Bacterial infections following lung transplantation

INTRODUCTION — Lung transplantation is an effective treatment for a wide range of advanced lung diseases. While the survival of lung transplant recipients continues to improve, outcomes after lung transplantation remain inferior to other types of solid organ transplantation [1,2]. Infectious complications contribute substantially to morbidity and mortality following lung transplantation and account for over 25 percent of all post-transplant deaths [2].

This topic reviews the most common bacterial infections in lung transplant recipients. Infections caused by fungi, mycobacteria, and viruses in lung transplant recipients and general issues regarding infections in solid organ transplant recipients are discussed separately. (See "Fungal infections following lung transplantation" and "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Infection in the solid organ transplant recipient" and "Evaluation for infection before solid organ transplantation" and "Prophylaxis of infections in solid organ transplantation" and "Immunizations in solid organ transplant candidates and recipients".)

RISK OF INFECTION — Lung transplant recipients are at increased risk for infectious complications due to the following factors:

●The high level of immunosuppression required to prevent rejection

●Adverse effects of transplantation on local pulmonary host defenses (loss of lymphatics, reduced mucociliary clearance, decreased cough)

●Constant environmental contact allowing pathogens direct access into the allograft

The likelihood and type of infection varies with the degree of host immunosuppression, timing since transplantation, nature and duration of antimicrobial prophylaxis, and local hospital and regional microbiology.

Pneumonia, particularly bacterial pneumonia, is the most common type of infection in lung transplant recipients, although bloodstream, pleural space, and wound infections are also common [3,4]. Bacterial, viral, fungal, and mycobacterial infections all occur at an increased frequency after lung transplantation. (See "Fungal infections following lung transplantation" and "Prevention of cytomegalovirus infection in lung transplant recipients" and "Tuberculosis in solid organ transplant candidates and recipients" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

In addition to the direct morbidity and mortality caused by infectious complications, they may also lead to loss of allograft function and contribute to the development of bronchiolitis obliterans syndrome [5-7]. (See "Infection in the solid organ transplant recipient" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

TIMELINE OF INFECTION — Infections are generally thought to arise in a predictable pattern following solid organ transplantation, though deviations occur. The post-transplant period can be divided into three stages: the first month post-transplant, one to six months post-transplant, and more than six months post-transplant.

●During the early post-transplant period, bacterial infections predominate. During the first month, there are three major causes of infection:

•Infection transmitted with the donor allograft

•Infection derived from the recipient

•Infectious complications of the transplant surgery and hospitalization

●From one to six months post-transplant, patients are most at risk for opportunistic infections, although residual donor-derived infections arising from the perioperative period can persist.

●More than six months post-transplant, most patients are receiving stable and reduced levels of immunosuppression. These patients are subject to pneumonia caused by an extended range of bacteria, including pneumococcus, gram-negative bacilli, Legionella, and other common pathogens rather than opportunistic infections.

The pattern of infection seen during these periods is discussed in greater detail separately. (See "Infection in the solid organ transplant recipient", section on 'Timing of infection post-transplantation'.)

EVALUATION FOR INFECTION — Evaluation for infection in lung transplant recipients should follow the general approach used in all solid organ transplant recipients. (See "Infection in the solid organ transplant recipient", section on 'Evaluation and management'.)

Several unique considerations apply to lung transplant recipients in whom pneumonia is the most common type of infection [3]. Some lung transplant recipients with pneumonia present with fever, cough, dyspnea, and infiltrates on chest imaging. However, some patients have few or atypical symptoms due to the blunting of the immune response by immunosuppressive drugs. In addition, the presentation of infection often overlaps with that of allograft rejection; thus, a high index of suspicion for both infection and rejection should be maintained to ensure early appropriate diagnosis and therapy. (See "Evaluation and treatment of acute cellular lung transplant rejection".)

Diagnostic approach — Since pneumonia is the most common type of infection in lung transplant recipients, the diagnostic evaluation generally includes early and aggressive evaluation of the lungs as a potential source. Lung transplant recipients can deteriorate quickly in the absence of appropriate therapy. Thus, a reasonable approach to the lung transplant patient with respiratory symptoms involves initial empiric treatment for infection while awaiting microbiologic and histopathologic data. The specific organisms targeted by the empiric regimen depend upon the patient's risk factors and clinical presentation. (See 'Treatment' below.)

