In this article five things to know about treating Mycobacterium abscesses are discussed.
Authors: Hannah Brokmeier, Pharm.D. (PGY-1 resident) and Cassandra Schmitt, Pharm.D. (PGY-1 resident)
Mentors: Christina G Rivera, Pharm.D., BCPS, AAHIV-P and Ryan W Stevens, Pharm.D., BCPID
Article Posted 10 February 2021
Mycobacterium abscessus (MABS) is a non-tuberculous mycobacteria (NTM) that commonly presents in immunocompromised hosts and is emerging as a pathogen of concern. Epidemiology studies have indicated that 2.6-13% of mycobacterial pulmonary infections are caused by MABS, which is only second to Mycobacterium avium complex (MAC) [1]. MABS is frequently associated with NTM infections in the Western United States and Asia, for instance, the incidence of MABS composes 17.2% of all pulmonary mycobacterial infections in Taiwan [2-6]. Outbreaks in cystic fibrosis treatment centers have caused significant alarm surrounding adaptations occurring in MABS subspecies making it difficult to identify sources of outbreaks [7].
Further characterization of MABS reveals three subspecies: abscessus, bolletti, and massiliense. Each subspecies is associated with different virulence factors and resistance to antimicrobial therapy discussed further below. Identification of the MABS subspecies is critical to clinical outcomes and often requires advanced diagnostic techniques not available at most institutions. This can include 16s rRNA gene sequencing to identify hsp65, rpoB, secA genes, or the absence of erythromycin ribosomal methyltransferase (erm(41)) macrolide resistance gene [8].
In this article we will explore 5 things for pharmacists to know about treating Mycobacterium abscessus.
Let’s consider a case: RS is an 89 year-old male admitted to the hospital for surgical management of cholangitis. He received an ERCP one week ago, but returned to the ED and was found to have a stricture in his common bile duct that required a repeat ERCP with stenting. RS became febrile on hospital day 3 which prompted an infectious work-up. Anaerobic and aerobic bacterial blood cultures remained negative but the fungal smear was positive for acid fast bacilli. Mycobacterium abscessus complex was subsequently identified after 120 hours of incubation in 2/3 bottles.
1. Mycobacterium abscessus can cause pulmonary and non-pulmonary disease – in either case it is difficult to treat
The above patient is found to have an NTM bloodstream infection. Many are familiar with mycobacteria causing pulmonary disease; however, it is important to note that NTM infection can also manifest as cutaneous lesions or as disseminated disease. In fact, MABS was first reported in 1953 following isolation from cutaneous lesions and aspirated fluid from a native left knee septic arthritis.(9)
MABS typically demonstrate faster culture growth as compared to other slower growing NTM species, aka, MABS is a “NTM rapid grower”. MABS colonies exists as two main morphologies: smooth and rough. The smooth morphology is contains a glycopeptidolipid layer within the cell wall that initially evades immune system detection, allowing for MABS colonization of airway spaces. Sudden loss of the glycopeptidolipid layer converts smooth MABS isolates to virulent, rough isolates that are recognized by the immune system.(10,11) The glycopeptidolipid layer and the initial dormant state pose two problems to treatment. First, the lipid-rich cellular membrane of mycobacteria reduces antimicrobial penetration, especially for hydrophilic antibiotics. Second, antibiotics are most effective during the virulent stage of the MABS lifecycle.
Common antimicrobial agents active against MABS species include clarithromycin, amikacin, ciprofloxacin, imipenem, linezolid, and tigecycline. However, extensive antibiotic resistance found mainly in M. abscessus and M. massiliense subspecies represents a third challenge to the treatment of MABS. Identification of the erm(41) gene further elucidates the presence of inducible macrolide resistance in the two subspecies, whereas this gene is typically absent in the macrolide-susceptible M. bolletti subspecies.(12) Given molecular identification of erm(41) gene is rarely available in clinical practice, many microbiology laboratories incubate MABs isolates for an extended time for clarithromycin with resistance after 14 days indicating likely presence of erm(41) gene.
2. Induction therapy for Mycobacterium abscessus involves at least one intravenous (IV) antimicrobial
Due to anti-mycobacterial resistance, at least three antimicrobial agents should be utilized for MABS, and at least one should be administered via the IV route [13,14]. The backbone induction regimen consists of a macrolide, IV amikacin, and at least one additional agent. If there is suspected or confirmed macrolide resistance, at least four active drugs should be used, if possible [13].
