Treatment of actinomycosis

INTRODUCTION — 

Management of classic actinomycosis often entails prolonged courses of antimicrobials. Most infections are polymicrobial. Adjunctive surgical intervention may also be necessary in selected cases, such as infection in critical spaces (eg, epidural infections, brain abscesses), patients with massive hemoptysis, large abscesses not amenable to percutaneous drainage, failure of appropriate medical therapy, or when devitalized tissue is present.

The treatment of actinomycosis will be discussed here. The clinical manifestations and diagnosis of actinomycosis are reviewed separately. (See "Actinomycosis: Microbiology, epidemiology, clinical manifestations, and diagnosis".)

ANTIMICROBIAL THERAPY

Monomicrobial infections

Preferred regimens — For patients with monomicrobial actinomycosis, we suggest high-dose penicillin. Penicillin is the most well-known agent for treatment of actinomycosis and has the greatest amount of experience behind it [1,2]. Ampicillin and amoxicillin are equally efficacious and can be substituted for penicillin. The route of administration depends on the severity and extent of infection.

●Severe or extensive actinomycosis – Severe, extensive infection is often manifested by invasive, bulky disease that may cross tissue boundaries and can be associated with significant purulence, mass-like features, or fistulous tracts. For these infections, we recommend an initial course of intravenous (IV) penicillin G (20 to 24 million units daily in divided doses every four to six hours) [3-5]. IV ceftriaxone (2 g every 24 hours) or ampicillin (2 g every four to six hours) are reasonable alternatives. Patients who require IV antibiotics in the outpatient setting may be switched to ceftriaxone for ease of dosing [6]. Penicillin G can also be administered in the outpatient setting with a continuous infusion via a portable infusion pump. Adjunctive surgery may be warranted in selected cases. (See 'Adjunctive surgical management in select cases' below.)

Initial parenteral therapy is typically given for two to six weeks. Switching from IV 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 [3]. Data informing the optimal dose of amoxicillin is limited, but we generally use 2 to 3 g per day, divided into three or four daily doses. Tetracyclines and macrolides are potential oral alternatives. For all the antibiotic regimens, we use a dose at the higher end of the range for more serious infections to optimize antibiotic penetration to the tissues [7].

●Mild actinomycosis (eg, limited oral disease) – Initial oral antimicrobial therapy is appropriate for mild cases. We suggest oral penicillin V (2 to 4 g per day, divided into four daily doses) or oral amoxicillin (2 to 3 g per day, divided into three or four daily doses). Tetracycline (500 mg every six hours), doxycycline (100 mg twice a day), erythromycin (500 mg every six hours), and azithromycin (500 mg daily) are each reasonable alternative options. In cases where copathogens are suspected (eg, oral disease), oral amoxicillin-clavulanate can be used [8]. (See 'Polymicrobial infections' below.)

No randomized controlled studies have evaluated antimicrobial regimens for actinomycosis, and clinical recommendations are largely based on prior experience. The preference for penicillin is based on in vitro antimicrobial susceptibility testing and small case series where high-dose penicillin was used successfully [2,3,9-11]. 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 which can be difficult due to the thick-walled tissue that commonly occurs and to sulfur granules, which may act similarly to a biofilm [7].

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 [2].

For penicillin-allergic patients, the approach to regimen selection depends on the type of allergy and the severity of disease; consultation with an allergist may be appropriate.

●For patients with severe infection:

•For patients with nonsevere or immunoglobulin E (IgE)-mediated reaction to penicillin, we generally use ceftriaxone (1 to 2 g every 24 hours) as initial therapy for two to six weeks prior to oral step-down therapy.

•For patients with severe non-IgE-mediated reactions (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome), we suggest doxycycline (100 mg every 12 hours), since cephalosporins should be avoided in these circumstances [4,12]. IV carbapenems are a potential option after consultation with an allergist; ertapenem offers the advantage of once-daily dosing for outpatient parenteral therapy [13].

