An Ancient Drug for a Modern Era: Minocycline for the Treatment of Multi-Drug-Resistant Acinetobacter baumannii

Introduction: Infections caused by Acinetobacter baumannii are a major cause of health concerns in the hospital setting. Moreover, the presence of extreme drug resistance in A. baumannii has made the scenario more challenging due to limited treatment options thereby encouraging the researchers to explore the existing antimicrobial agents to combat the infections caused by them. This study focuses on the susceptibility of multi-drug-resistant A. baumannii (MDR-AB) strains to minocycline and also to colistin. Methodology: A cross-sectional study was conducted from June 2022 to June 2023. One hundred isolates of A. baumannii obtained from various clinical samples were sent to Central Laboratory, Department of Microbiology, Sree Balaji Medical College and Hospital, Chrompet, Chennai, India. The antimicrobial susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines, 2022. For the standard antibiotics, the disc diffusion method was performed. For minocycline and colistin, the minimum inhibitory concentration (MIC) was determined using an epsilometer strip (E-strip) test. Results: In this study, 100 isolates of A. baumannii were obtained, and 83% of the isolates were multi-drug-resistant. Among the MDR-AB, 50 (60%) were susceptible to minocycline and 40 (48%) were susceptible to colistin. Out of the 40 colistin-susceptible A. baumannii strains, 29 (73%) were susceptible to minocycline with a statistically significant P-value of <0.05. Among the 43 colistin-resistant A. baumannii strains, 21 (53%) were susceptible to minocycline with a statistically significant P-value of <0.05. Conclusions: When taking into account the expense of treating carbapenemase-producing Gram-negative bacteria, colistin and minocycline can be used as an alternative drug as they have fewer side effects and are more affordable. Minocycline can be used as an alternative to colistin because it is feasible to convert from an injectable to an oral formulation.


Introduction
Acinetobacter is a nonmotile Gram-negative coccobacillus that is most frequently found in soil, water, and sewage [1].It was listed by the American Society of Infectious Diseases (IDSA) as one of the six most dangerous microorganisms and the second most frequent nonfermenting Gram-negative pathogen isolated from clinical samples after Pseudomonas aeruginosa [2].The Centers for Disease Control and Prevention 2019 listed carbapenem-resistant Acinetobacter baumannii (CRAB) as an emerging threat, particularly in hospital-acquired infections (HAI) [3].Despite a decrease in CRAB infections probably due to infection control practices and antimicrobial stewardship [4], CRAB remains a threat due to limited treatment options [5].There are more than 30 species in the genus Acinetobacter, although A. baumannii and, to a lesser extent, Acinetobacter genospecies 3 and 13TU are mostly linked to nosocomial infections in the clinical environment [6].
Immunocompromised people frequently contract A. baumannii, especially if they had a prolonged hospital stay (>90 days).Long hospital stays are the most common risk factor for infections caused by this organism, which can also cause HAIs like catheter-associated urinary tract infections (CAUTI), ventilator-associated events (VAE), surgical site infections (SSIs), catheter-associated bloodstream infections (CLABSI), and meningitis [7].Furthermore, multi-drug resistance (MDR) and intrinsic resistance provide a worldwide medical concern [8].MDR is defined as resistance to at least one drug in three or more antimicrobial categories.Carbapenems, the cornerstone of treatment in the past, are no longer successful in reducing the infections caused by this organism [9].
The percentage of organisms resistant to minocycline decreased during this time, falling from 56.5% in 2003-2005 to 30.5% in 2009-2012 [10].The resistance towards colistin (2.8% in 2006-2008 and 6.9% in 2009-2012) and carbapenems (21.0% in 2003-2005 and 47.9% in 2009-2012) have more than doubled in the previous decade.Recent studies identified the percentage of resistance to minocycline and colistin as 7.2% and 1.7% respectively [11].In the clinical environment, minocycline has been used as a second-line drug for a variety of bacterial infections.According to recent research, minocycline has gained importance in treating infections caused by multi-drug-resistant A. baumannii (MDR-AB) [12,13], due to the ability to boost colistin's efficacy against MDR-AB isolates [14].Minocycline has better pharmacokinetic activity than other tetracyclines [15].Thus, our study was conducted to determine the susceptibility of A. baumannii, with special reference to minocycline.

Materials And Methods
A cross-sectional study was conducted from June 2022 to June 2023 in the Central Laboratory, Department of Microbiology at a tertiary care hospital, Chennai, South India, after obtaining Institutional Human Ethics Committee (IHEC) approval.