Amikacin is usually paired with a beta-lactam such as cefoxitin or imipenem/cilastatin (imipenem), which are slowly hydrolyzed by M. abscessus beta-lactamase (BlaMab) [13,15]. Cefoxitin and imipenem can both cause cytopenias, while imipenem is associated with increased seizure risk, particularly in those with underlying seizure disorder. Tigecycline is another IV option for the treatment backbone [13]. Gastrointestinal adverse events (e.g., nausea and vomiting) are commonly associated with tigecycline use and more rarely, hepatitis or pancreatitis. While breakpoints from the Clinical Laboratory Standards Institute (CLSI) for tigecycline are not available for MABS, for other rapidly growing mycobacteria isolates, MICs <2 mcg/mL are considered susceptible [16]. Following initiation of antimicrobial therapy, an induction phase continues for at least 8 weeks, though patient tolerability may limit the duration of induction [13,14].
3. Oral antimicrobials may be used as part of the induction therapy and are a pillar of maintenance therapy for Mycobacterium abscessus
While IV agents often make-up the majority of induction phase for MABS treatment, several oral agents can be utilized as well.
A macrolide is a key component of the induction and maintenance regimens for isolates without suspected or confirmed resistance, such as in M. abscessus ssp massiliense, and has been associated with an increase in microbiologic success [17,18]. Azithromycin or clarithromycin can be used, although azithromycin offers the advantages of a single daily dose, less drug-interactions, and is better tolerated [19,20].
Linezolid is another oral option, however MABS isolates seem to be less susceptible compared to other NTM species [21]. The 2020 IDSA Guidelines for NTM Pulmonary Disease recommend linezolid dosed either 600 mg once or twice daily [13]. While most other infectious indications have a dosing frequency of twice daily for linezolid, NTM infections require prolonged durations and once daily administration may reduce the incidence of toxicities including:. thrombocytopenia, anemia, peripheral neuropathy, optic neuritis, and gastrointestinal intolerance [22,23]. One retrospective study assessing anti-mycobacterial tolerability noted approximately 80% of patients being treated for NTM infections were on linezolid 600 mg once daily [23]. Linezolid could enhance the serotonergic effects of medications, so patients should be reviewed for drug-drug interactions by a clinical pharmacist before initiation.
While not commercially available in the United States, clofazimine has displayed MABS activity and can be requested under a single patient investigational new drug (IND) application through the Food and Drug Administration (FDA) [24].
While most anti-tuberculosis medications do not treat the MABS, bedaquiline has some effect [25]. This should be reserved for refractory disease due to its US black box warning for increased mortality [26]. Caution also is warranted with concomitant β-lactam use as bedaquiline may decrease their bactericidal activity [27].
Fluoroquinolones, sulfamethoxazole/trimethoprim, and tetracyclines such as doxycycline are also part of a recommended susceptibility testing panel, although resistance is common and these agents are generally not used as empiric therapy [13].
After the induction phase, patients often remain on 2-3 oral or inhaled antimicrobials for a consolidation phase, with the duration determined by patient tolerability.
4. Amikacin dosing is unique for mycobacterium
As previously mentioned, aminoglycosides are often a critical component of most MABS regimens. Amikacin is perhaps the most frequently employed aminoglycoside in this scenario, followed by tobramycin. Parenteral amikacin requires close therapeutic drug monitoring due to major concerns for the development of ototoxicity, vestibular toxicity, and/or nephrotoxicity. Once daily “pulse” administration of amikacin IV 15-20 mg/kg adjusted body weight aims to mitigate these adverse effects by allowing the kidneys adequate time to clear the drug between doses [13]. When daily amikacin IV is utilized, a peak of 35-45 mcg/mL and trough of <5 mcg/mL should be targeted, though undetectable troughs are desirable [28].
Amikacin peaks should be extrapolated on the basis of two post-infusions levels in order to avoid sampling before reaching serum-tissue drug equilibrium. For this strategy, serum amikacin levels are obtained two and six hours after the end of an infusion and the peak extrapolated based on the patient specific elimination rate constant. If two-level serum levels are not readily available, then an approximate peak can be measured 1 hour from the end of the infusion with a goal of 25-35 mcg/mL. Alternative amikacin dosing strategies exist if the patient is unable to achieve the goal trough level between doses.
