Doxycycline Defying Antimicrobial Resistance in India: Results from 2020 Study
In an era of increasing multidrug-resistance, rationalizing the use of effective and durable antimicrobial agents has become essential. There is more focus in this domain of research. Healthcare systems particularly, general physicians and diagnostic laboratories are being sensitized to be aware of the changing trends of antibiotic susceptibility and evaluate existing agents as much as possible for common infections.(1). An Indian study assessing the susceptibility of Doxycycline among other commonly prescribed antimicrobial agents is reviewed. This study re-emphasizes the therapeutic value and relevance of doxycycline in Indian practice settings.
Pharmaco-Clinical Relevance of Doxycycline: Antimicrobial Activity and Beyond
Doxycycline has broad-spectrum activity against a range of gram-positive, gram-negative, and 'atypical' bacteria as well as some protozoan pathogens such as malaria.(1) It is still efficacious in many indications in India and worldwide.(2) Doxycycline is an asset to developing countries as it is an easily available, cost-effective antimicrobial agent1 rendering practical advantages to Indian patients.
Many scientific papers have reviewed the antiviral potential of doxycycline on viruses including dengue virus (DNV), vesicular stomatitis virus (VSV), and chikungunya virus (CHIKV). Doxycycline possesses its anti-viral activity through multiple mechanisms. It includes interference with viral adsorption as against DNV and CHIKV as well as inhibition of replication against VSV. Studies have also reported that doxycycline can inhibit DNV and CHIKV proteases which are involved in the cleavage of viral polyproteins in modus similar to the SARS-CoV-2 replication process(3)
Doxycycline also possesses anti-inflammatory activity which is achieved through modulation of expression of interleukins 6 (IL-6), interleukins 8 (IL-8), and Tumour Necrosis Factor-alpha (TNF-α) (4). It inhibits the migration of neutrophils to the lungs exposed to intratracheal lipopolysaccharide which potentially helps to fight against respiratory infections.
Doxycycline - Superior Susceptibility over Commonly used Antimicrobial Agents: Indian Study
Background: Real-world evidence based on real-time surveillance is a great tool to understand the changing resistance patterns of antimicrobials agents. A study was conducted in 2020 in India to estimate the current status of antimicrobial resistance (AMR) against doxycycline in comparison to three antimicrobial agents from different classes - Azithromycin (Macrolides), Cefuroxime (2nd generation cephalosporin), and Amoxicillin (Penicillin)
Objective: The objective of this study was to assess the antimicrobial susceptibility patterns of commonly isolated pathogens against doxycycline and compare them with azithromycin, cefuroxime, and amoxicillin
Study Type: The study was an observational, retrospective study conducted on secondary data extracted from multi-center diagnostic laboratories across four cities from Western India.
Study Methodology – Platform, Sampling, and Data Analysis
Study Platform: Antimicrobial susceptibility data on blood, urine, pus, and sputum (includes sputum/bronchoalveolar lavage [BAL] or bronchoalveolar washings/brushings/aspirates) were used in the study. The culture-positive samples were segregated. The susceptibility status of various pathogens against four antimicrobials, namely doxycycline, azithromycin, cefuroxime, and amoxicillin was analyzed. The susceptibility testing was done on an automated platform called Vitek 2.
Sampling: A total sample of 58,863 specimens (blood, urine, pus, and sputum) was considered for this study. After removing the duplicates, 21,975 unique cases where organism growth was seen were enrolled further. Eventually, data on the susceptibility status of doxycycline and comparative antimicrobial agents (azithromycin, cefuroxime, and amoxicillin) was extracted, and 2951 samples were included in the study, as these samples were tested for all four antimicrobials.
A total of 1831 samples out of 2951 were community-based and 1110 were from hospitals. Out of these samples, 1370 (46.4%) were of pus, 607 (20.5%) blood, 239 (8.0%) urine and 735 (24.9%) were sputum. About 47.6 % of samples were from females and the rest males. The mean age of females and males whose samples were utilized was 46.7 years and 52.6 years, respectively. The confidentiality of subjects was maintained by using anonymized data.
Data analysis: Data was analyzed through the use of Microsoft Excel and R (v 3.4.1, 2018). Culture susceptibilities were reported in the form of proportions. Samples described as intermediate or resistant were considered as resistant. A Chi-square test was used to compare categorical variables. Association between variables was considered statistically significant if the p-value was <0.05.
Results
For all samples: Doxycycline demonstrated good coverage for most bacterial pathogens (90-100%) as compared to the other three antibiotic agents. Staphylococcus spp. and Methicillin Susceptible Staphylococcus aureus (MSSA) were found sensitive (96-100%) to doxycycline across all the clinical specimen types tested. Good susceptibility was also shown against the most challenging gram-positive bacteria Methicillin-Resistant Staphylococcus aureus (MRSA) as compared to other antimicrobials. MRSA strains from all the samples were almost 100% susceptible to doxycycline.