Inclusion criteria
Nonrepetitive MDR-AB isolated from the culture samples sent to the Central Laboratory, Department of Microbiology during the study period were included in the study.

Exclusion criteria
Repetitive samples and highly susceptible A. baumannii were excluded from the study.

Discussion
CRAB has become more common though carbapenems are effective treatments for MDR-AB infections.In Asia, 60% of the isolates were CRAB and pan-drug-resistant A. baumannii.In the United States and Europe, 65% of the isolates were identified as CRAB [18].Numerous tigecycline resistance mechanisms in A.
baumannii can be circumvented by minocycline.Additionally, minocycline has good in vitro action against drug-resistant A. baumannii and favorable pharmacokinetic and pharmacodynamic characteristics.
Minocycline is considered to be an effective alternative against MDR infections, particularly in conditions where limited antimicrobials are accessible and in patients requiring prolonged hospitalization.Akers et al. demonstrated a favorable clinical outcome in such patients with minocycline in their trial in a military center against MDR Acinetobacter spp.[19].Flamm et al. showed minocycline to be progressively efficient against MDR pathogens in a comparison investigation using tetracycline, doxycycline, and minocycline.70% of MDR organisms were sensitive to minocycline in their study [20].Greig and Scott detected a susceptibility of 80% toward minocycline among MDR Acinetobacter spp.[21].
Fragkou et al. found that the clinical and microbiological success rates after minocycline treatment were 72.6% and 60.2%, respectively [22].In our study, out of 83 MDR-AB, 50 (60%) were susceptible to minocycline, 20 (24%) were intermediate, and 13 (16%) were resistant, which implies minocycline is effective against multi-drug-resistant Acinetobacter spp.either by oral or by intravenous (IV) route.Greig and Scott explained the potential role of IV minocycline efficacy against MDR Acinetobacter spp.especially when combined with a second antibacterial agent [21].IV minocycline has been approved by the US FDA for the treatment of culture-positive MDR Acinetobacter species in hospitalized patients.The "Generating Antibiotic Incentives Now Act (GAIN Act)" designates its approval as a Qualified Infectious Disease Product (QIDP) [23].Fragkou PC et al. in the systematic review of the outcome of minocycline treatment towards MDR-AB emphasized a substantial percentage of success in clinical (72.6%) and microbiological (60.2%) aspects [22].In the study conducted by Kuo SC et al. approximately 20% of A. baumannii isolates were resistant to minocycline [24].However, its therapeutic appeal has been increased by the simplicity of switching from IV to oral formulations.This is especially true for patients who are hard to treat and have resistant Acinetobacter infections, as the data that is now available supports the efficacy of therapy in these tough clinical situations [15].
Colistin is used as a rescue therapy for severe infections and is regarded as one of the final therapeutic alternatives for the treatment of MDR-AB infections [25,26].Due to increasing resistance to colistin and due to its toxicity and higher cost, we can use minocycline as an alternative to colistin in most multi-drugresistant Acinetobacter cases.The most commonly used therapeutic combinations for MDR-AB include carbapenems, tigecycline, minocycline, polymyxins, and daptomycin.Bowers et al. in a study, where minocycline and polymyxin B were used as a combination on pan-drug-resistant A. baumannii found out that the MIC of each medication significantly dropped [27].As a result, either as a single drug or in combination with other drugs it is very effective against MDR Acinetobacter spp.

Limitations of the study
This study includes only bacterial isolates from the lab, and hence, patient details, clinical outcomes, and correlation were not analyzed.The comparison of various antimicrobial susceptibility methods for colistin such as the micro-broth dilution method was not performed.

Conclusions
Choosing the right medications is still crucial in treating infections caused by multi-drug-resistant organisms such as A. baumannii.In certain circumstances, minocycline can be used in the place of colistin.This is notably true for patients with MDR organisms hospitalized in intensive care units, where minocycline has fewer side effects and is more affordable.When taking into account the expense of treating Gramnegative bacteria that produce carbapenemases, colistin, and minocycline can be taken as an alternative drug.A potential therapeutic niche for minocycline would be the conversion of an injectable mode to oral formulation in stable patients who need a longer course of treatment.

FIGURE 1 :
FIGURE 1: Antimicrobial susceptibility pattern of MDR-Acinetobacter baumannii by the Kirby-Bauer disc diffusion method.