32–34 However, most centers avoid systemic colistin and aminoglycosides if possible because of cumulative nephrotoxicity when combined with calcineurin inhibitors for immunosuppression. Synergy testing may be beneficial in patients with CF with MDR P aeruginosa who are undergoing lung transplant, based on lower rates of septicemia and pleural infections seen in a retrospective study. Inhaled tobramycin and colistin are components of successful eradication strategies for de novo P aeruginosa in pediatric patients with CF, and may have a role in preventing colonization of the new allograft after transplant. However, the efficacy of these agents for posttransplant eradication has not been well studied. Surgical debridement of the sinuses after transplant has also been associated with reduced incidence of bacterial pneumonia and BOS.

Burkholderia Species

Microbiology and ecology

Burkholderia species are gram-negative bacteria found ubiquitously in the soil and moist environment. Members of this genus include Burkholderia cepacia complex, gladioli and mallei, and pseudomallei. Previously believed to represent 1 species, advances in geneticshave shown thatthe B cepacia complex (BCC) comprises several phylogenetically similar but distinct species, including B multivorans and B cenocepacia. The latter has recently been further subdivided into epidemic (transmissible) and nonepidemic strains. Because patient-to-patient transmission of Burkholderia species has been consistently documented, the CF Foundation has recommended segregation of patients infected with BCC from each other and from other patients. Recent subclassification of Burkholderia species has shown strain-specific differences in the virulence of these pathogens, in the pretransplant and posttransplant settings.

Epidemiology

Although BCC are generally not pathogenic in healthy hosts, Burkholderia species colonize the respiratory tract in 15% to 22% of patients with CF. Although early eradication strategies have been used in the CF population, most patients who acquire these organisms develop chronic infection.³⁵ Chronic infection with BCC, defined as the isolation of a species on 2 or more occasions over a minimum of 6 months, has been associated with an accelerated decline in lung function and increased mortality in recipients with CF.³⁶ Unfortunately, pretransplant colonization with B cenocepacia has been associated with the highest risk for posttransplant mortality (relative risk 8.43, P<.005) and most lung transplant centers have denied transplantation to candidates infected with this species.^37–39 More recently, it has been appreciated that infection with transmissible strains of B cenocepacia may not be as hazardous as infection with the nontransmissible strains.³⁷ Further studies are needed to determine if patient selection criteria or other factors also played a role in the observed mortality differences. Pretransplant colonization with B gladioli has also been associated with increased mortality in lung transplant recipients (hazard ratio 2.23, P = .04) and complications that include mediastinal abscesses, pleural infection, and chest wall infection.^37,40–42 There is currently insufficient data to determine whether the increased posttransplant mortality is primarily attributable to chronic and MDR infection or also extends to those transiently infected with B gladioli before transplant. Many transplant centers currently consider B gladioli to be a relative contraindication to lung transplant. Given the strain and species, and the specific virulence of the various members of the BCC, programs should refer specimens to reference laboratories with DNA fingerprinting capacity, if needed to determine the exact species and strain.

Treatment

Treatment of most acute exacerbations with Burkholderia species include trimethoprim sulfamethoxazole as the drug of choice as well as typical antipseudomonal antibiotics, such as ceftazidime and meropenem.^40,43 As a result of multiple resistance mechanisms, including an efflux pump, chronic infection with BCC is associated with an 80% prevalence of MDR, defined as resistance to 3 or more classes of antibiotics.^40,44 In this setting, some experts recommend synergy testing to determine optimal antibiotic combinations, although its efficacy is uncertain.⁴⁵ There are limited data about the optimal treatment approach after transplant, although most centers recommend prolonged combination antibiotic therapy given the high risk of fatal infection after transplant.

