Bacterial infections after bone marrow transplant

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Bacterial infections after bone marrow transplant

What every physician needs to know about bacterial infections after bone marrow transplant:

Brief Overview:

Bacterial infections are common after bone marrow transplant (BMT), with primary risks involving both an inability to mount effective immune responses, most frequently associated with neutropenia and hypogammaglobulinemia, as well as breaches in innate defenses (disruption of skin by catheters and gastrointestinal (GI) tract mucositis).

There are several key concepts that BMT physicians should be aware of, focused largely on risks and prevention, appropriate management in an era of antimicrobial drug resistance, and classic presentations of typical syndromes. These are discussed below, with a syndromic approach.

Bacterial bloodstream infection

Gram-negative bacteria were historically the most common cause of bloodstream invasion, until effective prevention strategies changed our epidemiology in favor of infection caused by gram-positive bacteria. All of these organisms usually come from the skin, GI tract, or respiratory tract before invading blood.

Today, a lot of attention is being placed on the continued increase in appearance of multidrug-resistant gram-negative and gram-positive bacteria, such as extended-spectrum beta-lactamases (ESBL) - or Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae, Stenotrophomonas spp., Acinetobacter spp., Methicillin-resistant Staphylococcus aureus (MRSA), and Vancomycin-resistant Enterococcus faecium (VRE), as infection with these organisms is associated with difficulties in management and poor outcomes.

A very short discussion of the microbiology is presented here, as these concepts are important to understand in order to craft effective prevention and treatment strategies.

Microbiology and antibacterial drug resistance

Aerobic bacteria generally come in two "flavors", depending on how they appear on a gram stain. Gram-positive bacteria appear purple, secondary to internalized crystal violet that remains after alcohol-based decolorization; gram negative bacteria appear pink, as the decolorization step more effectively destroys their cell walls.

This tells you something about the type of drugs that we use; the peptidoglycan-rich cell wall in gram-positive bacteria is a target for some old (vancomycin) and new drugs (daptomycin), and changes in the cell wall can render resistance. Likewise, in gram-negative bacteria, where the target of the drug is frequently intracellular, bacteria can do crafty things like increase expression of efflux pumps to become resistant over time.

Some of the more common "problem bugs" are discussed here briefly. This list is not complete!

Pseudomonas aeruginosa

P. aeruginosa is a gram-negative bacterium that is commonly found in the environment and in water supplies. Because it can create biofilms readily, the most common infections that it causes are associated with catheters and the lungs.

It can readily become resistant to drugs using multiple different mechanisms. Occasionally, you will see an organism with pan-antibacterial susceptibility; this is a tip that the bacteria likely came from the environment and sneaked into the bloodstream through a catheter rather than as part of endogenous (GI or respiratory tract) flora. Other environmental gram-negatives do this too. It's not just an academic issue, as this tip can be helpful when considering whether the catheter needs to be removed.

There's controversy regarding whether severe infections with this organism requires combination drug therapy, with no definitive data giving us guidance. I accept that there is no clear 'right answer' and approach each case individually. When someone has a clear focus of infection that might be difficult to remove – the perfect example is pneumonia – I think that two drugs may be better as it may help decrease the likelihood of emergent resistance and poor responses in someone which severe immunosuppression. I think that these two drugs can be of different combinations, but should contain a base therapy with a beta-lactam or carbapenem (with or without the addition of an aminoglycoside or a quinolone, depending on severity of illness and the patient's organ function). In general, in the setting of instability, the aminoglycoside is the best option for additional therapy.

There are data that suggest that pneumonia caused by P. aeruginosa should be treated longer than the standard 2-week regimen, as BMT recipients have a higher rate of recurrent pneumonia and poor outcomes. In the setting of pneumonia, I extend therapy to at least three weeks.

Extended-spectrum beta-lactamase-producing bacteria

Resistance to beta-lactam antibiotics can be exhibited by many different mechanisms, and is common. However, certain Enterobacteriaceae (the gram-negative organisms that typically live in the GI tract) have acquired mechanisms to become resistant to the extended-spectrum beta-lactam antibiotics, by producing these enzymes- "ESBLs". This is most common with Escherichia coli and K. pneumoniae, and it has become quite a problem in certain hospitals, and especially in certain parts of the world, such as in Asia.

In BMT patients, infections are associated with high mortality, largely due to difficulties in choosing the most appropriate initial drug. Keep in mind that the antibiotic susceptibility testing can be confusing with these organisms, as they may have results that appear susceptible to extended-spectrum beta-lactam antibiotics (such as piperacillin-tazobactam); the laboratory typically identifies which organisms appear as if they can become resistant, and does another test to indicate that the organism is an ESBL-producer.

