Clinical features, diagnosis, therapy, and prevention of Rhodococcus equi infections

INTRODUCTION — The first case of infection caused by Rhodococcus equi (also known as Rhodococcus hoagii) was reported in 1967 [1], and only 12 additional cases were recorded in the next 15 years [2]. While still not commonplace, a dramatic increase occurred early in the HIV pandemic and R. equi has increasingly been appreciated, especially as an opportunistic pathogen. Increasing recognition of R. equi as a pathogen has subsequently led to improved laboratory identification of infections in both immunocompromised and normal humans.

The clinical manifestations, diagnosis, treatment, and prevention of R. equi infections will be reviewed here. The microbiology, epidemiology, and pathogenesis of R. equi infections are discussed separately. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections".)

CLINICAL FEATURES — R. equi has increasingly been appreciated as a cause of infection in patients with immune system dysfunction [3-13]. The majority of R. equi infections occur in adults, but infection in children and infants (including preterm infants) has also been reported [14]. Although such patients often have epidemiologic risk factors for disease (eg, contact with horses), disease has been reported even in those without a known exposure [13]. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections".)

Pulmonary infections are the most common form of human disease caused by R. equi. Extrapulmonary disease, with or without a concurrent pulmonary infection, can also occur. In one large review of 72 cases, pneumonia occurred in 76 percent of patients, and the lung was the sole site of infection in 82 percent [7]. Pneumonia was accompanied by extrapulmonary infection in 18 percent of cases, while infection at extrapulmonary sites occurred without evidence of pulmonary involvement in 24 percent.

Immunocompromised hosts

Pulmonary infection — Most published cases of pneumonia have occurred in immunocompromised hosts, including transplant recipients (both solid organ and hematopoietic stem cell recipients) [13,15,16]. In such patients, infection is typically subacute in onset but results in high fever, cough (which may or may not be productive), and prominent fatigue [3-11]. Chest pain and weight loss are also common [17].

Hemoptysis can occur in some patients, and is sometimes severe enough to require multiple transfusions and even pneumonectomy. In a series of 67 HIV-infected patients with R. equi infection, cough, sputum production, and hemoptysis were present in 88, 85, and 31 percent, respectively [12]. However, in a case-control study that evaluated 18 transplant patients, none had hemoptysis [13].

A number of local complications can occur in R. equi pulmonary infection. Cavitation arises in greater than 50 percent of cases and pleural effusion in approximately 20 percent. Invasion of contiguous chest structures (chest wall, pericardium, mediastinum) and recurrent pneumothorax are unusual complications. In endemic regions, this can mimic tuberculosis. (See 'Differential diagnosis' below.)

Malakoplakia, a rare chronic granulomatous condition, can also occur in the setting of R. equi infection. Although malakoplakia is a nonspecific finding when seen elsewhere [18], when seen in lung parenchyma, it is generally more specific to R. equi. Pulmonary masses from malakoplakia may mimic lung tumors [19]. Pathologically, malakoplakia appears as a dense tissue infiltrate, comprising sheets of foamy histiocytes, with abundant cytoplasm-containing coccobacilli, and extra- or intracellular, target-like, calcific inclusions (Michaelis Gutmann bodies) that likely represent infected phagocytes with ingested bacteria which likely behave as a nidus for mineralization [20].

Extrapulmonary infection — The signs and symptoms of extrapulmonary infection depend upon whether the patient has concurrent pulmonary disease.

With concurrent pulmonary infection — For immunocompromised patients with pulmonary infection, the most common extrapulmonary sites are the skin (subcutaneous abscesses) and brain. Brain abscesses, surrounding cerebral edema, and sometimes meningitis [21] may result in a variety of neurologic symptoms such as confusion, agitation, obtundation, coma, seizures, and motor weakness. Kidney and bone involvement, as well as isolated bacteremia, may also be seen. (See 'Diagnosis' below.)

Extrapulmonary manifestations can occur at various times during infection. As examples:

●Extrapulmonary infections typically become evident for weeks up to two years after antimicrobial therapy for pulmonary disease is discontinued. Recurrence of the initial pulmonary disease may not be associated with late recurrence at another site.

