Treatment of actinomycosis

INTRODUCTION — Management of actinomycosis often entails prolonged courses of antimicrobials. Surgical intervention may also be necessary in more complicated cases, such as infection in critical spaces (eg, epidural infections, brain abscesses), patients with massive hemoptysis, or when extensive abscesses and fistulous tracts are present.

The treatment of actinomycosis will be discussed here. The clinical manifestations and diagnosis of actinomycosis are reviewed separately. (See "Cervicofacial actinomycosis" and "Abdominal actinomycosis".)

ANTIMICROBIAL THERAPY

Monomicrobial infections

Preferred regimens — We generally suggest high-dose penicillin for actinomycosis [1-3]. Reasonable alternatives include ceftriaxone and amoxicillin. The route of administration depends on the severity of infection:

●Severe or extensive actinomycosis – Severe, extensive infection is often invasive and associated with significant purulence or fistulous tracts, and often occurs in patients with significant underlying comorbidities. For severe infection, we recommend an initial course of intravenous penicillin G (10 to 20 million units daily in divided doses every four to six hours) [4-6]. In the outpatient setting, administering penicillin G as a continuous infusion may make dosing less cumbersome. Ceftriaxone (1 to 2 g every 24 hours) is a reasonable alternative that can also be more easily administered for treatment in the outpatient setting [7]. Surgery is also warranted in certain severe cases. (See 'Surgical management in select cases' below.)

Initial parenteral therapy is typically given for four to six weeks. Switching from intravenous to oral therapy is usually possible after there is significant improvement in the patient's condition, which typically happens within this time frame. The parenteral regimen is followed by oral penicillin V (2 to 4 g per day, divided into four daily doses). Oral amoxicillin is probably equally efficacious [4]. Data informing the optimal dose of amoxicillin are limited, but we generally use 1.5 to 3 g per day, divided into three or four daily doses. For all the antibiotic regimens, we use a dose at the higher end of the range for more serious infections.

●Mild actinomycosis (eg, limited oral disease) – Initial oral antimicrobial therapy is appropriate for mild cases. We recommend oral penicillin V (2 to 4 g per day, divided into four daily doses). Oral amoxicillin (1.5 to 3 g per day, divided into three or four daily doses) is another option. In cases where copathogens are suspected, oral amoxicillin-clavulanate can be used [8]. (See 'Polymicrobial infections' below.)

Oral antimicrobials are typically administered for a prolonged course for both severe and mild infection; duration is discussed in detail elsewhere. (See 'Duration of antimicrobial therapy' below.)

No randomized controlled studies have evaluated antimicrobial regimens for actinomycosis. The preference for penicillin is based on in vitro antimicrobial susceptibility testing and small case series where high-dose penicillin was used successfully [3,4,9-11]. Furthermore, acquired resistance to penicillin G by Actinomyces during prolonged therapy is rare. Penicillin is given in high doses because of the need to obtain effective concentration in the infected tissues [12].

Alternatives for penicillin-allergic patients — Acceptable alternatives to penicillin include ceftriaxone, doxycycline, macrolides (erythromycin, clarithromycin, or azithromycin), and carbapenems. These agents can be used in those who cannot tolerate penicillin [3].

For penicillin-allergic patients, the approach to regimen selection depends on the type of allergy and the severity of disease:

●For patients with severe infection and a mild, non-immunoglobulin (Ig)E-mediated reaction to penicillin (eg, maculopapular rash beginning days into therapy), we generally use ceftriaxone (1 to 2 g every 24 hours) as initial therapy for four to six weeks prior to oral step-down therapy. Ceftriaxone can also be administered with a test dose procedure to patients with suspected IgE mediated reaction to penicillin (eg, urticaria, anaphylaxis). (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Management of mild reactions WITHOUT history of features of immediate allergy (minimal risk of immediate allergy)' and "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Management of reactions WITH features of immediate allergy (some risk)'.)

●For patients with severe infection and an allergy that precludes ceftriaxone use (eg, serious delayed reactions to beta-lactams), we generally use doxycycline (100 mg every 12 hours, by mouth or intravenous).

●For oral step-down therapy with severe infection and for mild infection in patients with a penicillin allergy, we generally use doxycycline (100 mg every 12 hours) [5,13]. Another acceptable alternative to penicillin is erythromycin base 500 mg orally every six hours [14,15].

These alternatives have in vitro activity against Actinomyces and have been used successfully against Actinomyces in limited clinical series. Imipenem is another potential alternative based on even more limited clinical reports [16]. Ertapenem is also likely to be effective and offers the advantage of once-daily dosing for outpatient parenteral therapy.

Agents that should be avoided — Aminoglycosides, metronidazole, aztreonam, trimethoprim-sulfamethoxazole, penicillinase-resistant penicillins (eg, nafcillin, oxacillin), cephalexin, ceftazidime, and antifungal drugs are not active against these organisms and should not be used for therapy [13-15,17,18].