After initiation of empiric antimicrobial therapy and imaging with a chest radiograph, invasive diagnostic testing should be considered in most lung transplant recipients unless contraindications exist. In addition, chest computed tomography may be helpful in patients when a pulmonary infection is uncertain based on clinical history, exam, and chest radiographs alone.

Bronchoscopy with bronchoalveolar lavage is the most sensitive diagnostic study to identify the etiology of pulmonary infections and rule out atypical etiologies (table 1). Due to the similar clinical presentation, we normally perform transbronchial biopsies at the same time to rule out rejection [8]. In addition, it is possible that infection and rejection may coexist.

BACTERIAL INFECTIONS — Bacterial infection is the most common early infectious complication after lung transplantation and remains a leading cause of death throughout the post-transplant period [9,10]. In addition to pneumonia, lung transplant recipients are at risk for other types of bacterial infections including empyema, bloodstream infection, and wound infection.

Sites of infection

Pneumonia — The risk for the development of bacterial pneumonia is influenced by both donor and recipient factors, and the risk is highest during the early post-transplant period. Despite antibiotic prophylaxis, the incidence of bacterial pneumonia is approximately 10 to 20 percent in the first 30 days post-transplant [11,12]. In a prospective multicenter study of pneumonia in lung transplant recipients, 40 of 85 episodes of pneumonia (44 percent) occurred during the first 30 days following transplantation [13]. Early post-transplant pneumonias are typically caused by hospital-acquired bacteria, including multidrug-resistant Pseudomonas aeruginosa, Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults".)

Bacterial infections can be transmitted from the donor or develop in the setting of the post-transplant intensive care unit admission. Although approximately 60 percent of donor lungs are colonized, only 6 to 12 percent of recipients develop active infection transmitted from the donor lungs if they receive appropriate antibiotic prophylaxis [12,14]. The detection of certain bacteria from the donor lung(s) warrants additional antibacterials beyond the usual period of perioperative prophylaxis, as discussed below. (See 'Routine perioperative prophylaxis' below and 'Positive donor lung cultures' below.)

Later in the time course (especially more than six months post-transplant), lung transplant recipients are also at risk for developing pneumonia from community-acquired bacterial pathogens. In addition, the risk for infection with multidrug-resistant bacteria remains elevated due to the transplant recipient's frequent exposure to health care facilities and increased use of antibacterial agents. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults".)

In addition to the usual community-acquired and hospital-acquired pathogens, lung transplant recipients are at increased risk for pneumonia with bacteria that are typically nonpathogenic in the immunocompetent host, such as Mycoplasma hominis [15], Ureaplasma urealyticum [16], and Nocardia spp [17-20], and, for fungal pneumonia, most commonly caused by Aspergillus fumigatus. M. hominis has been reported as donor derived [21]. (See "Fungal infections following lung transplantation".)

Lung transplantation recipients are also at increased risk for aspiration pneumonia, both in the early post-transplant period and thereafter. This risk is enhanced in the early postoperative period due to oropharyngeal dysfunction, surgical irritation or damage to the phrenic nerve, and resultant delay in gastric emptying that could persist for weeks. In addition, underlying disorders that impair esophageal function (eg, scleroderma) and/or airway protection (eg, stroke) may coexist. (See "Aspiration pneumonia in adults".)

Patients with cystic fibrosis (CF) are at a significantly higher risk of pneumonia compared with other lung transplant recipients [11,22] and are more likely to be colonized with multidrug-resistant P. aeruginosa and Burkholderia cepacia [23]. Despite a decreased bacterial burden after removal of the native lungs, patients with CF are at high risk of post-transplant infection due to the potential for contamination of the bloodstream and the thoracic cavity during transplantation. Furthermore, these patients remain at increased risk for infection post-transplant because the native upper airways and sinuses of CF patients retain the chloride channel defect and remain persistently colonized with the pathogens that were present pre-transplant, particularly P. aeruginosa and B. cepacia. (See 'Pseudomonas aeruginosa' below and 'Burkholderia cepacia' below and "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection" and "Pseudomonas aeruginosa pneumonia".)

