The Antibiotic Nightmare – M. Abscessus

Mycobacterium abscessus therapy is kind of a crapshoot. It is unfortunate to say it like that yet the resistance profiles for this complex of mycobacteria and the microbiology of it make it a frustrating organism to treat. This organism has been called an “antibiotic nightmare” for multiple reasons. 

Let’s start here. M. abscessus (as I will call the complex for now) is part of the “rapid growers” nontuberculous mycobacteria. Called this because they grow within 7 days in solid media, compared to MTB, which can take up to 6 weeks. Rapid growth relative to other mycobacteria, but when compared to bacteria such as Staphylococcus, still slow. I refer to these as the CAFfeinated organisms: M. chelonae, M. abscessus, and M. fortuitum (cute, I know). There are 3 main ones to know, but if you read Mendel, there are so many more that it’ll make your head hurt. Despite this, you will only likely see these 3 the most, with any of the others being something to write a case report about. 

As it so happens, microbiology is fairly complicated, and there is not just one M. abscessus, but rather 3 subspecies: M.abscessus ssp abscessus, M. abscessus spp massiliense, and M. abscessus spp bolletti. These all have different drug susceptibilities (1) and may behave in a different manner (Stout, 2). The classification can be a bit problematic. While the history is not terribly important, it gives context for data interpretation. Prior to 1992, M. abscessus was considered to be part of M. chelonae as the same species (“M. abscessus/M. chelonae). Thereafter, M .abscessus became its own species, with several changes occurring since then, including the previously mentioned subspecies of M. abscessus (3):

This makes interpreting literature a bit difficult, as prior to 2013, all of the complex was clumped into one organism, and as it so happens, there are treatment implications. Where do you find them? Usually in soil and water (1, 3, 4). So everyone is exposed, but those with underlying lung disease (i.e. those who cannot clear the organism effectively, or those whose blood supply is compromised, making it difficult to clear) are at higher risk. These are your cystic fibrosis patients, your bronchiectasis, yoru COPDers, your lung cavitary lesions (that don’t get blood supply). 

There are a few characteristics for M. abscessus (which is what I am going to  call the entire complex) that makes it difficult to kill:

1. They’re everywhere. So if you get rid of it, prepare to be shocked when someone gets reinfected
2. They make biofilms. ‘Nuff said. 
3. They grow relatively slowly. Considering that a lot of antibiotics, beta-lactams predominantly, need a replicating organism to work, many of the drugs target protein synthesis rather than the cell wall. There are 2 exceptions to the former rule when it comes to beta-lactams, though.
4. That cell wall has so much lipid, making antibiotics difficult to penetrate. That means all antibiotics have a harder time to get in. 
5. Erm41 gene. It is not present in all organisms, but if it is it will complicate therapy. In short, this gene confers resistance to macrolides, the one oral antibiotic that is fairly well tolerated and considered the “backbone” of therapy. The thing is, this is an inducible gene that requires the presence of a macrolide before you can pick it up with resistance testing. So you may see an “S” next to macrolides in a drug-susceptibility report, but they later become resistant once you introduce macrolides. You need to incubate the organism for 14 days with a macrolide before you see it (the one exception here is M. massiliense that does not have inducible resistance, as this gene is non-functional, 3). 
6. Not all organisms within the complex cause the same disease. M. abscessus spp abscessus is the most common and most resistant, but given the relative recency which we realized this was a complex, how that factors into presentation is unclear. 

The prevalence of M. abscessus/chelonae pulmonary infections is roughly 1/100,000 (3), and seems to be going up.

Diagnosis:

I won’t go into too much detail here, but I think it is helpful to realize that not everyone who grows M. abscessus off the lung means they’re infected. As a result, the combined IDSA/ATS guidelines suggests the following diagnostic criteria, which includes microbiological, radiographic, and symptomatic criteria, all of which must be present prior to starting therapy (4):

You’ll notice that you need to have at least 2 positive sputum cultures or a deep sample along with symptoms and something on CT imaging. 

About the erm41 gene:

As previously mentioned, the backbone of oral therapy is macrolides as they are well tolerated and have a fairly good side effect profile. Unfortunately, many M. abscessus express erm41 gene positivity that induces resistance to macrolides [note: from now on, when I say M. abscessus, I am referring to M. abscessus spp abscessus. M. massiliense refers to M. abscessus spp massiliense. Since M. bolletii is rare, I won’t talk about it]. One study evaluated the effect of erm41 in macrolide resistance by creating erm(41) knockout M. abscessus strains and erm(41) mutant M. massiliense (5). Exposure to either clarithromycin or azithromycin did not affect the MIC at day 14 to either antibiotic in M. abscessus knockout strains, while substantially increasing the MIC in the M. massiliense mutants, similar to M. abscessus wild-types:

The type of macrolide may also impact the degree of erm41 expression. mRNA levels of erm41 increased in a dose-dependent fashion with CLR, while only increasing slightly with AZM, with concentrations of erm(41) gene expression being significantly higher at any CLR dose at day 7:

Incubation of 25 isolates of M abscessus with either CLR or AZM revealed that by day 14, all strains had developed high levels of resistance to CLR while for AZM the MIC remained at 16ug/mL or less:

Antibiotic activity was greater for AZM in a mouse-model of M. abscessus infection, with AZM presenting significantly reduced bacterial counts in the lungs after 12-days of therapy (median CFU count, 1.43 log₁₀) compared to CLR-treated mice (2.90 log₁₀), a difference not seen in the M. massiliense model:

This pattern is seen in clinical practice. For instance, a retrospective review of 20 cases of extrapulmonary M. abscessus (10 M. abscessus and 10 M. massiliense) found that 80% of the spp abscessus had inducible clarithromycin at day 14 resistance compared to none of the spp massiliense (6):

Another retrospective study of 64 patients found all M. abscessus strains acquired clarithromycin resistance by day 14 (7):

Despite the fact that most strains of M. massiliense are macrolide-susceptible, there are some strains that are actually resistant and this may affect the outcome of patients. For instance, a cohort of 13 patients with macrolide-resistant M. abscessus found that none had favorable outcomes following therapy and the only patient that had any sputum culture conversion had surgical resection (8). Most received clofazimine, inhaled amikacin, or PO macrolides. Similarly, a cohort of 15 patients with macrolide-resistant M. massiliense found that only one patient had sputum culture conversion at the end of 12mo of therapy, and 2 had sputum culture conversion at the end of therapy (9). Notably, the patient who had sputum conversion at month 12 had undergone a lobectomy prior to conversion. It is rare for M. massiliense to harbor a functional erm41 gene, but if it is there, it seems to affect cure rates. As you’ll see later, those with M. massiliense tend to have better outcomes, and it is likely because of the availability of a fairly well tolerated oral option. 

Typical Resistance Patterns:

I mentioned previously that beta-lactams have minimal efficacy against mycobacterium, and this is due to the presence of a beta-lactamase that hydrolyzes most beta-lactams and are not affected by beta-lactamase inhibitors. Imipenem and cefoxitin are slowly hydrolyzed and retain some degree of activity (1). What about traditional TB drugs? One study evaluated 20 strains of M. abscessus and 17 of M. fortuitum and found that all traditional anti-tuberculous drugs were resistant (10):

The other drugs did not fare better. Azithromycin and linezolid tended to be the more susceptible ones, with amikacin having a high percentage of intermediate susceptibilities:

A review of several studies complied susceptibilities for M. abscessus complex, with most being susceptible to clarithromycin and amikacin (3):

Another retrospective study compared 64 patients with M. abscessus and 81 patients with M. massiliense (7). A high percentage of isolates were resistant to imipenem in both groups, with amikacin and clarithromycin having similar resistant profiles:

An analysis of 67 M. abscessus strains (42 subsp. Abcessus, 21 sub massiliense and four susbp. bolettii) found that only 4% demonstrated amikacin resistance. Clarithromycin, however, had a rate of resistance of 33% (11). The same study found that 8/19 strains demonstrated synergy with tigecycline and clofazimine. Overall, it seems amikacin and macrolides are the go-to antibiotics, with additional IV drugs such as imipenem or cefoxitin (see later) being added. Clofazimine, tigecycline, and others are typically used, however as seen above, the resistance patterns are not great for those drugs.

What Regimens to Use 

Guidelines recommend at least 3 active drugs, including macrolides, in all situations (4). If there is macrolide resistance, macrolides are still recommended for immunomodulatory properties (whatever those mean) but still require 3 active drugs. Further, at least one drug should be IV during the initial therapy period (either amikacin or one of the aforementioned beta-lactams, imipenem/cefoxitin) for at least 3 weeks. Some people will do 2 IV drugs upfront, usually for 4 weeks followed by either a PO regimen or a combination of PO/IV until culture negativity is achieved for 12 months. Which drugs are used depends on the cohort and experience of each center. In one analysis (12), the most common combination for pulmonary disease were those which included amikacin/macrolides (73%), with tigecycline, cefoxitin, or imipenem being added to that regimen. 12% of regimens did not include amikacin and included combinations of azithromycin, imipenem, tigecycline, cefoxitin, or inhaled amikacin. A meta-analysis also found that when looking at both M. abscess and M. massiliense (13), imipenem was associated with treatment success. When looking at just M. abscessus, azithromycin, imipenem, and amikacin all had a positive effect on treatment success:

A retrospective study of 244 patients evaluated efficacy of individual drugs, based on the frequency of drug usage in successful vs unsuccessful treated patients (14) Multiple regression analysis found that azithromycin was superior to clarithromycin when looking at an M. abscessus. Furthermore, the use of amikacin, imipenem, and linezolid were independently associated with treatment success overall and when looking at M. abscessus only. When looking at M. massiliense, only amikacin was significantly associated with treatment success:

Despite this, treatment success is overall poor. A meta-analysis of 8 studies, which included 303 patients (13) with pulmonary disease found that only 164 met criteria for treatment success (45.6%). Treatment success was higher for M. massiliense (57%) than for M. abscessus (33%). Symptomatic improvement was similar between groups (64% for M. abscessus and 64% for M. massiliense) but radiographic improvement was higher for the M. massiliense (71% vs 36%). In a large cohort (14), 110/244 had treatment success, with a higher proportion of success seen in the M. massiliense cohort (81%) compared to the M. abscessus cohort (33.5%).

It seems that macrolides + amikacin + Imipenem/cefoxitin are the way to go. Other drugs have been used with various degrees of success. For instance, one cohort used tigecycline as part of a compassionate use program (15). 52 patients, 36 of which had lung infection, were evaluated with around half receiving 100mg daily. 10/36 patients with pulmonary disease received tigecycline for <1 month, with 29 patients discontinuing it prematurely. 48.1% of the overall cohort had clinical improvement, with 44.4% of lung infections having experienced some sort of improvement. Omadacycline 300mg daily was also used in a case series of 4 patients, with 3 achieving clinical cure (16). Clofazamine, a drug that has seen resurgence due to its use in MDR-TB (see that post), has also been evaluated as a therapeutic option for M. abscessus. 

One analysis compared the killing efficacy of a combination of either amikacin-clofazimine and clarithromycin-clofazimine in both M. avium and M. abscessus spp abscessus and found that clofazimine alone was merely bacteriostatic with the effect being concentration dependent (17):

The highest efficacy was seen for the amikacin-clofazimine combination at 2x above MIC, with discrete killing being observed at 1x and 2x the MIC of amikacin:

Unfortunately, there are a few clinical studies on its use. A cohort of 42 patients with M. abscessus lung disease evaluated the use of clofazimine as initial therapy or salvage drug therapy in patients who had failed sputum culture conversion (18). All patients received it in combination with a macrolide. 81% of patients had symptomatic improvement overall, though only 24% of patients had culture conversion. Culture conversion was higher in patients who were treated with clofazimine initially compared to when used as salvage therapy:

One of the limiting factors of therapy with IV amikacin is side effects, of which the most concerning and devastating are ototoxicity and nephrotoxicity. While some experts recommend decreasing the frequency of IV amikacin to three times per week after the initial “induction period” the use of inhaled amikacin has been explored in some cohort studies. The use of inhaled amikacin was evaluated in a retrospective cohort of 26 patients with NTM lung disease, of which 23 had MAC and only 3 had M. abscessus infection (19). 13 patients had culture conversion with 7 demonstrating radiographic improvement after therapy. Ototoxicity occured in only 3.8% of patients, and no patient had any renal toxicity.  Most patients were able to tolerate daily inhaled amikacin for more than 3 months. A cohort of 82 treatment-naive M. abscessus pulmonary disease received a regimen of inhaled amikacin (20). All patients had IV amikacin during induction followed by inhaled amikacin as outpatients. 46 patients had M. massiliense while 36 had M. abscessus. 88% of patients had improved symptomatic response, while 68% had culture  conversion at the end of therapy. Improvement tended to favor M. massiliense cohort across all categories (symptomatic, radiographic, and microbiological cure):

Multivariate analysis found that M. massiliense was associated with cure after 12 months of therapy (aOR 23.86, 95% CI 6.85-86.03). 79% of patients who received inhaled amikacin (non-liposomal formulation) had ototoxicity while 16% ended up with nephrotoxicity:

In another cohort, amikacin was used as salvage therapy in 77 patients, of which 48 had M. abscessus and 20 had MAC (21). Patients were started on inhaled amikacin after a median of 38 months of therapy. Symptomatic improvement was seen in 49% of patients, while radiographic improvement was seen in 42% of patients. Culture conversion was achieved in 18% of patients overall:

Two RCTs were recently published evaluating inhaled liposomal amikacin (22, 23) in NTM disease. One looked exclusively at MAC patients and found benefit with liposomal therapy (22). 