The post-antibiotic kill effect of aminoglycosides combined with the fact that mycobacteria grow slowly, allow the dosing interval to be extended to three times weekly or even twice weekly. A three times weekly amikacin IV 25 mg/kg regimen three times weekly with a goal peak of 65-80 ug/mL has shown no difference in the incidence of adverse effects compared to once daily dosing [28]. Liposomal inhaled amikacin is also an option to treat NTM pulmonary disease, but is only recommended in patients who remain refractory to IV therapy after 6 months [13].
5. Other antimicrobial agents have been explored to meet the challenges of NTM resistance and anti-mycobacterial toxicities
Given the difficulties of treating MABS, there are several agents that have emerged as potential therapeutic options.
Omadacycline and eravacycline are novel oral tetracycline analogs with a spectrum of activity similar to tigecycline. One study demonstrated in vitro activity of twenty-eight MABS isolates that were tigecycline susceptible but resistant to other agents such as amikacin and imipenem [29]. Omadacycline has oral and IV formulations available while eravacycline is IV only. While oral omadacycline is associated with a high frequency of gastrointestinal adverse events, strict fasting requirements, and avoidance of dairy products, antacids, or multivitamins for 4 hours after administration, this may represent a viable agent for consideration in cases where consolidation therapy with an all oral regimen is desired.
Tedizolid is an oxazolidinone antimicrobial similar to linezolid; however, it is considered to have less serotonergic and hematologic issues than linezolid. It is very expensive in the US and generally only considered for use as a salvage agent. CLSI interpretive criteria for tedizolid in MABS are not yet available, but one study has demonstrated that it may have increased activity in MABS as compared to linezolid [30].
β-lactam synergy is also of interest for treating MABS [31]. Avibactam is the first β-lactamase inhibitor (BLI) to demonstrate activity against BlaMab, as sulbactam, clavulanate, tazobactam are hydrolyzed by the enzyme [15,32]. This could be attributed to the lack of a β-lactam ring in the chemical structure of avibactam, which is supported by vaborbactam and relebactam also demonstrating resistance to BlaMab [33,34]. These BLI produced a decrease in a variety of β-lactam MICs in MABS isolates [34]. While imipenem is manufactured in combination with relebactam, one study suggests that relebactam may not be as potent of BlaMab inhibitor compared to avibactam [35].
Similarly, amoxicillin and piperacillin also shown to have in vitro and in vivo activity against MABS when administered in combination with avibactam [32,36]. While this preliminary data is promising, there currently no clinical studies exploring the use of these non-β-lactam-based BLI. Furthermore, M. abscessus subspecies massiliense produces another β-lactamase (BlaMmas), and thereby has limited evidence to support the benefit of adding BLIs [37].
Dual β-lactams may also play a role in MABS treatment. As β-lactams inhibit cell wall synthesis of the bacteria through transpeptidase inhibition, mycobacteria utilize L,D-transpeptidases rather than D,D-transpeptidases (i.e., penicillin-binding proteins). This could allow for two β-lactams to work synergistically by targeting different transpeptidases. Avibactam is thought to have inhibitory effects on L,D-transpeptidases, which may explain how an improvement in activity was seen with the addition of avibactam to imipenem [38,39]. While ceftazidime alone has minimal activity against MABS, one study saw a further decrease in MICs when adding it to ceftazidime-avibactam with imipenem or ceftaroline [31]. Similarly, concomitant use of ceftaroline has shown to lower the MIC of imipenem in MABs isolates [35]. Although further studies are warranted, dual β-lactam therapy, including combinations with avibactam, is promising, especially for those who may not tolerate amikacin or tigecycline.
Phage therapy may be a future option for patients with resistant or disseminated MABS. This has been demonstrated in one pediatric patient where clinical improvement was seen following phage therapy. The patient had cystic fibrosis and received a lung transplant that was complicated by reactivation of a chronic Pseudomonas aeruginosa and M. abscessus spp. massiliense infection, the latter treated with 10 weeks with combination anti-mycobacterials with regimens including amikacin, tigecycline, and imipenem, oral linezolid and clarithromycin, clofazimine and bedaquiline therapy. Despite intensive medical management, she continued to develop new mycobacterial skin nodules. At about 40 weeks post-transplant, she received IV phage therapy twice daily in addition to her antimicrobial therapy for at least 32 weeks. Reported side effects were limited to sweating and flushing during the first two days of phage therapy. Her wounds, lung, and liver function improved gradually while on phage therapy until the time of the case report [40]. While difficult to manufacture phages for NTM, bacteriophages may be a future therapy in the treatment of highly drug resistant MABS.