Pleural space infections — Reaccumulation of pleural fluid after the initial post-transplant chest tube removal can occur due to hemorrhage, rejection, or infection. Pleural fluid accumulation that worsens beyond the first few days following transplantation warrants immediate investigation to exclude empyema [24]. Empyema occurs in 3 to 5 percent of lung transplant recipients; almost all of these infections occur during the first six months after transplantation, with 40 percent occurring within the first month [25-28]. In one large single-center study, pleural disease occurred in a bimodal occurrence after lung transplantation, with earlier disease more likely to be infectious than pleural disease occurring greater than one year after transplant [29]. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

The incidence of pleural space infections does not appear to be dependent on underlying lung disease or surgical procedure [25,30,31]. However, case reports show an increased incidence of pleural space infections due to B. cepacia in patients with cystic fibrosis who harbor this organism pre-transplant [32]. In a study of pleural space infections in 36 lung transplant recipients, the most common causes were fungi (in 61 percent) and bacteria (in 31 percent) [31]. No bacterial species predominated; there were two cases each of B. cepacia, Escherichia coli, and Mycoplasma hominis, and one case each of S. aureus, Enterococcus spp, P. aeruginosa, Serratia marcescens, and Roseomonas spp. Listeria monocytogenes, which rarely causes pneumonia, has been reported as a cause of empyema in a lung transplant recipient [33].

The short-term mortality of lung transplant recipients with empyema has been estimated to approach 40 percent [25,26].

Bloodstream infections — Bloodstream infections (BSIs) are an important cause of morbidity and mortality in lung transplant recipients. In a prospective multicenter study of lung transplant recipients over a five-year period, the incidence of bacteremia was 11.5 percent [34]. Risks for BSI include the use of central venous catheters, mechanical ventilation, and cystic fibrosis. BSIs in transplant recipients reflect the pattern of bloodstream infections in immunocompetent hospitalized patients and are most frequently due to S. aureus, P. aeruginosa, Enterococcus spp, and Candida spp [35]. In another prospective multicenter study, pulmonary and vascular catheter infections accounted for 47 and 41 percent of all BSIs after lung transplant, respectively [34]. The lungs were the predominant source of BSIs in the first year post-transplant, whereas vascular catheters predominated as the source after one year. Resistant gram-negative bacteremia was more likely with underlying pneumonia and in patients with cystic fibrosis. (See "Intravascular catheter-related infection: Epidemiology, pathogenesis, and microbiology" and "Epidemiology of Staphylococcus aureus bacteremia in adults" and "Gram-negative bacillary bacteremia in adults" and "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)

The development of BSI is associated with increased mortality for both adult and pediatric lung transplant recipients [35,36]. In a multivariate analysis, BSI was associated with an almost sixfold increased risk of death [35]. Blood cultures should be obtained in all lung transplant recipients presenting with pneumonia or any systemic signs or symptoms of infection following transplantation.

Skin and soft tissue infections — Although the high degree of immunosuppression places lung transplant recipients at risk for infection of the transplant surgical site, this occurs infrequently. The same nosocomial pathogens that cause early post-transplant bloodstream and lung infections (eg, P. aeruginosa, S. aureus, Candida spp) are the most common causes of surgical wound infections [37]. P. aeruginosa and nontuberculous mycobacteria (especially Mycobacterium abscessus) are of particular concern in patients with cystic fibrosis due to pretransplant colonization or chronic infection with those organisms and the risk for perioperative seeding of the surgical wound [38,39]. (See "Pseudomonas aeruginosa skin and soft tissue infections" and "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection".)

M. hominis and U. urealyticum are rare but reported causes of surgical wound infection after lung transplantation [40,41]. Unexplained hyperammonemia can be a clue to diagnosis [42].

Specific pathogens — Lung transplant recipients are susceptible to a broad range of gram-positive and gram-negative infections.

Patients with cystic fibrosis have unique risk factors for infection following transplantation. In particular, patients with CF are often colonized with methicillin-resistant S. aureus as well as such gram-negative bacteria as P. aeruginosa and B. cepacia, both of which are frequently multidrug resistant. The reported incidence of nontuberculous mycobacteria is also increasing, particularly among lung transplant recipients with cystic fibrosis. (See 'Nontuberculous mycobacteria' below.)