Acinetobacter baumannii

Microbiology

Acinetobacter is a gram-negative coccobacillus found in a broad variety of environments. Historically, a pathogen of humid climates, Acinetobacter species have become increasingly prevalent as causes of nosocomial infections.^46,47A baumannii can be particularly problematic due to some of the following virulence factors:

• Ability to survive dry environmental conditions for weeks⁴⁸

• Wide range of resistance mechanisms^49,50

• Enhanced adherence to bronchial epithelium using fimbriae⁵¹

• Production of a polysaccharide capsule that can delay phagocytosis⁵²

In the United States, transmission is typically traced to common source contamination in nosocomial settings, such as respiratory equipment in intensive care units, but community infection has been reported in other continents.

Epidemiology

Most of the nosocomial A baumannii infections occur in the setting of outbreaks; however, prolonged colonization can contribute to the endemicity of this pathogen after an outbreak. In 1 multicenter study, the prevalence of Acinetobacter in intensive care patients approximated 3%, predominantly as outbreaks.⁵³ Furthermore, the rapid acquisition of multiple mechanisms of resistance has led to the emergence of strains that are pan resistant.⁵⁴

Peritransplant management

Treatment of Acinetobacter infections is based on local susceptibility patterns, but typical antibiotic choices include third-generation or fourth-generation cephalosporins, carbapenems, and β-lactams/anti-β-lactamase combinations. Colistin may be of benefit with resistant strains. In the pretransplant setting, Acinetobacter infections may become more prevalent as more centers become willing to transplant candidates who are on mechanical ventilatory or extracorporeal life support. Although there are currently no published reports describing the incidence or effect of pretransplant Acinetobacter infections on posttransplant outcomes, the concern for fatal posttransplant infection likely prevents many from being considered for transplantation. Infections with MDR A baumannii in lung transplant recipients can have devastating outcomes. In 1 series of 6 patients infected with carbapenem-resistant A baumannii during a hospital outbreak, the organism was persistently recovered from the respiratory tract in 4 of 6 recipients despite aggressive treatment and all 4 died as a result of this infection.⁵⁵ In another report that included 16 solid-organ transplant recipients with A baumannii that was resistant to all antimicrobials except tigecycline and colistin, patients who were initially treated with colistin monotherapy demonstrated 91% mortality.⁵⁶ However, following a new protocol to determine the local mechanism of resistance (OXA-23 gene) and subsequent synergy testing, an initial treatment regimen of carbapenem and colistin resulted in a 60% survival rate in subsequent patients infected with A baumannii. Further studies are needed to determine the circumstances under which patients with pretransplant A baumannii infection can undergo lung transplantation with acceptable posttransplant outcomes.

Nontuberculous Mycobacteria

Infections with nontuberculous mycobacteria (NTM) are fairly prevalent in patients with several pretransplant chronic lung processes including adult-onset bronchiectasis and CF. Overall, there is no difference in posttransplant mortality between patients with or without positive NTM cultures, however the rate of NTM disease is highest in patients with Mycobacterium abscessus.⁵⁷ Key points about NTM and lung transplant candidates are^57–61

• Prevalence estimates of carriage are 3% to 13% in pretransplant patients and 10% to 22% after transplant.

• Many patients (~40%) who have pretransplant NTM continue to have positive cultures after transplant.

• M abscessus is considered a relative contraindication to transplant because of its virulence and intrinsic resistance to antimicrobial agents.

M abscessus

Microbiology

M abscessus, a rapidly growing mycobacterium (ie demonstrating visible growth on solid media within 7 days) is increasingly recognized as an important human pathogen.⁶² This bacteria is found in water and soil and is capable of colonizing skin surfaces, the gastrointestinal tract, and the respiratory tract of humans. It is one of the most resistant organisms to antimicrobial agents, the mechanisms of which are the focus of increasing research. Natural and acquired resistance mechanisms include

• The presence of a waxy impermeable cell wall

• Antibiotic-modifying enzymes

• Target-modifying enzymes that confer resistance to macrolides

• Efflux pumps

The complete genome sequence became available in 2009, allowing for further classification of substrains and the discovery that M abscessus shares several characteristics with slow-growing mycobacteria.