●For oral step-down therapy with severe infection and for mild infection in patients with a penicillin allergy, we suggest doxycycline (100 mg every 12 hours) [4,12]; acceptable alternatives include tetracycline (500 mg every six hours), erythromycin (500 mg every six hours), or azithromycin (500 mg daily) [14,15].

These alternatives have in vitro activity against Actinomyces and have been used successfully against Actinomyces in limited clinical series [4,12-15].

Agents that should be avoided — Aminoglycosides, metronidazole, aztreonam, trimethoprim-sulfamethoxazole, penicillinase-resistant penicillins (eg, nafcillin, oxacillin), cephalexin, ceftazidime, daptomycin, fluoroquinolones, and antifungal drugs are not active against these organisms and should not be used for therapy [12,14-17].

Although clindamycin has anecdotal historical success in the treatment of actinomycosis, reliable activity cannot be assumed. In vitro data have demonstrated greater than 20 percent resistance in the majority of Actinomyces spp [16,18,19].

Duration of antimicrobial therapy

Classic actinomycosis — We suggest continuing treatment for at least one to two months after resolution of the observed infection (as defined clinically and/or by imaging); this usually amounts to two to six months for mild disease and 6 to 12 months for severe disease. Within these ranges, individualization of the duration depends on the initial burden of disease, the site of infection, extent of surgical debridement (if performed), and the clinical and radiologic response to treatment [20,21]. 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. Antimicrobials are typically given for a prolonged duration for classic Actinomyces syndromes (eg, cervicofacial, thoracic, or abdominal actinomycosis with fibrotic reaction, sulfur granules, or invasion of contiguous structures) because the infection has a tendency to recur with a shorter course of therapy, especially in thoracic infections [22,23].

Shorter courses may be appropriate, even for initially severe cases, especially when adequate surgical resection of infected tissues has been performed, there is no bone involvement, and the 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. For example, several case series have reported that courses of treatment <6 months have been successful, especially in cervicofacial actinomycosis [3,24-26]. Another study of 17 patients with thoracic actinomycosis reported successful outcomes with two weeks of IV penicillin followed by three months of oral penicillin; over half the patients received surgical intervention to distinguish malignancy from an alternative process [27]. 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 [28].

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 [25]. 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 [29]. Reports of thoracic actinomycosis have also shown success of short-term treatment [27,30]. One study with 19 patients, seven of whom had surgical resection, reported cure with a median duration of six weeks of antibiotic therapy [30]. Close monitoring of patients is essential when shorter treatment durations are planned.

Nonclassic presentations — Treatment of infections that are not a classic actinomycosis syndrome (eg, 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 (eg, two to six weeks) than for classic actinomycosis. For example, limited dental disease, such as periapical infection can be successfully treated with 10 to 14 days of therapy [24].

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. Regardless, close follow-up is warranted.

Polymicrobial infections — Approximately 75 to 95 percent of cultures in which Actinomyces is isolated grow other organisms. The most common co-isolates 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 [31].

●Which copathogens to treat – Whether treatment of co-isolates is warranted depends on the organism. Treatment of Staphylococcus aureus, Proteus, and Pseudomonas is always warranted. Treating copathogens is also particularly important in invasive infections and lower abdominal infections, in which significant copathogens (eg, Enterobacterales) may be recovered in culture. When known pathogens are isolated with Actinomyces, they can act synergistically, and in such cases, antimicrobial coverage for these additional organisms is appropriate. 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 [4].

●What antibiotic agents to use – When broader therapy for coverage of copathogens is warranted, a site-specific agent that covers both Actinomyces and the identified or predicted copathogens should be employed. In general, we prefer to use an antibiotic with a beta-lactamase inhibitor because some copathogens can produce a beta-lactamase that can "shield" Actinomyces from penicillin [4], and addition of the beta-lactamase inhibitor can overcome this. For example, for abdominal infection, we typically use piperacillin-tazobactam (3.375 g intravenously every six hours) because it is a broad-spectrum penicillin (and thus has activity against Actinomyces as well as other typical gut bacteria such as Enterobacterales, Pseudomonas aeruginosa, and gut anaerobes). Other antibiotics that have similar spectrum of activity to piperacillin-tazobactam are also reasonable. For oral-cervicofacial polymicrobial actinomycosis, we typically use IV or oral amoxicillin-clavulanate. Carbapenems are a potential alternative as they have been anecdotally successful in treating actinomycosis, are predicted to be active against Actinomyces based on in vitro data, and have activity against other pathogens as well. Additional antibiotic agents may be necessary in cases of resistant pathogens (eg, methicillin-resistant S. aureus).