While certain viral and fungal infections have been associated with an increased risk for chronic lung allograft dysfunction (CLAD), and specifically to the bronchiolitis obliterans phenotype, the role of bacterial pathogens in the development of CLAD remains uncertain. Some reports suggest an association between P. aeruginosa and Chlamydia pneumoniae and a higher incidence of chronic lung rejection, though those results have not been consistently replicated [43,44]. (See 'Chlamydia pneumoniae' below and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

Microbiome sequencing is being used to help determine role of the respiratory microbiota in the development of CLAD. In a prospective cohort study evaluating bronchoalveolar lavage (BAL) fluid from lung transplant recipients one year post-transplant, investigators found that increased bacterial burden within the BAL fluid was predictive of the development of CLAD at 500 days post-transplant [45].

Pseudomonas aeruginosa — Nearly 50 percent of Pseudomonas isolates in lung transplant recipients are resistant to one or more antibiotics [46]. While the safety of lung transplantation in patients colonized or chronically infected with multidrug-resistant pathogens has been a matter of controversy since the beginning of lung transplantation, an increasing number of studies has shown acceptable survival for lung transplantation in patients colonized with multidrug-resistant gram-negative bacteria prior to transplant [47-50]. As an example, in one retrospective study, one-year survival for CF patients colonized with multidrug-resistant P. aeruginosa was greater than 80 percent and was similar to other patients with CF who were not colonized with resistant bacteria [47]. Based on these findings, pretransplant colonization with multidrug-resistant P. aeruginosa should not exclude patients from consideration for transplant. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

Burkholderia cepacia — B. cepacia (formerly known as Pseudomonas cepacia) is a gram-negative rod that commonly colonizes the lungs of patients with cystic fibrosis and is frequently multidrug resistant [51]. B. cepacia has been classified into nine genomovars, which are phenotypically similar but genotypically distinct [52]. Burkholderia cenocepacia (genomovar III) and Burkholderia multivorans (genomovar II) are the most common causes of B. cepacia colonization and infection in CF patients, although the prevalence of each genomovar varies by geographic region. (See "Epidemiology of pulmonary infections in immunocompromised patients".)

It has been shown that pretransplant B. cepacia colonization is associated with higher early post-transplant mortality [47,53-55]. However, subsequent studies have suggested that increased post-transplant mortality is associated only with B. cenocepacia (genomovar III) but not with B. multivorans (genomovar II) or other genomovars [52-57].

In a study of 75 lung transplant recipients with CF, 7 were colonized with B. cenocepacia, 9 were colonized with other genomovars of B. cepacia, and 59 were not colonized with B. cepacia pretransplant [52]. One-year survival of patients with B. cenocepacia was 29 percent, compared with 89 percent for those with other B. cepacia genomovars and 92 percent for those without B. cepacia. A single center reviewed 216 patients with CF who underwent lung transplantation. Of these, 22 had confirmed preoperative B. cepacia complex (BCC) infection, with 12 of these being B. cenocepacia. Nine B. cenocepacia-infected recipients died within the first year, and in eight recipients, BCC sepsis was considered to be the cause of death. Despite instituting a tailored perioperative immunosuppressive and microbiologic care approach for such patients, post-transplantation BCC septic deaths occurred frequently in those with pretransplantation B. cenocepacia infection. In contrast, recipients infected with other BCC species had significantly better outcomes, with post-transplantation survival comparable to other recipients with CF [55]. Later complications of B. cepacia colonization include lung abscess and empyema.

Burkholderia dolosa (genomovar VI) is a less common genomovar. In a retrospective study of 11 patients transplanted with known colonization with B. dolosa, survival rates were 73, 53, and 30 percent for 1, 3, and 5 years, respectively, with a median survival of 44 months. While survival appears lower than patients without pretransplant Burkholderia colonization, it remains notably higher than historical survival with B. cenocepacia [53].

Available data support screening of all patients with CF for B. cenocepacia. Colonization with this strain is viewed as a relative contraindication to transplantation. If transplantation is attempted in patients who harbor B. cenocepacia, early aggressive antimicrobial prophylaxis should be employed in an effort to decrease early B. cepacia-related mortality. (See 'Positive native lung cultures' below.)

Other gram-negative bacteria — In addition to P. aeruginosa and B. cepacia, other gram-negative bacteria species can cause pneumonia in lung transplant recipients, some of which are multidrug resistant [58]. Commonly encountered gram-negative species include Acinetobacter spp, Stenotrophomonas maltophilia, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and E. coli [4]. (See "Acinetobacter infection: Treatment and prevention" and "Stenotrophomonas maltophilia" and "Clinical features, diagnosis, and treatment of Klebsiella pneumoniae infection" and "Infections due to Serratia species" and "Gram-negative bacillary bacteremia in adults".)

