Bacterial infections remain the most common cause of infectious morbidity in immunosuppressed cardiac transplant patients within the early post-transplantation period [26], and can present as wound infections, pneumonias, urinary tract infections (UTIs), bacteremia from venous catheter-associated infections, and rarely, infective endocarditis. Broadly speaking, the pathogens in the early post-transplantation period are similar to those causing infections in non-transplant surgical patients. Here, the most common bacterial organisms and their treatment will be covered.

As a general rule, the ISHLT guidelines state with regard to antibiotic therapy [3]: that prophylaxis should be used before the transplant operation; that drugs should be selected based upon their activity against usual skin flora; that in the event of a chronically infected device such as a VAD, that peri-operative antibiotics should be selected based on microbiologic sensitivities; and that in the event that a donor had an ongoing infection, that a course of suitable antibiotics should be considered.

The Staphylococcus species are the most common Gram-positive organisms causing infectious disease in the cardiac transplant patient, especially in the early period post-transplantation [27]. The coagulase-positive S. aureus is the most common, and is usually methicillin sensitive if community-acquired; it may manifest as wound infection, line sepsis, pneumonia or a UTI. Rarely, S. aureus has been associated with endocarditis shortly after transplant [28]. Hospital-acquired strains are usually methicillin resistant (MRSA). The methicillin-sensitive variant may be treated with oxacillin or nafcillin, or cefazolin as a possible alternative. For MRSA, vancomycin is the preferred first-line drug. In severe staphylococcal infections, rifampin or gentamicin may also be necessary.

The coagulase-negative S. epidermidis is another commonly occurring infection in post-cardiac transplant patients [1]. Almost all cases are nosocomially acquired. Because they normally reside on human skin and mucous membranes, they are usually found in wound infections. There is a higher rate of methicillin resistance among the coagulase-negative Gram-positive cocci; these methicillin-resistant coagulase-negative infections tend to occur later in transplant course rather than in the early period. If methicillin-sensitive, oxacillin or nafcillin should be used, but if resistant, vancomycin is the recommended first-line drug. Where applicable, wounds should be debrided.

Because enterococci engage in synergistic relationships with other gut flora, they are more likely to be involved in polymicrobial infections, and are more difficult to treat. For sensitive enterococci, the treatment of choice is ampicillin or vancomycin. However, in recent years the emergence of vancomycin-resistant Enterococcus (VRE) has provided a major source of morbidity and mortality associated with infections [29]. Rates of VRE infection have been reported from 1% to 16% in solid organ transplant recipients, and mostly occur within the first month post-transplantation [29].

Cardiac transplant recipients are at increased risk of Streptococcus pneumoniae infection compared to the normal population, given their immunosuppressed state. S. pneumoniae is an alpha-hemolytic, facultative anaerobe, and infection most commonly manifests as bacteremia, meningitis or pneumonia [30]. Pneumococcal infection is more often community acquired and tends to present later after transplantation. The treatment of choice is penicillin; penicillin-resistant strains may be treated with ceftriaxone, and even vancomycin in cephalosporin-resistant strains. In cases of pneumococcal sepsis, vancomycin should be administered empirically in addition pending sensitivities.

A Gram-positive bacillus, Listeria monocytogenes is a reasonably common pathogen in the immunocompromised host. Typically presenting early after transplantation or during treatment of rejection when boluses of immunosuppression have just been administered, Listeria is a common cause of bacterial meningitis in solid organ transplant recipients [31], and may also cause other central nervous system (CNS) infections, such as encephalitis, brain abcesses and cerebritis; bacteremia also often occurs [32]. Patients displaying meningitic symptoms should undergo prompt lumbar puncture for cerebrospinal fluid analysis and should be treated with broad-spectrum antibiotics empirically. Occasionally, listeriosis may occur later after transplant, as Listeria is known to be associated with certain unpasteurized meat and dairy products; thus patients should be told to avoid these. The treatment of choice for Listeria is ampicillin; in the penicillin-allergic patient, a carbapenem or trimethoprim/sulfamethoxazole is appropriate.