Although clindamycin and fluoroquinolones have some in vitro activity against Actinomyces, resistance to these agents is not uncommon and since susceptibility testing is not typically available, reliable activity cannot be assumed [17,19,20].

Duration of antimicrobial therapy

Classic actinomycosis — We typically treat patients with classic Actinomyces syndromes (eg, cervicofacial, thoracic, or abdominal actinomycosis with fibrotic reaction, sulfur granules, or invasion of contiguous structures) for an extended period of time to prevent disease recrudescence. Treatment should generally be continued for at least one to two months after resolution of the observed infection; this usually amounts to 2 to 6 months for mild disease and 6 to 12 months for severe.

Within these ranges, individualization of the duration depends on the initial burden of disease, the site of infection, success of any surgical debridement, and the clinical and radiologic response to treatment [21,22]. Extension of the duration to 12 to 18 months may be warranted for complicated and invasive cases, immunocompromised patients, and patients with human immunodeficiency virus (HIV) infection. Shorter courses may also be appropriate, even for initially severe cases, if there has been adequate surgical resection of infected tissues, there is no bone involvement, and response to treatment is rapid. Infections that are recognized early and cause smaller and less indurated lesions have also been successfully treated with shorter durations of therapy. Close monitoring of patients is essential when shorter treatment durations are planned.

Antimicrobials are typically given for a prolonged duration for classic actinomycosis because the infection has a tendency to recur, especially in thoracic infections [23,24]. However, several case series have reported that courses of treatment <6 months have been successful, especially in cervicofacial actinomycosis [4,25-27]. Another study with 17 patients with thoracic actinomycosis reported successful outcomes with two weeks of intravenous penicillin followed by three months of penicillin orally; over half the patients received surgical intervention to distinguish malignancy from an alternative process. [28]. Shorter courses of therapy should be used with caution in patients with thoracic disease who have not undergone surgical debridement as patients treated with antibiotics alone for less than three months may be at higher risk of recurrence [29].

Even shorter courses have been described in some cases, although we do not generally recommend a treatment course less than two months for classic actinomycosis given the limited data. In one report, 19 patients with cervicofacial actinomycosis were successfully treated with one to four weeks of antibiotics [26]. Most patients had presented within seven days of the onset of symptoms and 84 percent had surgical debridement in addition to antibiotic therapy. In one case report of pelvic actinomycosis associated with an intrauterine device (IUD) that presented as a mass lesion, infection resolved after a total of six weeks of oral antibiotic therapy and IUD removal without accompanying surgical debridement [30]. Reports of thoracic actinomycosis have also shown success of short-term treatment [28,31]. One study with 19 patients, seven of whom had surgical resection, reported cure with a median duration of six weeks of antibiotic therapy [31].

Non-classic presentations — Treatment of polymicrobial infections that are not a classic actinomycosis syndrome (ie, subcutaneous drained abscess, periodontitis, isolation from the sputum in the absence of involvement of the chest wall or other contiguous structures, lack of a fibrotic reaction or sulfur granules) can be shorter than for classic actinomycosis (eg, two to six weeks). Limited dental disease, such as periapical infection can be successfully treated with 10 to 14 days of therapy [25].

Data informing the duration of treatment in these cases are limited, but in the absence of bulky, extending or fistulous disease, the risk of relapse with shorter courses of therapy is thought to be lower.

Polymicrobial infections — Approximately 75 to 95 percent of cultures in which Actinomyces is isolated grow other organisms. The most common coisolates are Actinobacillus actinomycetemcomitans, Eikenella corrodens, Fusobacterium, Bacteroides, Capnocytophaga, Staphylococcus, Streptococcus, and Enterococcus spp [1]. Concomitant pulmonary infection of tuberculosis and actinomycosis has been rarely reported [32]. Whether treatment of co-isolates is warranted depends on the organism. When known pathogens are isolated with Actinomyces, they can act synergistically, and in such cases, antimicrobial coverage for these additional organisms is appropriate. Managing copathogens is particularly important in invasive infections and lower-abdominal infections, in which significant copathogens may be recovered in culture. Treatment of Staphylococcus aureus, Proteus, and Pseudomonas is always warranted.

When broader therapy for coverage of copathogens is warranted, we use a combination beta-lactam plus beta-lactamase inhibitor. Examples include piperacillin-tazobactam (3.375 g intravenously every six hours) and amoxicillin-clavulanate (immediate release 500 mg orally every 8 hours or 875 mg orally every 12 hours). These agents offer the advantage of coverage against penicillin-resistant aerobic and anaerobic pathogens. Some copathogens can produce a beta-lactamase that can "shield" Actinomyces from penicillin [5], and addition of the beta-lactamase inhibitor can overcome this. Carbapenems are a potential alternative as they are likely active against Actinomyces and will cover other pathogens as well. Additional coverage may be warranted in cases of resistant pathogens (eg, methicillin-resistant S. aureus).