In the setting in which this is suspected, carbapenems are the appropriate first line therapy.

It is wise to treat people who are known to be colonized (or previously infected) with ESBL-producing organisms with carbapenems first-line, even with suspected infection during fever and neutropenia. Risks should be judged according to prior infections, colonizing organisms (if known), as well as endemicity, given the high rates of carriage in people from certain parts of the world (e.g., India, other parts of Asia). The utility of eradicating colonization is being actively evaluated.

Klebsiella pneumoniae carbapenemase-producing bacteria

Klebsiella pneumoniae carbapenemases (KPC) can also be produced by several Enterobacteriaceae, and, sometimes, P. aeruginosa, with resultant resistance to these drugs, and other beta-lactams.

Infection with these organisms is typically associated with poor outcomes, again due to difficulty in choosing the appropriate first-line drug, and the fact that these organisms can demonstrate resistance to many different classes of drugs simultaneously. These infections can be difficult to treat, and may require a combination of different classes of drugs; therapy should be guided by susceptibility testing, and Infectious Diseases (ID) consultants should be involved.

Acinetobacter spp.

Acinetobacter baumannii is another potentially problematic gram-negative organism that can cause disease in BMT patients, usually by infected catheters or lungs. These infections can be very severe, as this organism is another that can become resistant to essentially all drugs, through many different mechanisms. Drugs that were previously considered too toxic for widespread use (e.g., colistin) are now coming back off-the-shelf to treat these infections.

Stenotrophomonas spp.

This is the classic organism that can be resistant to the drugs that we typically use empirically – extended-spectrum beta-lactam antibiotics, and carbapenems. Other drugs that are less frequently used – trimethoprim sulfamethoxazole, timentin, and levofloxacin – are alternatives. Although one needs to keep these infections in mind in people who are failing and known to be colonized or have a history of prior infection, I don't typically use these drugs to cover empirically, as these infections are still rather uncommon.

Methicillin-resistant Staphylococcus aureus (MRSA)

Methicillin-resistant S. aureus strains are a problem in the hospital, most frequently causing disease in the bloodstream (via catheter), wounds, and lung infection. Oxacillin is the best treatment for S. aureus infections that are susceptible; vancomycin or other more recently available drugs – linezolid or daptomycin – are alternatives.

"Nosocomial" MRSA is the organism that has been around for a while; other, "community acquired" MRSA strains (CA-MRSA) have become more common, especially as a cause of aggressive pneumonia, due to production of additional virulence factors (toxins). Most infections in BMT patients are nosocomial strains; typified by higher level resistance to other drugs as well (e.g., clindamycin). However, I have seen patients develop early pneumonia with CA-MRSA after conditioning, with poor outcomes. In this setting, infection likely progresses from respiratory tract colonization pre-conditioning.

These organisms are "sticky", and care should be taken to assure that no other sites are infected after bloodstream invasion, using echocardiography and other tests, driven by symptoms. Catheters really should be changed in the setting of bloodstream infection with MRSA. Aggressive source-control management with fluid drainage is necessary.

Higher levels of vancomycin are needed (aim for between 15 and 20 mcg/mL). Linezolid is one option and a couple of studies have shown relative safety in non-oncology/BMT patients. Platelet counts can decrease with extended therapy, warranting close monitoring. Daptomycin doesn't work for pneumonia, but otherwise is a good option; take care with dosing this drug aggressively enough but according to weight and renal function.

Vancomycin-resistant Enterococcus (VRE)

Enterococcus faecium (and less frequently E. faecalis) can become resistant to vancomycin, and it's creating quite a problem in some transplant centers. Typically, these organisms cause more chronic colonization and infection through the GI tract, urinary tract, and catheters; rarely do VRE actually cause pneumonia, so think about other causes even in people with sputum showing Enterococcus.

Infections can be difficult to clear, and patients are usually sick so outcomes are poor, although there is debate about the proportional attributable mortality vs. disease-related mortality.

Linezolid and daptomycin are treatment options; keep in mind that resistance to both can occur as these organisms start changing the structure of their cell walls. New drugs such as tigecycline may be useful, but treatment continues to be quite complex, so source control needs to be considered priority.

Management of Bacteremia

Bloodstream involvement is common and should be approached according to the organism.

Diagnosis: Where's it coming from?