Staphylococcus aureus — S. aureus, including methicillin-resistant S. aureus, is a common cause of hospital-acquired, health care-associated, and ventilator-associated pneumonia, as well as bacteremia and surgical-site infections [59]. Specific infections caused by S. aureus are discussed in detail separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology" and "Epidemiology of Staphylococcus aureus bacteremia in adults" and "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections" and "Clinical approach to Staphylococcus aureus bacteremia in adults" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)

Streptococcus pneumoniae — Lung transplant recipients in the late post-transplant period (more than six months following transplantation) are susceptible to typical community-acquired pathogens such as Streptococcus pneumoniae. Despite the use of trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis, lung transplant recipients have a greater likelihood of developing invasive pneumococcal infection and bacteremia [60]. In addition, they have an increased incidence of infection with resistant S. pneumoniae, with approximately 80 percent of isolates resistant to trimethoprim-sulfamethoxazole and 60 percent with intermediate- or high-level penicillin resistance [60]. (See "Pneumococcal pneumonia in patients requiring hospitalization" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

All adult lung transplant candidates and recipients in the United States should be vaccinated against pneumococcus (table 2). (See "Pneumococcal vaccination in adults".)

Chlamydia pneumoniae — The obligate intracellular bacteria C. pneumoniae can cause upper and lower respiratory tract infections. Due to the difficulty in culturing Chlamydia, diagnosis relies on serological and molecular techniques. These limitations have led to an underestimation of the frequency of Chlamydia infection in the early post-transplant period.

One study employed polymerase chain reaction (PCR) for Chlamydia on BAL fluid in lung transplant recipients during the early post-transplant period. A positive PCR for Chlamydia was identified in 25 percent of patients within the first month post-transplant [61]. The identification of Chlamydia spp was associated with adverse outcomes, including allograft rejection, airway complications, and increased mortality. In addition, possible donor transmission of Chlamydia was observed in three patients. Until newer diagnostic techniques are widely available, clinicians must have a high index of suspicion for this underappreciated pathogen in lung transplant recipients.

Nocardia — Infections caused by Nocardia species are rare. The majority of cases occur in immunocompromised patients, including solid organ transplant recipients. Approximately 1.9 to 3.5 percent of lung transplant recipients develop nocardiosis [17,18,62], with a mean onset of 14.3 months after transplantation (range 1.5 to 39 months) [17]. Although trimethoprim-sulfamethoxazole has activity against Nocardia species, cases of nocardiosis have occurred in patients receiving thrice-weekly trimethoprim-sulfamethoxazole prophylaxis, and thus daily trimethoprim-sulfamethoxazole may be more effective at preventing this infection [17,18]. Nocardia species most commonly cause pneumonia in lung transplant recipients, typically with a subacute presentation [19].

Nocardiosis should be considered in lung transplant recipients with pneumonia, particularly if it does not respond to empiric therapy. Special staining (modified acid-fast bacillus staining) and cultures should be requested when infection with Nocardia spp is suspected (table 1). (See "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis" and "Treatment of nocardiosis" and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis", section on 'Lungs'.)

Clostridioides difficile — Clostridioides difficile infection is a common problem in lung transplant recipients, with an estimated incidence of 7 to 31 percent [63-65]. C. difficile infection occurs most frequently in the early period following transplantation and in those requiring prolonged hospitalization. The intense immunosuppression and frequent exposure to antimicrobial agents that occur shortly after transplantation likely contribute to the increased risk for C. difficile infection during this period [64]. In a single-center retrospective analysis of 500 lung transplant recipients, 6 percent developed C. difficile infections within 90 days of postoperative antimicrobial prophylaxis [66]. The duration of antibiotics with gram-positive activity and intensive care unit stay appeared to increase the risk. In another study, C. difficile infection was an independent predictor of death among lung transplant recipients, especially if it occurred in the first six months post-transplant [67]. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis" and "Clostridioides difficile infection in adults: Treatment and prevention".)