Another RCT of 89 patients evaluated liposomal amikacin with placebo in patients with NTM pulmonary disease who had a minimum of 6 months of therapy, of which 36% had predominantly M. abscessus disease (23). Patients in the inhaled amikacin group had a greater reduction in a semiquantitative mycobacterial growth when compared to placebo at day 84, but this did not reach statistical significance. Following the initial trial period, an open-label period was followed where both groups had achieved similar changes in semiquantitative mycobacterial growth:

Culture conversion favored the inhaled amikacin group, though the difference when looking at M. abscessus was not great:

Furthermore, culture conversion seemed to hold over time, and 6MWT distances improved significantly more in the inhaled amikacin group:

In one study (22), tinnitus was reported in 7.6% of patients while 4.5% reported hearing loss, with no reports of nephrotoxicity, while in the other (23) there were no difference in ototoxicity or nephrotoxicity between amikacin and placebo. Otherwise, it seems inhaled amikacin, specifically the liposomal version (which consists of liposomes that encapsulates amikacin; these are taken up by macrophages, allowing high levels of intracellular amikacin to be reached with minimal toxicity), can be used in the “consolidation phase” as part of a multidrug regimen. 

Does the Strain Matter?

I have alluded to the fact that M. massiliense tends to portend a better prognosis overall, most likely due to the presence of a non-functional erm41 gene which allows the use of oral macrolides. This, of course, minimizes the number of drugs required which in turn, allows less toxicity and better tolerability of a long, multidrug therapy. There seems to be no difference in terms of presentation. For instance, one retrospective study of 48 patients with pulmonary M. abscessus found that those with spp abscessus tended to have more cavitary disease compared to spp massiliense, though this did not reach statistical significance (24):

PFTs, AFB smear positivity, and symptoms were overall similar between patients. A retrospective study of 58 patients with M. abscessus spp abscessus or spp massilience evaluated CT chest finding while on antibiotic (25). In both, the rate of bronchiectasis and cavitation were similar at the start of therapy, with 84% of the M. massiliense group having a decrease in the overall CT score at follow up, compared to only 33% in the M. abscessus group:

At the end of follow up, 94% of patients with M. massiliense disease demonstrated improvement based on imaging whereas 46% of M. abscessus patients demonstrated increased CT scores (aka worsening of disease on imaging). Another cohort study found that symptomatic and radiologic improvement were higher in those with M. massiliense than in those with M. abscessus (97% vs 75% for symptomatic improvement; 82% vs 42% for radiographic improvement, respectively, 7). Sputum conversion rates were also higher in the M. massiliense group (97% vs 42%), with lower rates of recurrence as well. 

In another cohort (24), outcomes tended to favor those with spp massilience, with 95% of M. massiliense infection achieving treatment completion compared to only 42% of those with spp Abscessus. 

A retrospective study of 107 patients with pulmonary M. abscessus disease found that most patients presented with cough, sputum production, fatigue, and dyspnea, with CT findings consisting mostly of bronchiectasis and nodular opacities (26). Cavitation was found in 44% of the cases in the cohort. 24 patients underwent surgical procedures, and overall, culture conversion status was higher in the surgical cohort compared to the medical cohort:

Finally, a meta-analysis of 19 studies evaluating over 1000 patients with pulmonary M. abscessus found that a higher rate of M. massiliense patients had culture conversion compared to M. abscessus (27):

Recurrence disease was also lower in the M. massiliense cohort (7%) compared to M. abscessus (40%), with OR of recurrence 6.189 (95% CI 2.317 to 8.046). 

What do you do if you encounter M. abscessus in the wild?

1. Do not jump the gun to treatment! Get a repeat sputum culture and then get a CT.
2. Remember, even if the CT shows some degree of disease (i.e fibrocavitary disease or bronchiectasis) if the patient is not symptomatic, some would argue not to treat.
3. If you have a) a patient who is symptomatic, b) CT changes and c) either 2 consecutive positive sputum cultures OR one positive BAL = see if your lab is able to identify the subspecies. Again, this has prognostic and therapeutic implications. Do not jump the gun!
4. If M. massiliense is identified => proceed with therapy
5. If M. abscessus is identified => a bit tricky. I would see if we can detect macrolide inducible resistance, with the knowledge that macrolies will still be used no matter what. If you need to add another drug that is active based on susceptibility will depend on whether or not there is inducible resistance
6. Always, always, always = consult someone within ID who knows how to treat this. As you can see from this post, there is no great data here due to the lack of RCTs (both due to the relative scarcity of cases and the ethics of randomizing patients to different therapies that can take years to complete). As such, experience is key. 

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I didn’t know where to put this, as it likely has no clinical implications. Here, M. abscessus spp abscessus was inoculated with a 27-spice blend, which  increased the zone of susceptibility in both linezolid and amikacin, suggesting a synergistic effect (28):

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