The first question that should be entertained is - 'where did this come from'? Most likely sources are the intravenous catheter, GI tract during mucositis, lungs, and urinary tract. Treatment duration and complications differ for each source, so it's important to characterize with cultures and radiographs.

Bacteremia isn't always from the catheter and is frequently from the gut; especially with gram-negative bacteria. The catheter doesn't always have to be removed. It does have to be removed if the organism is S. aureus or another pernicious biofilm-producing bug (e.g., some P. aeruginosa). It should be removed with exit-site infections, and these can paradoxically get much worse during neutrophil engraftment.


Pneumonia is one of the most common infectious complications in BMT recipients. Risks include immunologic and airway deficiencies, and extend late after allogeneic BMT, largely due to immunoglobulin deficiency. The most common radiographic findings include air-space consolidations, small centrilobular nodules and ground-glass opacities; distribution most frequently involves the central and peripheral regions of the middle and lower lung zones.

The differential diagnosis of pneumonia includes non-infectious etiologies, especially late after allogeneic BMT (e.g., bronchiolitis obliterans organizing pneumonia [BOOP]). For this reason, and because there are numerous different drug-resistant bacteria, fungi, and viruses that cause infection, diagnosis should be aggressively pursued.

Several studies have shown safety in performing bronchoalveolar lavage (BAL) after transplant, even early pre-engraftment; lavage for culture provides more information for suspected bacterial pneumonia compared to biopsy (with the exception of other more chronic infections such as Mycobacterial infection).

One retrospective study by Shannon et al of 501 consecutive, adult, nonintubated patients who underwent 598 BALs for evaluation of new pulmonary infiltrates during the first 100 days of BMT reported that the overall yield of BAL for clinically significant pathogens was 55%, with a 2.5-fold higher recovery in procedures performed within the first four days of presentation compared to those performed late. However, late antibiotic adjustments were associated with a higher rate of death. I believe that BAL should be performed whenever possible, even when biopsy is not possible due to thrombocytopenia.

Keep in mind that Enterococci and Candida species are poor pulmonary pathogens and may not be the cause of disease even when recovered from airway secretions.

"Atypical" bacterial pulmonary infections

Clinicians should be aware that there are numerous bacterial causes of pneumonia, some of which necessitate additional empirical treatment. For instance, Legionella are a known cause of pneumonia, sometimes severe and associated with outbreaks. As antigen assays only detect a specific serotype of Legionella, negative tests do not rule out infection. This is basis for a quinolone or macrolide in empirical pneumonia treatment regimens.

Other bacteria cause more chronic pulmonary infections, such as Nocardia species, Actinomycetes, and Mycobacteria (tuberculosis [TB] and non-TB). These may manifest in more nodular lesions and disease involving upper lobes (especially with reactivation TB). Treatment of both TB- and non-TB mycobacterial infections (which can also involve the catheter) is complicated and warrants advice from ID experts.

GI tract infections: neutropenic enterocolitis and Clostridium difficile colitis

Neutropenic enterocolitis

Neutropenic enterocolitis occurs when the gut barrier is damaged by conditioning therapy, allowing for invasion of organisms that inhabit the gut lumen.

It most frequently is caused by a mix of aerobic and anaerobic bacteria that commonly inhabit the gut, and should thus be treated with an antibacterial drug with wide-spectrum activity (e.g., piperacillin-tazobactam or a carbapenem). Vancomycin is not usually indicated.

I have seen enterocolitis caused by focal invasion of fungi, especially Candida albicans and even filamentous fungi; keep this in mind especially when treatment is not responding to antibacterial therapy. The role of surgery is a little questionable; most patients can be treated successfully without surgical resection. The need for a more aggressive management should be judged by serial computed tomography (CT) scans and clinical examination.

Clostridium difficile colitis

Clostridium difficile is another important cause of colitis, usually manifested by diarrhea. It most frequently occurs early after BMT, both after autologous and allogeneic transplant recipients, although allogeneic BMT patients appear to have a low level of protracted risks, especially with concurrent graft-versus-host disease (GVHD).

The clinical signs and symptoms of disease do not mimic what is found in the generalized hospital population, as these patients may not mount a significant neutrophil count and severe complications requiring surgical management is actually uncommon.

Different tests are available to diagnose C. difficile disease: these detect the presence of the bacterial toxin in stool. Polymerase chain reaction (PCR) is more sensitive than enzyme immunoassays, and many institutions are moving towards utilizing these advanced molecular tests.