While decreased due to the advent of trimethoprim-sulfamethoxazole prophylaxis and cyclosporine-based immunosuppression, infectious complications due to Nocardia species are still relatively common within the first 6 months post-transplantation, with frequency reported from 0.7% to 3.5% in solid organ transplant recipients [33]. Nocardiosis may occur in a localized or disseminated form, with the most common form localized to the lungs, although hematogenous spread to the brain, skin and subcutaneous tissues, bone and eye have been reported [33]. As localized lung disease is most common, nocardiosis typically presents as a subacute pneumonia with associated symptoms for a week or more. If treated promptly, survival is high, unless there is considerable spread to the CNS [33]. The treatment of choice is trimethoprim-sulfamethoxazole, or alternatively, third generation cephalosporins or imipenem; treatment should last for at least 6 months or longer, dependent on response. Antibiotic therapy should be guided by sensitivities [33].

Diarrhea is relatively common in the early period post-transplantation; the most common causes are an infectious agent, or medication. Clostridium difficile is the most common infectious cause [34], and is typically acquired nosocomially, with broad spectrum antibiotics often an exacerbating factor. Patients with prolonged hospitalization or who have recently be treated for rejection with monoclonal antibodies may also be at risk. Possible complications of C. difficile infection include pseudomembranous colitis, and potentially intestinal perforation and toxic megacolon. These can lead to electrolyte abnormalities and malabsorption of immunosuppressive agents, and thus must be treated promptly. Oral metronidazole with fluid electrolyte replacement is the first line treatment for milder cases of C. difficile infection, with vancomycin for severe or metronidazole-resistant disease [34].

A Gram-positive aerobic coccobacillus, R. equi typically causes infection in animals but can also affect immunocompromised humans, most commonly causing pulmonary infection later after transplantation [35]. It typically presents with a nodular or cavitary necrotizing pneumonia and empyema and is commonly confused with tuberculosis [36]. Suitable treatment includes the quinolones, vancomycin, carbapenems, doxycycline, erythromycin and trimethoprim-sulfamethoxazole; in some cases, surgical drainage of the empyema may be required.

Aerobic gram-negative bacilli are common causes of infection in the immunosuppressed post-transplant patient, and may cause pneumonia, wound infection, UTIs, intra-abdominal sepsis, bacteremia and rarely endocarditis; infections normally present within the first 1–2 months post-transplant. Multidrug resistance is increasingly a problem in this cohort of pathogens. The usual sources for these pathogens are the gut and the respiratory tract. Respiratory tract gram-negative bacilli include Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia; enteric Gram-negative bacilli include Escherichia coli, Pseudomonas spp., Enterobacter spp., Serratia spp., Klebsiella spp., Proteus spp., and Citrobacter spp [37]. Treatment for gram-negative bacilli is typically based on susceptibility patterns per institution, but empiric therapy should typically include a broad-spectrum penicillin and an aminoglycoside such as gentamicin.

The ISHLT guidelines [3] recommend perioperative anti-viral prophylaxis in all transplant recipients against Cytomegalovirus (CMV) and Herpes simplex virus (HSV). Intravenous ganciclovir may be administered to high-risk patients (i.e. CMV seropositive donor to CMV seronegative recipients, or previously CMV seropositive recipients), whereas patients at low risk for CMV infection may only receive anti-HSV prophylaxis with acyclovir. Some centers may also use CMV immunoglobulin in addition to valganciclovir in high risk patients. Dosages of these drugs are given in Table 11.2, while recommendations for viral prophylaxis in heart transplant recipients according to risk category are summarized in Table 11.3.