The duration of treatment for copathogens (with the exception of mycobacterium) is shorter than what is needed for actinomycosis and should be dictated by the infectious syndrome; subsequent to that, continued antimicrobial therapy can be directed to Actinomyces alone. (See 'Monomicrobial infections' above.)

Therapy does not usually need to be directed against commensal flora (ie, Staphylococcus epidermidis, Cutibacterium [formerly Propionibacterium] acnes) that are recovered along with Actinomyces, since antimicrobial regimens effective against Actinomyces alone are usually curative unless foreign material is present [5].

SURGICAL MANAGEMENT IN SELECT CASES

The need for surgery or percutaneous intervention depends on the severity, extent, and location of disease. Surgical or percutaneous management is generally not necessary for mild infections in which there is no bony involvement, no fistulous tracts, no abscesses, and no necrotic tissue. It may be warranted in more complicated cases, such as infection in critical spaces (eg, epidural infections, intracranial abscesses [33], hepatic abscesses [34]), infection complicated by massive hemoptysis, or when extensive abscesses and fistulous tracts are present. The main objective of surgical management is to reduce the bulk of disease, and in some cases it is necessary to prevent life-threatening complications [35,36]. As an example, in a report of 94 patients with pulmonary actinomycosis, half of the patients ultimately required surgery, many for cure due to refractory hemoptysis [37]. If amenable to percutaneous drainage, abscesses can often be successfully managed this way [35].

However, even in severe cases, surgical or percutaneous intervention may not be necessary if infection does not involve critical spaces (eg, cervicofacial infection at the angle of the jaw) and in such cases, the need for intervention should be individualized (eg, taking into account the risk for surgery in patients with other comorbidities). Reports of successful treatment of Actinomyces infections, including extensive infections, with antimicrobials alone are increasing [29,38]. In a series of 46 patients with pulmonary actinomycosis who did not undergo surgical intervention, all 43 patients with follow-up data had documented clinical cure following intravenous antimicrobial treatment for a median of 22 days then oral antimicrobial treatment for a median of 115 days [29].

If indicated, surgery (or percutaneous management) is always performed in conjunction with antimicrobial therapy; surgical management alone is rarely successful without concurrent antimicrobial therapy based on clinical experience [1,39]. (See 'Antimicrobial therapy' above.)

SPECIFIC CONSIDERATIONS

IUD associated infections — Actinomyces may be seen as an incidental finding on Pap smear in women with intrauterine devices (IUDs). In the absence of signs or symptoms of pelvic inflammatory disease (PID), therapy for Actinomyces and removal of the IUD are not necessary.

However, features concerning for PID in this setting suggest active infection with Actinomyces, which warrants IUD removal, culture, and radiographic definition of the extent of disease (eg, ultrasound). If Actinomyces grows on culture in this setting, targeted treatment for this pathogen is given in addition to the standard empiric PID therapy. Antimicrobial regimens for Actinomyces are the same as discussed above. (See 'Antimicrobial therapy' above.)

If imaging suggests invasive disease (eg, abscess), Actinomyces-targeted treatment typically consists of several weeks of intravenous therapy followed by oral therapy until at least one to two months following clinical and radiographic resolution of disease. If imaging does not suggest invasive disease, this likely represents an early stage of IUD-associated infection and can likely be treated with a shorter course of therapy against Actinomyces. (See 'Duration of antimicrobial therapy' above.)

Management of the IUD in the setting of Actinomyces is discussed in detail elsewhere. (See "Intrauterine contraception: Management of side effects and complications", section on 'Actinomyces and related organisms'.)

Bisphosphonate and radiation-associated osteonecrosis — Bisphosphonate and radiation-associated osteonecrosis have been associated with Actinomyces infection of the jaw. [40,41]. If Actinomyces is isolated from a patient with this, we suggest treatment as for typical actinomycosis. (See 'Antimicrobial therapy' above.)

It has been postulated that Actinomyces has a direct effect on bisphosphonate osteonecrosis and treatment; directed antibiotics can lessen ongoing bone destruction.

Prosthetic joint infection — Prosthetic joint infections caused by Actinomyces are rare and treatment strategies are not established. In a case series of 11 patients with Actinomyces knee and hip prosthetic joint infections, antimicrobials were administered before a two-stage exchange of the joint in 8 (72 percent) cases and 10 (91 percent) recovered after a median follow-up duration of two years [42].

Bacteremia without defined disease — Bacteremia with Actinomyces species has been reported. Most cases of isolated bacteremia with Actinomyces (ie, without other site of evident infection) likely require no treatment but warrant close follow up, especially if risk factors are present. In one series, patients without risk factors for invasive disease (eg diabetes mellitus, local tissue trauma, recent surgery, immunosuppression) were not treated for actinomycosis and suffered no ill consequences [43].