●Duration of therapy – 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; after that, continued antimicrobial therapy can be directed to Actinomyces alone for the full duration of actinomycosis therapy (see 'Monomicrobial infections' above). We prefer treating polymicrobial infections in critical locations (eg, Ludwig's angina, central nervous system) with a more prolonged duration of IV antibiotics given the severity of the infection and risk for poor outcomes. (See 'Duration of antimicrobial therapy' above.)

ADJUNCTIVE SURGICAL MANAGEMENT IN SELECT CASES — 

The need and timing for surgery or percutaneous intervention depend on the severity, extent, and location of disease.

●Indications – Percutaneous drainage is preferred when actinomycosis manifests as a well-defined abscess in a suitable location (eg, hepatic abscess) [32]. Adjunctive surgery is typically warranted in more complicated cases, such as infection in critical spaces (eg, epidural infections, intracranial abscesses), infection complicated by massive hemoptysis, infection with extensive abscesses not amenable to percutaneous drainage, or when there is failure of medical therapy [33,34]. In some cases, it is necessary to prevent life-threatening complications [32,35-37]. As an example, in a report of 94 patients with pulmonary actinomycosis, half of the patients ultimately required surgery, many due to refractory hemoptysis [37].

In contrast, surgical intervention is rarely necessary for mild infections in which there is no bony involvement, no fistulous tracts, no abscesses, and no necrotic tissue. Even extensive, bulky disease can be cured with medical therapy alone [28,38-41].

●Timing – Most easy-to-access, percutaneous drainage interventions should be done early in the treatment course. However, in situations where immediate surgical intervention is not necessary and would require possible removal or damage to critical organs (eg, bladder, reproductive organs), it is reasonable to initiate antimicrobial therapy and monitor to see if there is a reduction in size of the mass prior to resection. In some cases, surgical intervention may not be needed at all. In a case series of 46 patients with pulmonary actinomycosis who did not undergo surgical intervention, all patients with follow-up data (43 patients) had documented cure with medical therapy alone (intravenous [IV] for several weeks followed by a six-month course of oral antibiotics) [28].

Occasionally, actinomycosis is diagnosed after a surgical intervention for a presumed malignancy. In these cases, the extent of surgery may influence duration of antimicrobial therapy, with extensive resections allowing for a shorter course of antimicrobial therapy. (See 'Duration of antimicrobial therapy' above.)

Surgery or percutaneous management should always be performed in conjunction with antimicrobial therapy. Concomitant antimicrobial therapy may obviate the need for invasive surgical intervention or may reduce the size of the mass to allow for a safer resection. Surgical or percutaneous intervention alone is rarely successful [1,42].

SPECIFIC CONSIDERATIONS

IUD-associated infections — Actinomyces-like organisms 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 infection, we do not give therapy for Actinomyces and do not remove the IUD.

However, features concerning for pelvic infection (eg, lower abdominal pain, vaginal bleeding and/or discharge, tenderness to palpation) suggest active infection with Actinomyces spp. In these cases, we remove the IUD and send it for culture and cytology, and obtain computed tomography (CT) or magnetic resonance imaging (MRI) with and without contrast of the pelvis to define the extent of disease. If imaging is consistent with classic actinomycosis (eg, solid mass), and malignancy is excluded, then management should proceed for this syndrome as discussed above. (See 'Antimicrobial therapy' above.)

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.)