Cytomegaloviruses, which are double-stranded DNA viruses, are extremely widespread agents that commonly infect humans; transmission may occur through direct or indirect contact with an infected person, and prevalence has been noted to be as high as 90% in certain regional populations [20]. In the normal host, CMV infection stimulates the development of cellular and antibody-mediated immunity, which controls viral persistence; in the immunocompromised host, latent CMV may become reactivated. During transplant, transmission may occur from a seropositive donor to a seropositive recipient, or via infected blood transfusions. Subsequent risk factors for acquiring CMV in the transplant population include the use of perioperative induction therapy, and dose and duration of immunosuppression. It is estimated that following cardiac transplantation, nearly 20–50% will experience at least one CMV infection in the first 2 years, with the majority of cases occurring within the first 2 months post-transplant [42]. The combination of CMV-positive donor with a CMV-negative recipient, if left untreated, has been demonstrated to result in worse outcomes [43]. This is thought to be related to the known association between CMV infection and immune dysregulation and inflammation [44]. CMV infection has also been demonstrated to result in a predisposition for acquiring other fungal and bacterial diseases in transplant recipients [45].

Active CMV infection may be symptomatic, causing a constellation of symptoms including fever, chills, malaise with leukopenia and thrombocytopenia; this is known as CMV syndrome. Alternatively, active CMV infection may be asymptomatic. Primary CMV infection occurs when a CMV-seronegative recipient receives a CMV-positive donor organ, whereas secondary CMV infection represents infection in a previously infected seropositive host, caused by reactivation of latent virus or additional infection with a new viral strain. The term “CMV disease” is used to refer to the clinical symptoms of CMV syndrome as well as features of any invasive CMV disease such as pneumonitis, hepatitis, cholecystitis, or colitis/enteritis. Rarely, invasive CMV disease may also include the myocardium (necrotizing myocarditis) and retinitis.

Where suspected, testing for serum IgG anti-CMV by ELISA is useful to record seroconversion, but has little relevance is diagnosing acute CMV disease. Traditional tissue culture methods may be used, and could still be performed in invasive cases of CMV, but are time consuming and rarely routinely used in transplant recipients. For rapid quantitative diagnosis of acute disease, the CMV pp65 antigenemia test and CMV quantitative nucleic acid testing (QNAT) are the tests of choice. Both are highly sensitive in the diagnosis of CMV disease [21] and are useful for monitoring response to antiviral therapies through their quantitative ability, although there has historically been a lack of standardization with QNAT.

While prophylaxis for CMV is addressed above, effective prophylaxis has greatly decreased CMV-associated morbidity and mortality. Treatment for active CMV disease should involve oral valganciclovir, an acyclic guanine nucleoside analog, to clear CMV viremia in mild to moderate cases. In more severe cases intravenous administration of ganciclovir should be performed. Therapy typically lasts 2–3 weeks, with weekly monitoring of blood viral load using QNAT or pp65 antigenemia to assess response [21]. The length of time for which a patient remains on valganciclovir depends on a number of factors, including donor seropositivity and other known risk factors for CMV reinfection. The potential adverse effects of valganciclovir should be noted: these include neutropenia and thrombocytopenia due to the myelosuppressive nature of the drug, as well as fever, rash, nausea, seizures, nausea, and liver enzyme abnormalities. Since CMV disease itself also presents with leukopenia, there can be confusion as to whether it is CMV or drug-induced; persistent leukopenia is likely to be valganciclovir-induced.

The development of valganciclovir-resistant CMV may occur after prolonged courses of administration; genotypic testing for resistance should be performed. Possible solutions include switching to a sirolimus or everlomus based regimen, due to the reportedly lower risk of CMV risk with this regimen; other options may include foscarnet or cidofovir [21].

Herpes simplex virus (HSV) infection generally develops early after transplantation and predominantly affects mucosal surfaces, although in rare cases dissemination to the esophagus, liver and lungs and even brain may occur. In the transplant population, most cases of active HSV infection are caused by reactivation in previously infected patients. Diagnosis is based on the visual appearance of typical vesiculoulcerative lesions and positive immunofluorescent stain specific for HS. For cases of suspected HSV encephalitis, PCR should also be employed. Prophylaxis is typically administered perioperatively, and treatment for active HSV infection typically involves oral or intravenous acyclovir, depending on severity.