●When extrapulmonary infection occurs during antimicrobial therapy, it is usually associated with concurrent pulmonary relapse [3-11].

●On occasion, extrapulmonary sites have been the first site of diagnosed infection, even when a pulmonary infection is also present. These sites have included rib osteomyelitis and hepatic abscess resulting from contiguous spread from the lungs; otitis media, probably due to spread within the respiratory tract; and subcutaneous abscess, probably from hematogenous dissemination.

Patients without pulmonary infection — Extrapulmonary infections not associated with pulmonary disease have been reported in approximately 25 percent of patients with R. equi infection [7]. They can be categorized by several patterns, including:

●Wound infections – Septic arthritis, mixed flora cellulitis, and meningitis have occurred after puncture wounds; in addition, cases of endophthalmitis have developed following corneal lacerations. In these cases, there has been no evidence of invasion beyond the primary site of infection.

●Peritoneal catheter-related infections – Catheters have represented the apparent route of inoculation in a few cases of peritonitis related to peritoneal dialysis [22-26]. (See 'Antimicrobial therapy' below.)

●Fever and isolated bacteremia – These manifestations have been reported in patients with central venous catheters, neutropenia, or recent chemotherapy associated with underlying malignancies [7,27-29]. Antibiotic therapy for greater than two weeks may be curative in some cases without catheter removal, but removal also may be required.

Primary inoculation via the lungs or gastrointestinal tract with spread to regional lymph nodes can also occur. Although infection may be asymptomatic [30], patients can present with cervical, thoracic, or mesenteric lymphadenitis [31-33]; peritonitis [34,35]; and pelvic and/or paraspinous masses, which may also involve adjacent bone [32,36,37]. Rare cases of osteomyelitis have been described [38]. Relapse after discontinuation of antimicrobial therapy can occur [31,34,37].

Immunocompetent hosts — Pneumonia due to R. equi has been described in immunocompetent hosts [7,39-41]. However, this is uncommon, representing only about 10 percent of cases in the literature. Most reported cases have had cavitary lesions on chest roentgenograms, and have recovered with either prolonged antibiotic therapy or lobectomy without antibiotics. Extrapulmonary complications are rarely reported.

DIAGNOSIS — A diagnosis of R. equi infection should be suspected in immunocompromised patients with cavitary lung disease and epidemiologic risk factors for disease [17]. (See 'Clinical features' above and "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections", section on 'Microbiology'.)

A diagnosis is typically made by culturing the organism from a clinical specimen. R. equi is easily cultivated on ordinary nonselective media when incubated aerobically at 37ºC. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections", section on 'Microbiology'.)

The sites of infection and the specimens from which R. equi can be isolated include [3-12]:

●Pulmonary (usually the primary site of infection) – Sputum, bronchial washings, lung tissue or abscess contents, pleural fluid (empyema)

●Blood (predominantly dissemination from lung infection)

●Central nervous system (predominantly hematogenous spread) – Brain abscesses, cerebrospinal fluid

●Subcutaneous and other soft tissue or organ abscesses (predominantly hematogenous spread)

●Wound drainage, infected joints, vitreous fluid (usually due to traumatic inoculation)

●Implanted indwelling devices such as peritoneal dialysis and intravenous catheters

●Other sites such as pharynx, middle ear, lymph nodes, bone, and stool

Blood cultures are positive in more than one-half of immunocompromised patients with R. equi infection compared with only 10 percent of normal hosts [7,13]. Patients with AIDS have the highest rate of accompanying bacteremia. The magnitude of the bacteremia may correlate with the risk of hematogenous dissemination. Occasionally, the isolation of R. equi from blood or tissue is the first clue to the etiology of an infection. If R. equi infection is diagnosed in an apparently normal host, further evaluation of the patient's immune status should be pursued. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections", section on 'Immune response' and "Laboratory evaluation of the immune system", section on 'Evaluation for specific types of disorders'.)

One of the most important factors in the timely diagnosis of R. equi infection is communication between clinicians and laboratory personnel. Although the organism is easy to grow, it can easily be dismissed as a contaminant, given its appearance as a diphtheroid. In addition, Rhodococcus are sometimes called "aerobic actinomycetes" [20]. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections", section on 'Microbiology'.)