Epidemiology

Before transplant, the most frequently isolated species are Mycobacterium avium complex (41%) followed by M abscessus (7%). M abscessus can cause skin infections in nosocomial settings, bronchopulmonary infections in patients with chronic lung diseases, and disseminated infections in immunocompromised hosts. There are few data on the clinical outcome of M abscessus infections in transplant recipients. Chernenko and colleagues⁶⁰ conducted a follow-up survey of 62 centers to determine the incidence and clinical outcomes of M abscessus infections before and after lung transplant.⁶¹ Seventeen of 5200 transplant recipients were infected with M abscessus after transplant; of these, only 2 were infected with M abscessus before transplant, suggesting that pretransplant infection with M abscessus may have been a contraindication to transplant at many centers.

Peritransplant treatment

Treatment is recommended in patients who have progressive disease, or who may need lung transplantation in the future. M abscessus infections are intrinsically resistant to most standard antibiotics and antituberculous agents. Typical modal minimum inhibitory concentrations are less than tissue/serum levels only for clarithromycin, aminoglycosides, cefoxitin, and tigecycline, with some strain-specific variability in susceptibility patterns. Most recommendations are to use a multidrug regimen including clarithromycin, aminoglycoside, and a third agent for 24 months, but the efficacy of the multidrug approach is mixed. The success rates of sputum conversion and maintenance of negative cultures depend significantly on resistance profiles, ranging from 60% for macrolide-sensitive organisms to less than 20% in macrolide-resistant strains. Although Mycobacterium avium complex is more frequently recovered from respiratory samples, the isolation of the species rarely meets the American Thoracic Society (ATS) definition of clinical disease and may not require treatment.⁵⁸ In those cases that meet the ATS criteria, standard treatment approaches include clarithromycin, ethambutol, and rifampin for a minimum of 12 months.⁶²

Scedosporium Species

Scedosporium colonization is common in patients with advanced CF, and infections are a problem in lung transplant recipients.⁶³ Among North American lung transplant recipients, Scedosporium species are the second most common cause of filamentous fungal infection, following only aspergillosis.^64,65Scedosporium colonization is a risk factor for invasive disease after lung transplant.⁶⁵ Patients who are colonized with Scedosporium before transplant can develop infections with the same strain after the transplant.⁶⁶ Identifying patients who are carrying Scedosporium before transplant is crucial in that it gives clinicians a chance to try to modify the risk for posttransplant infection. Such information can also be used to inform decisions regarding the suitability of the patient for lung transplant.

Ecology and microbiology of Scedosporium

Clinically relevant species include S prolificans, S apiospermum, and the closely related Pseudallescheria boydii. Recent work has identified S aurantiacum as a new species within the P boydii complex.⁶⁷ Because the nomenclature has evolved in recent years, references to these fungi in the literature can be confusing. For example, S apiospermum, P boydii and S aurantiacum have previously been reported as 1 species.

Scedosporium species are found in soil, water, and air. Their abundance is related to increasing nitrogen concentrations and decreasing pH within a range of 6.1 to 7.5. Human activity, including intense fertilization and hydrocarbon waste, supports growth of Scedosporium species in the environment. Some of the highest concentrations of Scedosporium species can be found at industrial sites, near gas stations, in urban parks, and within agricultural areas.⁶⁸

Geographic locale affects the epidemiology and microbiology of Scedosporium carriage in at-risk patients.

• Scedosporium colonization and infection are particularly prevalent in Australia.

• Environmental sampling in Australia has revealed an abundance of S aurantiacum and S prolificans in locations of high human activity.⁶⁹

In 1 Australian medical center, molecular epidemiology analysis showed a single common type isolated in multiple patients suggesting a shared exposure source.⁷⁰ In general, however, exposure tends to be spread out over diverse regions, and in most studies a point source cannot be identified.^71,72

Epidemiology of Scedosporium carriage

Presence of Scedosporium species can be a common finding in the respiratory tract and sinuses of patients with CF, bronchiectasis, and even interstitial lung disease.^70,73–75

• Patients with late-stage CF are at particularly high risk for carriage.