Now let’s return to our patient case: RS was empirically started on a regimen of clarithromycin, amikacin, and imipenem while waiting for his culture susceptibilities to result. Initial dosing of IV amikacin consisted a 15 mg/kg dose (1100 mg) once daily. Random levels collected at 2 hours and 6 hours random levels were 19 and 12.7 ug/mL, respectively. Calculating an elimination rate constant and half-life allows back calculation of a peak of 22 ug/mL and trough of 2.7 ug/mL. His peak is below the goal of 35-45 ug/mL and his trough is <5 ug/mL but is still detectable. Raising the once daily dose will raise both the peak and the trough and is not ideal in this patient. RS was transitioned to a Monday-Wednesday-Friday dosing regimen at 1600 mg (~22 mg/kg) that resulted in a peak of 38 ug/mL and a trough of <0.8 ug/mL.
Not unexpectedly, the susceptibilities that return on the isolated M. abscessus complex indicated significant antimicrobial resistance including macrolide resistant. The clarithromycin is discontinued and RS continues IV amikacin and tigecycline in addition to imipenem.
|
M. abscessus complex Susceptibility, BP (mcg/mL) |
|
| Amikacin | 16 mcg/mL Susceptible |
| Cefoxitin | 32 mcg/mL Intermediate |
| Ciprofloxacin | >4 mcg/mL Resistant |
| Clarithryomycin | >16 mcg/mL Resistant |
| Doxycycline | >16 mcg/mL Resistant |
| Omadocycline | 0.25 mcg/mL* |
| Eravacycline | 0.25 mcg/mL* |
| Imipenem | 8 mcg/mL Intermediate |
| Linezolid | 8 mcg/mL Susceptible |
| Minocycline | >8 mcg/mL Intermediate |
| Moxifloxacin | >8 mcg/mL Resistant |
| Tigecycline | 0.5 mcg/mL |
| Tobramycin | 16 mcg/mL Resistant |
| TMP/SMX | >8/152 mcg/mL Resistant |
*Breakpoints not established; susceptibility can be inferred from tigecycline.
After RS completed his 8 weeks of induction therapy with IV amikacin, tigecycline, and imipenem, the tigecycline and imipenem are transition to oral omadacycline and linezolid. RS remains on triple therapy with close follow-up by the infectious diseases and outpatient antimicrobial therapy services to ensure ongoing safety and efficacy.
Conclusion
Overall, infections due to MABS present several challenges due to the organism’s extensive antimicrobial resistance profile. Typical antimicrobial regimens, both empiric and definitive, are combination in nature and are composed of complex, broad-spectrum agents. As such, careful attention should be given to determination of the subspecies, obtainment of susceptibility testing of the isolate, and potential adverse drug reaction profiles of each agent utilized. The duration of therapy can be limited by the toxicity of the antibiotics that are used, and infections secondary to MABS are best managed through consultation and close follow-up with an infectious diseases specialists.
ABOUT THE AUTHORS
Hannah Brokmeier, Pharm.D is currently a PGY1 Pharmacy Resident at Mayo Clinic Hospital – Rochester where she will also complete a PGY2 in Critical Care in June 2022. She graduated with a Doctor of Pharmacy degree from South Dakota State University in Brookings, South Dakota.
Her practice interests include cirrhosis management, TEG interpretation, and novel beta-lactamase inhibitor use.
You can find her on Twitter @hannahbrokmeier
Cassandra Schmitt, PharmD graduated with a Doctor of Pharmacy degree from Virginia Commonwealth University in Richmond, Virginia. She is a current PGY1 Pharmacy Resident at Mayo Clinic Hospital – Rochester and will be staying at Mayo Clinic for a 2021-2022 PGY2 in Emergency Medicine.
Her practice interests include ACLS, acute ischemic stroke, and anticoagulant reversal with professional interests in public policy and healthcare leadership.
You can find her on Twitter @cjschmitt2
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Disclosures: CGR has received honorarium from PowerPak CE funded by Insmed.
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