Newer technologies, such as 16S rRNA sequencing and Mass Absorption Laser Depolarizing Ionization time-of-flight, may also be useful to diagnose "difficult to identify" bacteria from clinical specimens, or (for 16S rRNA sequencing) to identify the etiology of culture-negative infections. (See "Approach to Gram stain and culture results in the microbiology laboratory", section on 'MALDI-TOF'.)

DIFFERENTIAL DIAGNOSIS — For immunocompromised patients with cavitary lung disease, the differential diagnosis includes fungal, bacterial, and mycobacterial pathogens. The clinical presentation of these different infections depends in part upon the type of immunosuppression. As examples:

●In patients with HIV and significant immunosuppression (eg, CD4 count <200 cells/microL), R. equi pulmonary infection frequently produces a cavitary lesion [3-10]. By contrast, tuberculosis or nontuberculous mycobacterial infections less often cavitate in these hosts [42]. (See "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Diagnosis of pulmonary tuberculosis in adults".)

●In immunocompromised patients without AIDS, radiographic features of lung abscess caused by Mycobacterium tuberculosis, Nocardia spp, and R. equi are similar [43]. Among transplant recipients, diabetes and a recent opportunistic infection have been associated with Rhodococcus infection [13].

Other factors that may help support one diagnosis over the other include:

•Tuberculosis – M. tuberculosis and R. equi can cause chronic pneumonia and cavitary lung disease, and both can be detected using acid fast staining. However, nucleic acid amplification testing can be used to rapidly identify organisms belonging to the M. tuberculosis complex in patients with suspected tuberculosis. (See "Diagnosis of pulmonary tuberculosis in adults".)

•Nontuberculous mycobacterial infection – Nontuberculous mycobacteria such as M. kansasii and M. avium complex can cause cavitary lung infection. However, the cavities caused by these organisms may have thin walls. In addition, nontuberculous mycobacteria may take weeks to grow, whereas R. equi can grow in 48 hours. (See "Diagnosis of nontuberculous mycobacterial infections of the lungs" and "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections", section on 'Microbiology'.)

•Nocardiosis – Similar to R. equi, Nocardia can present with brain, soft tissue, or cutaneous lesions and a concurrent or recent pulmonary process. Thus, epidemiologic risk factors (eg, exposure to horses) should alert the clinician to the possibility of R. equi infection. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections" and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis".)

•Legionella infection – Legionella micdadei is an acid-fast coccobacillus that could mimic Rhodococcus and appear similar by initial stains but not by further microbiological testing. (See "Microbiology, epidemiology, and pathogenesis of Legionella infection".)

•Aspergillosis – Invasive aspergillosis can produce cavitary lung disease in immunocompromised hosts. Distinguishing factors include radiographic findings, such as the "halo" and "air-crescent" sign, which are characteristic of aspergillosis. In addition, the galactomannan and beta D glucan may be positive in the setting of invasive fungal infection, but would not be detected in patients with infection due to R. equi. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Diagnosis of invasive aspergillosis".)

ANTIMICROBIAL THERAPY — The mainstay of treatment for R. equi is antimicrobial therapy. Adjunctive therapies are described below. (See 'Adjunctive treatment interventions' below.)

Multiple antibiotics can be used for the treatment of R. equi infections. Methods for determining in vitro susceptibilities are not standardized, and there are no established Clinical Laboratory Standards Institute guidelines for antibiotic testing for this organism. However, several series using disc diffusion and/or minimum inhibitory concentration (MIC) techniques have found that R. equi is usually susceptible in vitro to erythromycin and extended spectrum macrolides, rifampin, fluoroquinolones, aminoglycosides, glycopeptides (ie, vancomycin), linezolid, and imipenem [2-10,44]. Bactericidal agents against R. equi include vancomycin, amikacin, gentamicin, and fluoroquinolones [45].

Of concern, increased rates of multidrug-resistant R. equi have been reported in horses on breeding farms in the United States where mass macrolide/rifampin prophylaxis is used [46].