Mycoplasma hominis, Ureaplasma urealyticum, and hyperammonemia — Severe hyperammonemia has been reported as a rare and frequently fatal cause of coma in lung transplant recipients during the early postoperative period. Some cases of hyperammonemia in lung transplant recipients have been associated with Mycoplasma or Ureaplasma infection. The clinical manifestations, diagnosis, and treatment of M. hominis and Ureaplasma spp infections in lung transplant recipients with hyperammonemia are discussed in detail separately. (See "Noninfectious complications following lung transplantation", section on 'Hyperammonemia' and "Mycoplasma hominis and Ureaplasma infections", section on 'Treatment'.)

Nontuberculous mycobacteria — Nontuberculous mycobacteria are increasingly recognized as causes of infections in lung transplant recipients [38,68-70]. Mycobacterium avium and Mycobacterium intracellulare (together known as M. avium complex [MAC]) are the most common nontuberculous mycobacterial (NTM) species isolated after solid organ transplantation and infection with these organisms typically involves the lungs. Cutaneous and disseminated infections are the next most common presentations; however, the clinical presentation and severity of illness vary with the infecting NTM species and site(s) of involvement. (See "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients".)

TREATMENT — Empiric therapy should be based on prior culture data when available and antibiotics adjusted as needed by repeat cultures when possible.

Pneumonia — In lung transplant recipients, the immunocompromised status, commonness of multidrug-resistant (MDR) bacteria, and higher risk of mortality outweigh any other factors related to whether they are community dwelling, hospitalized, or ventilated. As such, we do not find the distinction among types of pneumonia as community acquired, hospital acquired, or ventilator associated to be as helpful in this patient population.

We favor empiric broad-spectrum antibiotics initially, taking into account prior infections and colonization as well as other likely potential pathogens, including methicillin-resistant S. aureus (MRSA), P. aeruginosa, other gram-negative bacilli, and atypical bacteria (eg, Mycoplasma pneumoniae, Legionella spp). Bronchoalveolar lavage (BAL) cultures and other diagnostic tests (eg, Legionella urinary antigen, pneumococcal urinary antigen) should be used to adjust antibiotic regimens as appropriate. Even if a specific microbiologic etiology is not identified, continued broad-spectrum antibiotics may remain necessary in certain cases. A high index of suspicion for nonbacterial etiologies is needed when there is no clinical improvement despite appropriate antibiotics.

The diagnosis and treatment of pneumonia as well as the approach to the patient with nonresolving pneumonia are discussed in detail separately. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults" and "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults" and "Nonresolving pneumonia".)

Duration — There are no high-quality data to guide the duration of antibiotic therapy for bacterial pneumonia in lung transplant recipients. Short-course antibiotic therapy for seven or eight days has only been validated in the immunocompetent host with ventilator-associated pneumonia [71]. In most cases, two weeks of antibiotics is an appropriate duration for lung transplant recipients with bacterial pneumonia. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Duration of therapy' and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Duration'.)

Other infections — The treatment of pleural space infections in lung transplant recipients requires drainage as well as a prolonged course of antimicrobial therapy. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

Some skin and soft tissue infections require surgical debridement as well as prolonged antibiotics. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections" and "Necrotizing soft tissue infections" and "Pseudomonas aeruginosa skin and soft tissue infections".)

The general approach to bloodstream infections is similar as the approach in nontransplant patients. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults" and "Intravascular non-hemodialysis catheter-related infection: Treatment" and "Clinical approach to Staphylococcus aureus bacteremia in adults" and "Gram-negative bacillary bacteremia in adults" and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia in adults" and "Treatment of enterococcal infections" and "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

PROPHYLAXIS — Although there are no randomized trials that prove the value of early post-transplant systemic antimicrobial prophylaxis, it is typically administered.

Systemic antibiotics — Antibiotic prophylaxis regimens should be chosen to broadly cover the common gram-positive and gram-negative pathogens associated with nosocomial infection at a particular institution and should also be tailored to cover likely pathogens in a given patient based on prior microbiology data and risk factors.

Routine perioperative prophylaxis — We usually use a regimen of vancomycin and cefepime perioperatively to prevent bacterial infection. Initial doses are administered prior to incision, typically between arrival in the operating room and positioning the patient for surgery (table 3). If cefepime is not available, alternative beta-lactams with anti-pseudomonal activity include ceftazidime and piperacillin-tazobactam. Such a regimen is designed to cover methicillin-resistant S. aureus (MRSA) as well as P. aeruginosa and other gram-negative bacteria, although the specific regimen chosen depends upon local resistance patterns and the patient's microbiologic data. For patients undergoing lung transplantation for cystic fibrosis (CF), in particular, the regimen should be tailored to cover the susceptibility patterns of the known pretransplant pathogens. For patients whose chest remains open post-transplant, we add a systemic antifungal agent that treats Candida species (eg, an echinocandin, such as micafungin).