• After Aspergillus, Scedosporium species are typically the most commonly isolated filamentous fungi in patients with CF.

• Carriage rates have been reported to be in the 3% to 10% range.^63,76,77

The intersection of environmental exposure and host factors affects the epidemiology of colonization and infection. In CF, the conditions created by viscous secretions, airway abnormalities, and the impact of chronic and recurrent bacterial colonization and infection favor carriage of these fungi. In 1 study, patients with Scedosporium colonization were significantly less likely to be colonized with mucoid strains of P aeruginosa, whereas colonization rates were higher in those who had received previous therapy with antistaphylococcal penicillins.⁷⁸

Accurate detection of respiratory tract colonization with Scedosporium and identification to the species level can be challenging. Because treatment regimens differ by infecting species, identifying Scedosporium to the species level is crucial. Molecular techniques can assist in this task. Additional techniques that are in development include use of mass spectroscopy and assays that detect a siderophore that is specific for S apiospermum.^79,80

• When using standard culture media, Scedosporium carriage can be underestimated because of overgrowth by faster-growing bacteria and fungi (eg, P aeruginosa and Aspergillus species).

• Specialized semiselective mycologic isolation medium such as SceSel can increase yield.^81,82 Such media should be used in addition to standard fungal culture techniques when evaluating patients.⁷⁷

• Once the fungus is grown in culture, a species-specific multiplex polymerase chain reaction (PCR) can differentiate between clinically relevant species.⁸³

• Application of PCR directly to sputum is another approach that can be used to detect occult organisms to the species level.⁸⁴

The natural history of Scedosporium carriage is variable. Colonization may be transient or persist in the bronchial passages or sinuses for years.⁸⁵ Once persistent colonization is established, it becomes difficult to eradicate.^86,87 Patients tend to become exclusively colonized with 1 species (eg, S prolificans, S aurantiacum or S apiospermum), but may carry multiple strains of that species.⁸⁸

Clinical manifestations and treatment before transplant

Clinical manifestations of Scedosporium in patients with CF (before transplant) include^63,86

• Asymptomatic carriage; this is the most common presentation.

• Mycetoma, which tends to occur in preexisting lung cavities and is sometimes referred to as a fungus ball.

• Allergic bronchopulmonary disease, which is a syndrome much like allergic bronchopulmonary aspergillosis.

• Invasive disease is uncommon, but may occur in patients with CF. Can be limited to the lung or present as disseminated infection.⁸⁹

Evaluation of a patient with CF with findings suggestive of invasive infection, mycetoma, or allergic bronchopulmonary disease should include a search for Scedosporium.

Scedosporium species are difficult to treat with antifungal agents. Based on in vitro data and clinical experience, treatment options for S apiospermum (and the related P boydii) and for S aurantiacum are^90,91

• Voriconazole, which is probably the best choice

• Combination therapy with an echinocandin and either voriconazole or amphotericin B (AmB)

S prolificans can be resistant to multiple antifungal agents, including voriconazole and AmB. Treatment options for invasive infection with S prolificans include^92–96

• Surgical management

• Micafungin combined with voriconazole or AmB

• Voriconazole combined with terbinafine has also been effective in vitro and in clinical S prolificans infections

The role of posaconazole for any of the Scedosporium species is unclear at this time, but may be an option for those that are intolerant or not responding to voriconazole.⁹⁷ Susceptibility testing, which generally requires sending the isolate to a reference laboratory, is an important element in constructing an antifungal regimen for such infections.