Treatment of immunocompromised hosts — We suggest combination antimicrobial therapy with at least two agents in immunocompromised hosts given concerns for emerging resistance. One report from Taiwan that described susceptibility patterns in 13 R. equi isolates noted the emergence of multidrug-resistant R. equi [11]. The emergence of resistance during treatment has also been demonstrated with doxycycline [6], rifampin [47], and trimethoprim-sulfamethoxazole (TMP-SMX) [2]. One study showed significantly more TMP-SMX resistance in Europe than the United States [41].

The ultimate combination should be based upon in vitro data regarding susceptibility, synergy, and antagonism. In vitro, the combination of a macrolide with rifampin considerably decreases the emergence of resistant mutants [48]. Studies in the veterinary literature (where combination therapy is frequently recommended) have found in vitro combinations that include a macrolide (erythromycin, clarithromycin, azithromycin) with either rifampin or doxycycline, or the combination of doxycycline plus rifampin were synergistic [45]. By contrast, amikacin, when administered with a macrolide or rifampin, or the combination of gentamicin plus rifampin were antagonistic.

Preferred agents — For initial therapy, we administer a macrolide or fluoroquinolone in combination with rifampin or in combination with two of the following: vancomycin, imipenem, linezolid, or an aminoglycoside. Use of antibiotics with intracellular activity, such as rifampin, fluoroquinolones, and azithromycin may be particularly useful because survival within histiocytes is a significant virulence determinant in R. equi pathogenesis [49-51]. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections", section on 'Pathogenesis'.)

Once susceptibility data are available, two active agents should be continued; at least one of these should be a macrolide or quinolone if possible. For patients with central nervous system (CNS) involvement, it is important that the second agent has good CNS penetration (eg, imipenem, vancomycin, rifampin, or linezolid) since macrolide and fluoroquinolone penetration into the cerebrospinal fluid is generally poor. The duration of therapy is described below (see 'Duration' below). Specific considerations regarding the individual agents include:

●Macrolides – In general, we prefer azithromycin (500 mg once as a loading dose, then 250 mg once daily); of the macrolides, it is most convenient due to once-daily dosing, and also has the least CYP 450 3A4 interaction. Clarithromycin (500 mg twice daily) or erythromycin stearate (500 mg four times daily) can also be used. Tacrolimus and cyclosporine levels may become elevated when administered with macrolides (especially erythromycin and clarithromycin). Thus, in organ transplant recipients, tacrolimus and cyclosporine levels need to be monitored and adjusted appropriately.

●Fluoroquinolones – Moxifloxacin (400 mg once a day), levofloxacin (500 mg once daily), and ciprofloxacin (750 mg twice daily) have activity against R. equi. However, in an analysis of 25 Rhodococcus isolates from cancer patients, moxifloxacin was more active than ciprofloxacin or levofloxacin [52].

●Rifampin – Rifampin (600 mg once daily) is typically used. However, rifampin is associated with significant drug interactions. As an example, coadministration of rifampin and HIV protease inhibitors should be avoided. In addition, rifampin usually causes tacrolimus, cyclosporine, sirolimus, and everolimus levels to plummet. Although rifabutin can be used instead of rifampin to decrease the risk of certain drug interactions, dose adjustments may still be required. Detailed information on drug interactions can be found in the drug interaction program within UpToDate.

●Vancomycin – Weight-based dosing of vancomycin should be used. Dosing is summarized in the table (table 1). (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)

●Carbapenems – We typically use imipenem (500 mg intravenously every six hours). Although there are case reports of ertapenem being used for R. equi infections [15], imipenem is generally preferable as the initial choice of therapy until susceptibility data are available.

●Linezolid – We generally administer linezolid as 600 mg every 12 hours, although some experts use once-daily dosing (600 mg every 24 hours) for these more slow-growing infections to reduce cytopenias and increase tolerability and thus duration of therapy.

●Aminoglycosides – Some clinicians might add an aminoglycoside for extensive pulmonary disease or metastatic disease. The aminoglycoside of choice would be gentamicin, with the caveat that it may be antagonistic if used with rifampin.

While on therapy, patients should be monitored for toxicity. As an example, monitoring of the QT interval is recommended when a patient is on multiple agents that may prolong the QT interval (macrolides, fluoroquinolones). Additional monitoring depends upon the specific agent that is used.