The optimal duration of antimicrobial prophylaxis is uncertain, varies at different transplant centers, but generally ranges from 72 hours to 7 days and is determined based upon several patient-specific factors. For patients without septic lung disease (eg, cystic fibrosis) who have an uncomplicated course following transplantation, we typically continue systemic antibacterial prophylaxis for 72 hours to allow time to determine whether donor cultures are positive. We generally continue prophylaxis against gram-positive organisms, particularly MRSA, as long as chest tubes remain in place. For a patient whose chest remains open following transplantation, we continue antimicrobial prophylaxis until the chest is closed. (See "Fungal infections following lung transplantation", section on 'Prophylaxis'.) .

Trimethoprim-sulfamethoxazole — Trimethoprim-sulfamethoxazole (TMP-SMX), which is the agent of choice for P. jirovecii (formerly P. carinii) pneumonia prophylaxis, has the added benefit of having activity against various other pathogens such as S. pneumoniae, L. monocytogenes, and Toxoplasma gondii. It also has activity against Nocardia spp, although cases of nocardiosis have occurred in solid organ transplant recipients receiving TMP-SMX prophylaxis. TMP-SMX should be started within one week postoperatively. The usual dosing is one double-strength tablet daily or three times per week or one single-strength tablet orally daily, continued indefinitely (table 3). (See "Fungal infections following lung transplantation", section on 'Pneumocystis pneumonia'.)

Positive lung cultures — When cultures are positive from either the donor lung at the time of transplantation or from the native lungs either from the pretransplant period or from the time of transplantation, treatment is advisable to prevent the development of anastomotic complications, pneumonia, and thoracic space infections.

Positive donor lung cultures — Bronchial washings are routinely obtained from the donor lungs for Gram stain and culture during transplantation. When such cultures are positive, the lung transplant recipient is usually treated with antimicrobial agents that target the isolated species. Lung transplant recipients should generally be treated for two weeks with directed antibacterial therapy against S. aureus or gram-negative bacilli when one of these pathogens is isolated from the donor lung(s) [72]. A shorter course is reasonable when less virulent bacteria are detected.

Positive native lung cultures — In patients colonized pretransplant with multidrug-resistant bacteria, such as P. aeruginosa or B. cepacia, aggressive antimicrobial prophylaxis with multiple agents from different classes is administered during the post-transplant period. The specific regimen depends upon the resistance patterns of the individual patient's isolates. Durations of IV antibiotics of two to three weeks are typical for most infections excluding B. cepacia, which requires a longer duration. (See 'Burkholderia cepacia' above and 'Pseudomonas aeruginosa' above.)

As discussed above, B. cenocepacia is associated with significantly worse post-transplant survival compared with CF patients not colonized with this organism [52,56,73-75]. For this reason, colonization with B. cenocepacia is considered a relative contraindication to transplantation and is generally performed only at a limited number of transplant centers with experience managing such patients. (See 'Burkholderia cepacia' above.)

Adjunctive strategies — Adjunctive approaches to systemic antibiotics include inhaled antimicrobial agents and removal of potential infectious reservoirs. While the role of inhaled antibiotics such as aminoglycosides has not been rigorously studied, the potential to decrease colonization of the allograft with minimal systemic toxicity may be an appealing strategy in patients at high risk for multidrug-resistant organisms, such as Pseudomonas and Burkholderia spp.

The use of inhaled aminoglycosides in addition to systemic therapy is often used for patients with cystic fibrosis or other septic lung disease in which patients are known to be colonized with gram-negative bacteria prior to transplant. Inhaled aminoglycosides are also frequently used post-transplant for multidrug-resistant gram-negative infections in any host.

Other prophylactic measures include clearance of the bacterial reservoir in the sinuses of patients with CF or other ciliary function defects. The sinuses serve as a major reservoir for bacterial pathogens in patients with CF. There are conflicting data regarding whether pretransplant sinus surgery decreases the incidence of bacterial colonization of the lungs, tracheobronchitis, or pneumonia after lung transplantation [76,77]. The American Society of Transplantation therefore does not recommend routine pretransplant surgery [51].