Antibiogram of blood samples revealed 100% susceptibility of MSSA against doxycycline. In comparison with other antimicrobials, only amoxicillin was more active (95.8 %) than doxycycline (72.9%) against Streptococcus spp.
For urine samples: It was inferred that doxycycline was highly active against MSSA (92.6%) as compared to cefuroxime (71.4%). For gram-positive Streptococcus spp., doxycycline was found less active (27.8%) as compared to amoxicillin(100%).
For pus samples: Doxycycline was found more active (53.7%) against Klebsiella pneumoniae in comparison to other antimicrobial agents. Staphylococcus spp. was found to be most susceptible (94.2%) to doxycycline followed by cefuroxime (50.0%) and amoxicillin (21.7%). Lesser susceptibility of E. coli to cefuroxime (23.6%), amoxicillin (10.1%), and doxycycline (37.5%) were noted from the published data.
For sputum analysis: Doxycycline was reported active against all the major pathogens. For Klebsiella pneumoniae from sputum, amoxicillin was the least active (35.7%). Doxycycline was most active (68.4%) followed by cefuroxime (45.0%). E. coli were tested as least sensitive to amoxicillin (8.2%). Doxycycline was concluded to be more active against E. coli (41.8%) as compared to cefuroxime (22.0%). For Enterobacter spp. and Acinetobacter baumannii, susceptibility of doxycycline was observed to be 90.6% and 67.4% respectively.
Susceptibility patterns of isolates for Doxycycline in comparison to Azithromycin, Cefuroxime, and Amoxicillin
Majority of bacterial isolates from blood were found to be susceptible to doxycycline (93%). Across all four samples, overall isolates collectively reported statistically significant (p <0.05) higher susceptibility to doxycycline in comparison to other three antimicrobials- azithromycin, cefuroxime, and amoxicillin.
The susceptibility of isolates to doxycycline across all four samples, which were resistant to all other three antimicrobials was estimated. Doxycycline was found to be active against isolates (from all four specimens) which were resistant to all other three antimicrobials. The individual comparison was also made for each antimicrobial separately with doxycycline. For samples resistant to azithromycin, doxycycline was most active (93.5%). For samples resistant to amoxicillin and cefuroxime, doxycycline was found to be active in 75.9% and 64.8% samples, respectively.
Study Conclusion & Implication for Practitioners -
√ Several bacterial isolates from all four sources were found to be susceptible to Doxycycline. The study suggested that doxycycline is a promising candidate against many important bacterial isolates from all the four specimens studied from Indian patients.
√ As per current data, doxycycline can be considered as a potential drug of choice against major antimicrobial agents like azithromycin, cefuroxime, and amoxicillin against gram-positive cocci in Indian practice settings.
√ Doxycycline is also potent to MRSA, which was difficult to treat bacteria and showed promising results for isolates that were resistant to other three antimicrobials of major classes (penicillins, second-generation cephalosporins, and macrolides).
Doxycycline remains a valuable antimicrobial agent by virtue of its potent microbiological profile; anti-inflammatory and immunomodulatory activity; and practical advantages like cost-effectiveness and ease of availability. Indian clinicians may like to consider doxycycline optimally for effective infection care. This may serve in the best interest of patients and the Indian healthcare system at large, in defying the massive battle against anti-microbial resistance.
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Doxycycline, click HERE
References:
Adapted from:
1. Suyog C Mehta, Susceptibility Pattern of Doxycycline in Comparison to Azithromycin, Cefuroxime and Amoxicillin against Common Isolates: A Retrospective Study Based on Diagnostic Laboratory Data, JAPI 2020;68:59-63
2. Ziegler T, Winkler C, Wege K, Schmechel H. Doxycycline-The forgotten antibiotic. Med Klin 2000; 95:629-31
3. D'Alessandro S, Scaccabarozzi D, Signorini L, et al. The use of antimalarial drugs against viral infection. Microorganisms. 2020 Jan 8;8(1):85. Available from: https://pubmed.ncbi.nlm.nih.gov/31936284/
4. Conforti C, Giuffrida R, Zalaudek I, et al. Doxycycline, a widely used antibiotic in dermatology with a possible anti-inflammatory action against IL-6 in COVID-19 outbreak [published online ahead of print, 2020 Apr 20]. Dermatol Ther. 2020;e13437. DOI:10.1111/dth.13437
5. Farouk A, Salman S. Dapsone and doxycycline could be potential treatment modalities for COVID-19 [published online ahead of print, 2020 Apr 22]. Med Hypotheses. 2020;140:109768.
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