Alternative agents — Additional agents that can be considered in the setting of allergies or other drug intolerances include doxycycline, TMP-SMX, meropenem, and amoxicillin-clavulanate or ampicillin-sulbactam. Rates of resistance to clindamycin likely preclude use of this agent until susceptibility has been demonstrated. Beta-lactams (such as cephalosporins) should generally be avoided, even if initial susceptibility testing is favorable, since resistance has been shown to develop during therapy [32,53,54].

Duration — Initial therapy in immunocompromised persons should last at least two months due to the frequency of relapses following shorter courses. However, radiographic improvement is needed to help guide the ultimate duration of treatment, and patients should have repeat imaging (eg, chest computed tomography [CT], brain magnetic resonance imaging [MRI]) prior to discontinuing therapy. Longer courses should be administered to patients who have persistent clinical or radiographic evidence of infection.

Secondary prophylaxis should be administered to patients who remain immunosuppressed, as such patients are likely to suffer relapses. The duration of prophylaxis has not been studied, but should potentially continue for the duration of immunosuppression. For organ transplant recipients, this may be lifelong. (See 'Secondary prevention' below.)

The duration of treatment is based largely upon case reports of patients with prolonged immunosuppression who had complex disease. Some experts have postulated that 10 to 14 days of treatment may be adequate therapy for simple infections (ie, no pulmonary masses or cavitary lesions) in patients who are unlikely to be immunosuppressed for a prolonged period of time (eg, a patient with HIV on antiretroviral therapy) [55]. However, there is insufficient evidence to support the use of shorter treatment courses, and we continue to administer prolonged courses pending further data.

Treatment of immunocompetent hosts — In immunocompetent persons, single-agent therapy with an extended-spectrum macrolide or fluoroquinolone is typically sufficient [56]. Duration may range from two to eight weeks (or longer), depending on the extent of disease, which should be monitored by clinical and radiographic exams. More detailed information regarding the specific agents is found above. (See 'Preferred agents' above.)

ADJUNCTIVE TREATMENT INTERVENTIONS

Improving immune function — Improving the host's immune function can be an important therapeutic adjunct in treating R. equi infections since the immune status of the host may have a substantial impact upon the outcome of the infection. This can be accomplished by reducing the use of immunosuppressive medications or in patients with AIDS, initiating antiretroviral therapy. In one case, an immune reconstitution syndrome secondary to Rhodococcus was reported with HIV [57]. (See "Immune reconstitution inflammatory syndrome".)

Chronic or fatal outcomes have been reported in approximately 70 to 80 percent of immunocompromised hosts [7]. By contrast, hosts with normal immune function generally can be cured of R. equi infection. In a series of 67 HIV-infected patients, 23 patients died of R. equi infection; however, none of these deaths occurred in patients receiving potent antiretroviral therapy [12].

Drainage/resection — In some circumstances, surgical resection of infected tissue combined with antimicrobial therapy has improved survival in patients with R. equi infection [3,58,59]. Resection may be particularly beneficial when lung infection has evolved into an inflammatory pseudotumor or large abscess [59]. Drainage procedures for localized abscesses and empyemas have also proven helpful in selected cases.

Resection alone has been curative in rare cases of lung infection. Whether additional antimicrobial therapy might decrease the risk of surgical site complications, including bronchopleural fistulae, has not been studied, but would generally be included in many situations.

Extrapulmonary disease — In addition to antimicrobial therapy and improving immune function, there are specific treatment considerations for certain extrapulmonary manifestations. The extrapulmonary manifestations of R. equi infection are described above. (See 'Extrapulmonary infection' above.)

Drainage of infected sites, where feasible, may hasten resolution when used in conjunction with antibiotics. For patients with peritoneal catheter infections, antibiotic therapy for greater than two weeks may be curative without catheter removal, but removal may be required in some cases. In cases of meningitis refractory to systemic therapy, vancomycin via Ommaya reservoir has been used [60].