If there is a high suspicion for IUD-associated actinomycosis, the inability to microbiologically identify Actinomyces should not preclude the diagnosis, since Actinomyces can be challenging to grow on culture and early antimicrobial therapy improves outcomes. Pelvic actinomycosis is often a polymicrobial infection; therefore initial treatment should also include standard empiric pelvic inflammatory disease therapy. (See "Pelvic inflammatory disease: Treatment in adults and adolescents".)

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'.)

Medication and radiation-associated osteonecrosis — Radiation, bisphosphonates, angiogenesis inhibitors, tyrosine kinase inhibitors, and anti-receptor activator of nuclear factor kappa-B ligand (RANKL) such as denosumab have been associated with osteonecrosis of the mandible and maxilla [43,44]. When Actinomyces organisms are identified in this setting, we typically administer a prolonged course of antimicrobial therapy (eg, at least six weeks) (see 'Antimicrobial therapy' above). The role of surgical debridement is less clear, but resection of at least the necrotic bone seems prudent.

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 eight (72 percent) cases and 10 (91 percent) recovered after a median follow-up duration of two years [45]. We treat prosthetic joint infections due to Actinomyces for a minimum of six weeks.

Bacteremia without defined disease — Bacteremia with Actinomyces species has been reported. Most cases of isolated bacteremia with Actinomyces (eg, 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 [46].

However, sepsis due to Actinomyces species, in the absence of classic actinomycosis, 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 [47]. In another case report, a premature newborn with Actinomyces odontolyticus sepsis was treated with ampicillin followed by amoxicillin [48].

FOLLOW-UP

Monitoring treatment response — The response to treatment should be carefully monitored and imaging with CT or MRI may be necessary to ensure resolution. Positron emission tomography (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 [49].

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 as a follow-up parameter.

Treatment failure — Persistence or recrudescence of symptoms or lack of a radiographic response should prompt evaluation for superinfection (eg, catheter-related infection, Clostridioides difficile colitis) and noninfectious causes of symptoms (eg, drug fever). Once those possibilities are excluded, we consider whether further source control of the infection is required (eg, persistent or undrained purulent fluid collections, presence of necrotic tissue/bone) [35,39,50,51]. Additionally, we consider if there is a need for treatment against identified or presumptive potential copathogens that were not treated or received suboptimal treatment initially [3,20,21,24-27,29,30]. (See 'Polymicrobial infections' above.)

It is unclear if Actinomyces spp can acquire resistance to penicillin G during treatment. However, if all other causes of persistent/recurrent symptoms have been excluded, we switch antimicrobial therapy to an alternative agent.

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]. Early suspicion and diagnosis of actinomycosis are important for improving outcomes, since they minimize unnecessary surgical interventions such as being mistaken for malignancy and having to undergo a resection.

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 20 to 24 million units daily in divided doses). Ampicillin 2 g every four to six hours is an equally efficacious alternative. For patients who cannot take penicillins, ceftriaxone is the preferred 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, limited oral disease). 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 two 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, two to six 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 source control, 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 mild disease. (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, a site-specific agent that covers both Actinomyces and the identified or predicted copathogens should be employed. (See 'Polymicrobial infections' above.)

●Adjunctive surgical management – Actinomycosis is usually successfully managed with medical therapy alone. Percutaneous drainage is preferred when actinomycosis manifests as a well-defined abscess in a suitable location. However, surgical intervention combined with medical therapy may also be necessary in selected cases, such as infection in critical spaces (eg, epidural infections, brain abscesses), patients with massive hemoptysis, large abscesses not amenable to percutaneous drainage, failure of appropriate medical therapy, or when devitalized tissue is present. (See 'Adjunctive surgical management in select cases' above.)

●Monitoring treatment response − The response to treatment should be carefully monitored and imaging with CT or MRI may be necessary to ensure resolution. Imaging studies should be 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. (See 'Follow-up' above.)

ACKNOWLEDGMENT — We are saddened by the death of Itzhak Brook, MD, MSc, who passed away in January 2025. UpToDate acknowledges Dr. Brook's past work as an author for this topic.