What to do with MDR Acinetobacter Baumannii?

Here in the DrGermophile ranks, we talk about all beta-lactamases and how awesome they are. In particular, we like sulbactam. It is in combination with ampicillin, and its use is unappreciated to the uninitiated, but it plays a role in infections such as anaerobic pneumonia. It has a reasonably broad spectrum of activity, losing out to piperacillin-tazobactam in terms of pseudomonas coverage. Its activity tends to dwindle when taking into consideration some unique gram negative such as stenotrophomonas, due to the different beta-lactamases that it tends to produce. Funnily enough, ampicillin-sulbactam tends to retain some degree of activity against Acinetobacter baumanii, specifically sulbactam. Yes, that sulbactam, the beta-lactamase inhibitor. Why is this the case? This is due to inhibition of several key enzymes that are needed for bacterial peptidoglycan synthesis, such as PBP1a, 1b, and 3. Despite this, there has been a decline in the in vitro susceptibility due to upregulated beta-lactamases. Here we will talk about some of the treatment options for A. baumanii

Does Sulbactam Work:

There seems to be some degree of activity that sulbactam retains. For instance, one retrospective study evaluating A. baumannii bacteremia found that the diagnosis of lymphoma/leukemia, presence of septic shock, inappropriate antibiotic therapy, and lack of surgical treatment of the source of bacteremia were associated with higher mortality in univariate analysis (1). Furthermore, the same analysis found that amp/sulbactam had the highest percentage of susceptible isolates, with 74%:

A retrospective study evaluated the efficacy of cefoperazone/sulbactam (looking mostly at sulbactam) on carbapenem-resistant A. baumannii VAP in elderly patients (2). 60 isolates were evaluated, of which susceptibility to all antibiotics except for polymyxin B, was <5%. The cohort with CFS had higher 30-day survival compared to the non-CFS (96.4% vs 73.3%, p < 0.05). Furthermore, when combined with meropenem, minocycline, or levofloxacin, the MIC 50 and MIC 90 were reduced when drugs were combined:

In one cohort of 40 patients with MDR A. baumannii nosocomial infections evaluated therapy with amp-sulbactam and found that 67.5% had improvement (3). Another cohort evaluated the combination of amp-sulbactam in non-life-threatening nosocomial infections with MDR A. baumannii. 42 patients were evaluated, of which 18 were treated with sulbactam alone. Only two cases did not achieve cure or improvement (4). Several older retrospective cohort studies have suggested that sulbactam, when compared to things such as colistin, imipenem, or tigecycline as monotherapy, is as efficacious as the more “toxic” drugs, though imipenem is the general comparator. For instance, a small retrospective study of 28 patients with A. baumannii VAP found that amp/sulbactam monotherapy was comparable to colistin monotherapy for clinical success (5):

A small retrospective study of 47 patients with A. baumanii bacteremia found no statistically significant difference between imipenem-cilastatin and cefoperazone/sulbactam in terms of 30 day mortality, though there was a trend towards benefit in those who got the sulbactam-containing regimen (6):

Similarly, an earlier study of A. baumanii bacteremia found more patients who received Amp-sulbactam tended to have end of treatment success when compared to imipenem-cilastatin (7):

Similar results were also seen in a cohort of 471 burn patients with a variety of different infections (8), and while eradication difference was not statistically different between the two cohorts, it tended to favor imipenem more. Despite these data suggesting the utility of sulbactam monotherapy (which, before I forget, is only available in combination with ampicillin in the US of A), the rise in resistance patterns means it is more commonly used as part of combination therapy, usually an antipseudomonal antibiotic such as a carbapenem. For instance, an in vitro study found that combination meropenem and sulbactam exhibited a prolonged bactericidal effect, which was prolonged when the dose of sulbactam was increased from 4 to 8mg/L (9):

Furthermore, in an animal study, a higher percentage of mice treated with the combination survived when compared to either drug alone:

This seems to pan out in clinical data, although the vast majority is retrospective and tends to have different comparators due to the nature of the disease. For instance, a retrospective cohort evaluated amp-sulbactam in 173 pneumonia cases, of which 138 received combination therapy (10). 119 of these had carbapenem therapy as well. Multivariate analysis found that malignancy (OR 2.778), bilateral pneumonia (OR 2.885), and shorter duration with sulbactam or amp-sulbactam (OR 0.933 95% CI 0.88-0.989) were associated with clinical failure. Outcomes between monotherapy with sulbactam/amp-sulbactam and combination therapy were not statistically different between groups (30 day mortality 36.4% for monotherapy vs 37.2%). In a matched cohort study (11), tigecycline was compared with amp-sulbactam for the treatment of pneumonia. 84 patients in tigecycline group were matched with 84 of sulbactam, with sulbactam group patients being more likely to have combination therapy, usually with carbapenems. Patients in the sulbactam cohort were more likely to experience eradication of Acinetobacter (64% vs 33%, p <0.0001). Despite this, pneumonia resolution or 30 day mortality was not statistically different between groups:

Given the lack of head-to-head trials for A. baumanii therapies, several network meta-analyses have been done in an attempt to compare different combinations. In one evaluating carbapenem-resistant Acinetobacter VAP/HAP, 18 studies that included 1835 patients were included (12). High dose sulbactam (>6g per day) combined with another antibiotic such as levofloxacin or tigecycline had highest efficacy when compared to other combinations for clinical improvement and clinical cure:

Colistin and rifampin were associated with higher rates of airway eradication, however no combination was associated with lower all-cause mortality:

Another network meta analysis of 23 studies utilizing IV colistin monotherapy as a common comparator found that sulbactam monotherapy ranked first for reducing all-cause mortality, however IV colistin/inhaled colistin were associated with higher rates of clinical cure (13):

Overall, if your resistances allow it then amp-sulbactam + a carbapenem is a reasonable option upfront. Imipenem is the go-to but meropenem is also another option.

MDR – What are your options?

Colistin. I could end that right now, as it is a commonly used option for several multi-drug resistant strains. For instance, a case series of 10 patients with multidrug resistant A. baumanii (R to carbapenem, colistin, and high tigecycline MIC >2) found that therapy with IV colistin, high-dose amp/sulbactam, high-dose tigecycline, and inhaled colistin achieved clinical success in 90% of patients (14). A cohort of 89 patients with A. baumannii VAP, colistin monotherapy was compared with colistin/sulbactam combination therapy (15). Those who had combination therapy were older and had higher APACHE II scores. Clinical cure at day 14 was numerically higher in the combination cohort, however mortality was also higher in this group. Despite this, none of the results were statistically different:

Another study of 101 patients found that combination therapy that included polymixin B was associated with lower 30 day mortality (16):

Most of the patients in this cohort (around 70%) received a combination of polymixin B and meropenem, and all but ~11% included a beta-lactam. Tigecycline has been used as another therapeutic option, usually in combination. One cohort evaluated tigecycline + imipenem/cilastatin vs sulbactam + imipenem/cilastatin in MDR Acinetobacter VAP cases  (17). 30 day survival was higher in the tigecycline group, with multivariate regression analysis finding that the combination of sulbactam-imipenem/cilastatin was associated with higher in-hospital mortality (OR 8.56, 95% CI 2.81-29.75):

In another network meta-analysis (18), triple therapy of tigecycline, colistin, and sulbactam achieved the highest rank among all therapies when compared to colistin and sulbactam therapy:
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Colistin combination therapy was associated with higher microbiological cure rate, as well as being associated with decreased all-cause mortality:

One review noted that carbapenems tended to be combined with colistin for empiric therapy (19) with UpToDate recommending carbapenem, sulbactam, or a broad-spectrum beta-lactam in combination with another agent if resistance rates are above 15%.

New Kids on the Block

The use of colistin has increased recently due to higher rates of resistance to more conventional antibiotics, however its toxicity has resulted in people looking towards new agents with lower rates of adverse events. One of these is cefiderocol, which was found to be susceptible in 95% of A. baumannii isolates in one in vitro study (20), however the one I want to talk about here is Durlobactam. This is a new DBO beta-lactamase inhibitor that has activity against class A, C, and D serine beta-lactamases, of which its activity against carbapanameses of the OXA family is a key factor in its activity against MDR A. baumannii (21). This makes it a better option than the other DBO, avibactam. A Chinese study of nearly 1000 Acinetobacter strains found the MIC for sulbactam/durlobactam tended to be significantly lower when compared to sulbactam alone and comparable MIC to tigecycline (what this means is unknown at this time). 85% of these isolates were resistant to imipenem (22).

In a similar study evaluating carbapenem resistant isolates, MICs for sulbactam/durlobactam were also around 2 (23):

Durlobactam had good activity against Oxa-23 and Oxa-40 isolates, with the only carbapenemase that had no activity against it being NDM. Another study of 1722 isolates found that the addition of durlobactam to sulbactam lowered the MIC90 by 32-fold (24):

Durlobactam’s older brother seems to retain some degree of activity against A. baumannii. For instance, the addition of avibactam to sulbactam decreased the MIC significantly in several strains of A. baumanii, specifically OXA-23. Similarly, relebactam had a similar effect, however not as great as sulbactam (25):

In another cohort, the addition of avibactam to sulbactam allowed 98% of isolates to achieve an MIC of MIC <4, with the exception being NDM-1 harboring isolates (26).

TL;DR

• Treatment with A. baummanii empirically consists of a carbapenem, ideally either of the ones with anti-pseudomonal activity + ampicillin-sulbactam.
• Tigecycline or colistin are choices for MDR A. baumanni, specifically carbapenem-resistant ones
• Triple therapy, with carbapenem + sulbactam + colistin is a reasonable choice if all things fail
• Avibactam and Durlobactam, while not yet studied in the clinical area, are potential 

References:

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