PREVENTION

Primary prevention — Among HIV-infected patients, the best way to prevent infection with R. equi is early initiation of antiretroviral therapy to preserve immunologic function [41]. (See "When to initiate antiretroviral therapy in persons with HIV" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Prospective evaluation of other approaches to prevent R. equi infection cannot be conducted since the infection occurs relatively infrequently and sporadically. However, immunocompromised persons living or working in environments near horses and other grazing animals should be advised about reducing exposure. In addition, lung transplant patients are sometimes maintained on long-term azithromycin (primarily for anti-inflammatory properties), which might be preventative.

Secondary prevention — Secondary prophylaxis should be administered to patients who are persistently immunocompromised, even if the patient appears to have achieved a full clinical remission of R. equi infection with initial treatment. Although there have been cases of cure without prolonged secondary prophylaxis in immunocompromised hosts [49], cases of relapsing disease in immunocompromised hosts are not uncommon [61]. (See 'Antimicrobial therapy' above.)

Antimicrobial therapy for secondary prophylaxis should consist of a single oral agent that has demonstrated in vitro activity against the specific isolate. Azithromycin and trimethoprim sulfamethoxazole would be common agents for secondary prophylaxis. Fluoroquinolones could also be considered, balancing the risk of tendinopathy. Linezolid and rifampin would be unlikely to be tolerated on a long-term basis, given the predilection for side effects (eg, bone marrow suppression) and drug interactions.

SUMMARY AND RECOMMENDATIONS

●Clinical features – Pulmonary disease is the most common manifestation of Rhocococcus equi infections. However, extrapulmonary disease, with or without a concurrent pulmonary infection, can also occur. (See 'Clinical features' above.)

•Infections in immunocompromised individuals – Most R. equi infections are in immunocompromised individuals.

-Pulmonary infection – Onset is typically subacute, but eventually patients develop high fever, dry or productive cough, and prominent fatigue. More than half develop cavitation, and 20 percent develop pleural effusion. (See 'Pulmonary infection' above.)

-Extrapulmonary infection – Wound infection, peritoneal catheter-related infections, or isolated bacteremia can occur. In patients with pulmonary infection, extrapulmonary manifestations include skin abscesses, brain abscess, or meningitis. (See 'Extrapulmonary infection' above.)

•Infections in immunocompetent individuals – Although uncommon, pneumonia (usually cavitary) can occur in individuals with normal immune function. Extrapulmonary complications have not been reported. (See 'Immunocompetent hosts' above.)

●When to suspect infection – R. equi infection should be suspected in immunocompromised patients with cavitary lung disease and epidemiologic risk factors for disease. (See "Microbiology, epidemiology, and pathogenesis of Rhodococcus equi infections", section on 'Transmission'.)

●Diagnostic tests – The diagnosis is typically made by culturing the organism from a clinical specimen. R. equi is easily cultivated on ordinary nonselective media. (See 'Diagnosis' above.)

●Antimicrobial therapy

•Immunocompromised individuals – We suggest combination therapy with at least two agents for these individuals (Grade 2C). We typically initiate therapy with rifampin plus either a macrolide or a fluoroquinolone. If rifampin cannot be given, we use either a macrolide or a fluoroquinolone plus two of the following agents: vancomycin, imipenem, linezolid, or an aminoglycoside. Once susceptibility data are available, two active agents should be continued for at least two months. (See 'Preferred agents' above.)  

•Immunocompetent individuals – For these persons, single-agent therapy with an extended-spectrum macrolide or fluoroquinolone is usually sufficient. Duration ranges from two to eight weeks, depending upon the extent of disease. (See 'Treatment of immunocompetent hosts' above.)

●Adjunctive therapy – Improving the host's immune function (eg, by reducing immunosuppressive medications) can improve the outcome for immunocompromised individuals. In addition, surgical resection of infected tissue may be beneficial in certain situations (eg, abscess). (See 'Adjunctive treatment interventions' above.)

●Role of secondary prophylaxis – For patients who remain chronically immunocompromised because of their underlying disorder or medications, we suggest secondary prophylaxis after completion of therapy (Grade 2C). A single oral agent that has demonstrated in vitro activity against the specific isolate should be chosen. (See 'Secondary prevention' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Leonard Slater, MD, who contributed to an earlier version of this topic review.