Treatment considerations in patients with chronic lung disease who are carrying Scedosporium depend on the species, the clinical scenario, and the prospects for lung transplant. The decision to treat is generally straightforward in patients with invasive disease. The approach to asymptomatic colonization is a more difficult decision point. Patients who are colonized with Scedosporium before transplantation may progress to disseminated infection after lung transplant. Therefore, an effort should be made to control the fungus in such patients.⁸⁵ Voriconazole is usually the drug of choice in this situation, but breakthrough infections have developed with this and other agents (eg, AmB and itraconazole).^66,97 Moreover, eradication of Scedosporium may not be possible, requiring consideration of indefinite fungal prophylaxis after transplant.

Infections after lung transplant

The clinical manifestations of Scedosporium infection after lung transplant are diverse and range from asymptomatic colonization to severe invasive disease.^97–100 In 1 study, proven (including disseminated) infection was diagnosed in 36% of lung recipients from whom Scedosporium was recovered.¹⁰¹

• Infection in lung transplant recipients generally originates in the lungs and sinuses, which are also the typical sites of pretransplant colonization.

• An important aspect of Scedosporium infections in lung transplant recipients is a tendency toward disseminated infection with clinical manifestations that include fungemia, brain abscess, endocarditis, cutaneous involvement, spondylodiscitis, and endophthalmitis.^{65,97,100,102}

• Once disseminated infection develops, the disease is nearly always fatal despite use of multiple antifungal agents and surgical excision.

Treatment options for invasive scedosporiosis after lung transplant are generally unsatisfactory.⁷⁵ Response to therapy depends on the extent of infection and the infecting organism. Disseminated infection with any of the Scedosporium species is nearly always associated with mortality. Infections caused by S prolificans are extraordinarily difficult to treat and tend to have poorer responses to antifungal therapy than those caused by S apiospermum.¹⁰³ The ideal treatment regimens for infection with the various Scedosporium species are not known. Treatment failures are common and, when successful, antifungal therapy generally needs to be given for months or longer. Relapses are common and lifelong therapy may be required.

The general approach to Scedosporium infection after transplant is

• S apiospermum and S aurantiacum: voriconazole ± echinocandin

• S prolificans: surgical therapy and adjunctive voriconazole ± an echinocandin ± terbinafine

Aspergillus terreus

Aspergillosis is the most common fungal infection in lung transplant recipients.¹⁰⁴ A small but significant proportion of cases are caused by Aspergullus terreus. Exposure to this difficult-to-treat fungus is via inhalation of airborne conidia from environmental sources. Colonization or infection in a patient with chronic lung disease before transplant can be particularly problematic. A terreus has been identified in outdoor air, home tapwater, and compost.^105–107 After transplant, A terreus infection can progress rapidly and is associated with a high mortality rate.¹⁰⁸A terreus tends to be resistant to AmB. Prophylactic use of aerosolized AmB, which is a common practice in lung transplant programs, is a risk factor for infection with this fungus.^109–113A terreus is generally susceptible to voriconazole and this is the drug of choice for invasive disease.

SUMMARY

Advances in supportive care, including broad use of antimicrobial agents, are prolonging the lives of patients with advanced lung disease. A byproduct of these advances has been an increasing prevalence of carriage and infection with MDR organisms. When such infections occur after transplant, the results can be disastrous. In this regard, infections with highly resistant strains of P aeruginosa, Burkholderia, Acinetobacter, nontuberculous mycobacteria, Scedosporium, and A terreus can be particularly problematic. An understanding of the epidemiology, diagnosis, and treatment of these infections is important when evaluating a pretransplant candidate.

KEY POINTS.

• In prospective transplant recipients, the most important multidrug-resistant (MDR) organisms are Pseudomonas aeruginosa, and species of Burkholderia, Acinetobacter, nontuberculous mycobacteria, and Scedosporium.

• Carriage of MDR organisms before transplant can predict the development of difficult-to-treat infections after lung transplantation.

• Identification of colonization and infection with MDR organisms is important to help guide antimicrobial decisions before and after transplant, and to determine suitability for lung transplantation.

• Development of personalized antimicrobial regimens for lung transplant recipients depends on an understanding of the epidemiology, microbiology, and clinical implications of these organisms.