Minocycline Activity against Unusual Clinically Significant Gram-Negative Pathogens

ABSTRACT The minocycline susceptibility of 3,856 isolates including Burkholderia, Achromobacter, Alcaligenes, Aeromonas, and Stenotrophomonas maltophilia from the SENTRY surveillance (2014 to 2019) were analyzed. The susceptibilities of these species (%S) were Achromobacter spp. (n = 411; 92.6%), Burkholderia cepacia species complex (n = 199; 85.9%), Aeromonas spp. (n = 127; 99.2%), Chryseobacterium spp. (n = 59; 94.9%), Alcaligenes faecalis (n = 42; 88.1%), and S. maltophilia (n = 2,287; 99.5%). These data suggest that minocycline is a useful treatment option for infections caused by unusual Gram-negative pathogens.

From 2014 to 2019, 3,856 unusual GN isolates were consecutively collected from hospitalized patients as part of the global SENTRY Antimicrobial Surveillance program (15). Briefly, laboratories submitted 1 isolate per patient per infection episode. Chart reviews were not performed to determine if the isolate was a colonizer rather than a pathogen. Identifications were performed by the submitting laboratory and confirmed at JMI Laboratories with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF; current BioTyper Compass software version 4.1.100.1; Bruker Daltonics, Billerica, MA, USA). BioTyper software updates were applied as available from the manufacturer throughout the surveillance period.
The most common GN species, Pseudomonas aeruginosa and Acinetobacter baumanniicalcoaceticus complex, were excluded from this analysis, as the focus was on less commonly isolated species. Each genus selected for analysis had at least 10 isolates. Some genera had multiple species, each with a small number of isolates that were combined for analysis; therefore, these results should be interpreted with caution.
The MIC frequency distribution and MIC 50/90 values of minocycline for the genera analyzed are shown in Table 1. Susceptibility for all isolates was 97.0% (3,739/3,856) and was over 90% for the genera shown, except for Alcaligenes faecalis, Burkholderia spp., and non-aeruginosa Pseudomonas spp. Minocycline susceptibility of A. faecalis was 88.1%, Burkholderia spp. was 86.8%, and B. cepacia species complex was 86.3%. The susceptibility of non-aeruginosa Pseudomonas spp. was 89.7%.
The MIC 50/90 values and susceptibilities to minocycline and comparators, including meropenem and meropenem-vaborbactam, for the largest organism groups are shown in Table 2. Minocycline had the highest susceptibility (98.8%) of the agents tested against Acinetobacter spp., followed by levofloxacin at 97.2%. Imipenem and meropenem also had 95% or greater susceptibility.
Of the 340 non-aeruginosa Pseudomonas species isolates, the P. putida group (n = 84) was the most common species ( Table 2). As CLSI breakpoints for P. aeruginosa are no longer applicable to non-aeruginosa species, the CLSI breakpoints for other non-Enterobacterales were applied (18). Minocycline inhibited 89.7% of isolates with a MIC value of #4 mg/liter. The two drugs with the highest susceptibilities were amikacin (97.6%) and gentamicin (94.1%).
Although minocycline was first introduced in 1967, its use for the treatment of infections caused by unusual GN has increased due to its potent in vitro activity, good tissue penetration, and low toxicity (19)(20)(21)(22). In addition, the approval of an improved intravenous formulation in the United States in 2015 facilitated its use in hospitalized patients with serious infections (22)(23)(24). Combination therapy with minocycline and various antimicrobials, including colistin and cefiderocol, have also been studied, although there is no consensus about which combinations are the most useful (25)(26)(27).
Overall, minocycline susceptibility was greater than 85% for the various species tested, including 99.2% susceptibility for Aeromonas spp., 98.8% for non-baumannii Acinetobacter, 92.7% for Achromobacter spp., and 99.5% for S. maltophilia. While colistin was also active against several species, its clinical use is discouraged due to toxicity and poor efficacy (28). Trimethoprim-sulfamethoxazole also had good in vitro activity against Achromobacter spp., Burkholderia spp., and S. maltophilia. Resistance to trimethoprim-sulfamethoxazole has been reported in S. maltophilia (29,30). In this study, 5.0% of isolates were resistant to trimethoprim-sulfamethoxazole and 92.9% of those isolates were susceptible to minocycline.  This study has several limitations: the recently approved drugs cefiderocol and eravacycline may have activity against these isolates but were not tested; most of the isolates analyzed were from the United States; there was no medical chart review, so it is unknown if any isolates were colonizers rather than pathogens; MALDI-TOF was used for isolate identification, which may not distinguish among relevant species of some analyzed genera; and no molecular characterization was performed.