Central venous catheters should be removed as early as possible post-transplant to limit the risk of bloodstream infection.

VACCINATION — Prevention of infection is of paramount importance to the lung transplant recipient. Infection in these patients results in excessive morbidity and mortality, and antimicrobial therapy is often less effective than in the immunocompetent host. Although immunization appears to be an obvious way to prevent infection, many immunocompromised patients are unable to mount protective immune responses.

Lung transplant candidates often have to wait unpredictable periods before a suitable donor is available. This waiting period should be used to maintain or boost antibody concentrations for all age-, exposure history-, and immune status-appropriate vaccines (table 4) [78]. The timing of resuming vaccinations post-transplant and other issues related to immunizations in solid organ transplant candidates and recipients are discussed in detail separately. (See "Immunizations in solid organ transplant candidates and recipients".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infections in solid organ transplant recipients".)

SUMMARY AND RECOMMENDATIONS

●Increased risk of infection − Lung transplant recipients are at increased risk for infectious complications due to the high level of immunosuppression required to prevent rejection, adverse effects of transplantation on local pulmonary host defenses (eg, reduced mucociliary clearance), and constant environmental contact allowing pathogens direct access into the allograft. (See 'Risk of infection' above.)

●Common infections − Pneumonia is the most common type of infection in lung transplant recipients, although bloodstream, pleural space, and wound infections are also common. (See 'Risk of infection' above.)

●Specific risks with cystic fibrosis − Patients with cystic fibrosis (CF) have unique risk factors for infection following transplantation. In particular, patients with CF are often colonized with such gram-negative bacteria as Pseudomonas aeruginosa and Burkholderia cepacia, both of which are frequently multidrug resistant. (See 'Specific pathogens' above.)

●Treatment of bacterial pneumonia − Patients suspected of having bacterial pneumonia should be treated empirically with broad-spectrum antibiotics, taking into account prior infections and colonization as well as other likely potential pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), P. aeruginosa, other gram-negative bacilli, and atypical bacteria (eg, Mycoplasma pneumoniae, Legionella spp). The treatment duration in lung transplant recipients with uncomplicated bacterial pneumonia should generally be two weeks. (See 'Pneumonia' above.)

●Perioperative antibacterial prophylaxis − We recommend perioperative antibacterial prophylaxis for all lung transplant recipients (Grade 1C). For routine perioperative antibacterial prophylaxis in lung transplant recipients, we favor vancomycin and ceftazidime, although the choice of regimen should be based upon local resistance patterns and the patient's microbiologic data. For patients without septic lung disease who have an uncomplicated course following transplantation, we typically continue systemic antibacterial prophylaxis for at least 72 hours. (See 'Prophylaxis' above.)

●Treatment of bacteria isolated from donor lungs − When S. aureus or gram-negative bacilli are isolated from the donor lung(s), we recommend that lung transplant recipients be treated with directed antibacterial therapy against the species isolated (Grade 1C). We favor a two-week course of antibiotics for these bacteria. (See 'Positive donor lung cultures' above.)

●Treatment of bacteria isolated from native lungs − In patients colonized pretransplant with multidrug-resistant bacteria, such as P. aeruginosa or B. cepacia, aggressive antimicrobial prophylaxis with multiple agents from different classes is administered during the post-transplant period. The specific regimen depends upon the resistance patterns of the individual patient's isolates. Durations of intravenous antibiotics of two to three weeks are typical for most infections excluding B. cepacia, which requires a longer duration. (See 'Positive native lung cultures' above.)

●Post-transplant antibacterial prophylaxis − We recommend trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis (Grade 1A); in addition to anti-Pneumocystis activity, trimethoprim-sulfamethoxazole also has activity against Streptococcus pneumoniae, Listeria, Nocardia, and Toxoplasma spp. The usual dosing is one double-strength tablet daily or three times per week or one single-strength tablet daily, continued indefinitely. (See 'Prophylaxis' above.)

●Screening for Burkholderia cenocepacia − All patients with cystic fibrosis should be screened for B. cenocepacia prior to transplantation. Colonization with this strain is viewed as a relative contraindication to transplantation. (See 'Burkholderia cepacia' above and 'Positive native lung cultures' above.)