However, sepsis due to Actinomyces species has been reported. In one case report, a patient developed sepsis due to Actinomyces neslundii that originated from chronic asymptomatic periapical tooth abscesses; the patient was treated with ampicillin intravenously for four weeks followed by oral amoxicillin for the next five months [44]. In another case report, a premature newborn with Actinomyces odontolyticus sepsis was treated with ampicillin/amoxicillin [45].

FOLLOW-UP

Monitoring treatment response — The response to treatment should be carefully monitored and imaging with computed tomography or magnetic resonance imaging may be necessary to ensure resolution. PET scan has also been used to follow resolution of disease during a course of treatment but needs to be used judiciously as findings may be misleading [46].

Imaging studies are obtained throughout treatment (eg, after the first four weeks and then every six weeks or as indicated by the patient's improvement) and prior to conclusion of therapy. Erythrocyte sedimentation rate and C-reactive protein levels are usually elevated but are not reliable for using as a follow-up parameter.

Treatment failure — If there is an incomplete response to antimicrobials alone, patients who did not initially undergo surgical debridement may ultimately require surgery [36,47-49]. If there is a failure of therapy, a change from penicillin to another antibiotic is warranted to cover copathogens that may be present; additionally, the need for surgical debridement should be assessed [4,21,22,25-28,30,31]. Additional empiric coverage for other potential aerobic and anaerobic copathogens may be needed in those who fail penicillin therapy especially if adequate cultures (eg, for anaerobic bacteria) were not obtained. (See 'Polymicrobial infections' above.)

OUTCOMES — The use of antimicrobials has greatly improved the prognosis for all forms of actinomycosis. Cure rates are high and neither deformity nor death is common [37].

SUMMARY AND RECOMMENDATIONS

●Preferred regimens − We suggest high-dose penicillin for antimicrobial treatment of actinomycosis (Grade 2C).

•Initial parenteral therapy for severe infections − Severe or extensive actinomycosis is initially treated with parenteral therapy (penicillin G 10 to 20 million units daily in divided doses). For patients who cannot take penicillin, ceftriaxone is an alternative. (See 'Preferred regimens' above.)

•Mild infections and oral step-down therapy − Oral penicillin (2 to 4 g daily in divided doses) is used for step-down therapy and for mild infections (eg, without significant suppuration or fistulous tracts). Amoxicillin is an alternative. (See 'Preferred regimens' above.)

●Alternatives for penicillin- and cephalosporin-allergic patients − For patients who cannot use penicillin, amoxicillin, or ceftriaxone, we suggest doxycycline as a non-beta-lactam alternative (Grade 2C). Other alternatives include macrolides and carbapenems. (See 'Alternatives for penicillin-allergic patients' above.)

●Duration of antimicrobial therapy

•Initial parenteral therapy in severe infections − When given, parenteral therapy is typically continued for four to six weeks before transitioning to oral therapy. (See 'Duration of antimicrobial therapy' above.)

•Total duration of therapy

-We suggest a prolonged total duration of antibiotic therapy (ie, 2 to 6 months for mild disease and 6 to 12 months for severe disease) in patients with classic forms of actinomycosis to prevent disease recrudescence (Grade 2C).

-Within this range, individualization of the duration depends on the initial burden of disease, the site of infection, success of surgical debridement, and the clinical and radiologic response to treatment. Shorter courses may be appropriate in cases where infection has been successfully debulked and response to treatment is rapid or in cases of nonclassic actinomycosis (eg, subcutaneous abscesses). (See 'Duration of antimicrobial therapy' above.)

●Polymicrobial infections − Approximately 75 to 95 percent of cultures in which Actinomyces is isolated grow other organisms; however, antimicrobial therapy does not always need to be adjusted to target those other microorganisms. Adjusting therapy is generally warranted when organisms isolated in addition to Actinomyces are considered typical pathogens. In such cases, the combination of a beta lactam and a beta-lactamase inhibitor (ie, piperacillin-tazobactam, amoxicillin-clavulanate) offers the advantage of coverage against penicillin-resistant aerobic and anaerobic pathogens. (See 'Polymicrobial infections' above.)

●Surgical management − Surgical management (or percutaneous management) is generally not necessary for mild infections. It may be warranted in more complicated cases, such as infection in critical spaces (eg, epidural infections, intracranial abscesses, abdominal actinomycetoma, hepatic abscesses), infection complicated by massive hemoptysis, or when extensive abscesses and fistulous tracts are present. (See 'Surgical management in select cases' above.)

●Monitoring treatment response − The response to treatment should be carefully monitored, and imaging should be incorporated into follow-up to ensure appropriate resolution. (See 'Follow-up' above.)