Treatment options include oral vancomycin (not intravenous [IV] vancomycin, as this does not cross back into the GI tract), and metronidazole. There is some indication that vancomycin is preferred, with fewer recurrences, and it is my drug of choice. In patients with severe disease, especially those who are not taking oral medication, the combination of the two may be applied (but there is no data to support).

A new drug (fidaxomicin) is available, and early studies indicate that there may be fewer recurrences compared to vancomycin, however, it has not yet been studied specifically in the BMT population. Limiting exposure to antibacterials that alter the gut flora is a good idea, when possible; people with recurrent disease should be referred to ID specialists for consideration of more definitive treatments (such as long-tapered vancomycin).

Skin and soft tissue infections

The most common cause of cellulitis are Streptococcus species and Staphylococcus species, however, in hospitalized patients and in those with altered immunity, infection can be caused by other organisms, such as gram-negative bacteria. For this reason, I treat cellulitis with a broader spectrum drug in BMT patients, assuring coverage of gram-negatives as well. It is important to assure that no other focus of infection is apparent and that there are not drainable fluid collections underlying the skin, as these usually do need to be addressed with drainage.

Skin infections, especially those that involve catheters or other non-removable foci, usually get worse with effective therapy and especially during neutrophil engraftment; for this reason, surgery may become necessary later in the course of therapy.

There are several soft tissue infections that require more aggressive surgical exploration and drainage: necrotizing fasciitis and Fournier's gangrene can be caused by numerous different organisms and rapidly progress without aggressive surgical management. Broad antibiotic therapy to include MRSA and anaerobic coverage is necessary, as well as rapid surgical evaluation.

What features of the presentation will guide me towards possible causes and next treatment steps:


What laboratory studies should you order to help make the diagnosis and how should you interpret the results?


What conditions can underlie bacterial infections after bone marrow transplant:


When do you need to get more aggressive tests:


What imaging studies (if any) will be helpful?


What therapies should you initiate immediately and under what circumstances - even if root cause is unidentified?


What other therapies are helpful for reducing complications?


What should you tell the patient and family about prognosis?


"What if" scenarios.




What other clinical manifestations may help me to diagnose bacterial infections after bone marrow transplant?


What other additional laboratory studies may be ordered?


What’s the evidence?

Hakki, M, Limaye, AP, Kim, HW, Kirby, KA, Corey, L, Boeckh, M. "Invasive Pseudomonas aeruginosa infections: high rate of recurrence and mortality after hematopoietic cell transplantation". Bone Marrow Transplant. vol. 39. 2007 Jun. pp. 687-93.

[This study is informative with consideration of predicted outcomes and duration of antibiotic therapy for pneumonia caused by P. aeruginosa.]

Zuckerman, T, Benyamini, N, Sprecher, H. "SCT in patients with carbapenem resistant Klebsiella pneumoniae: a single center experience with oral gentamicin for the eradication of carrier state". Bone Marrow Transplant. vol. 46. 2011. pp. 1226-30.

[This is one example of new investigational strategies to decolonize patients in the setting of complicated endogenous drug resistance.]

Mitchell, AE, Derrington, P, Turner, P, Hunt, LP, Oakhill, A, Marks, DI. "Gram-negative bacteraemia (GNB) after 428 unrelated donor bone marrow transplants (UD-BMT): risk factors, prophylaxis, therapy and outcome". Bone Marrow Transplant. vol. 33. 2004. pp. 303-10.

[This study demonstrates high risks in patients with GVHD and related therapies, also outlining epidemiology.]

Engelhard, D, Cordonnier, C, Shaw, PJ. "Infections Disease Working Party for the European Bone Marrow Transplantation (IDWP-EBMT). Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey". Br J Haematol. vol. 117. 2002. pp. 444-50.

[This large study demonstrates prolonged risks for pneumococcus infection post-allogeneic BMT.]

Labarca, JA, Leber, AL, Kern, VL. "Outbreak of Stenotrophomonas maltophilia bacteremia in allogeneic bone marrow transplant patients: role of neutropenia and mucositis". Clin Infect Dis. vol. 30. 2001. pp. 195-7.

[This study illustrates outcomes and risks for S. maltophilia bacteremia during an institutional outbreak.]

Shannon, VR, Andersson, BS, Lei, X, Champlin, RE, Kontoyiannis, DP. "Utility of early versus late fiberoptic bronchoscopy in the evaluation of new pulmonary infiltrates following hematopoietic stem cell transplantation". Bone Marrow Transplant. vol. 45. 2010. pp. 647-55.

[This large study demonstrates the relative safety and efficacy of bronchoscopy in BMT patients.]
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