Keywords
Microbial resistance, Efflux pump inhibitors, Selective serotonin reuptake inhibitors, Innate immunity, Nosocomial infection, Catheter-associated urinary tract infection
Commentary
The ability of mobile genetic elements to transfer drug resistance between bacteria can cause the rapid establishment of multi-drug resistance (MDR) [1,2], and human infection caused by multi-resistant, rather than susceptible organisms increases the likelihood of death [3]. Such antibiotic resistance will be the cause of millions of premature deaths and the loss of millions of pounds to the global economy [4].
Nosocomial strains of Staphylococcus pyogenes (S. pyogenes) resistant to penicillin were reported in 1947 with a mixture of resistant and sensitive strains in the same patient [5]. Within a decade, 70% of infections in one hospital were resistant to at least two antibiotics, however, a policy for prescribing them facilitated susceptibility to penicillin in 50% within a year, cutting prevalence of infection by a third [6]. From this it can be surmised that in a third of patients, antibiotic-susceptible S. pyogenes persisted following treatment.
The innate immune system of humans relies on pattern recognition receptors (PRRs) recognising endogenous and exogenous molecular patterns related to pathogens [7]. Toll-like receptors (TLR) function as transmembrane PRRs and release inflammatory cytokines, interferons (IFNs), and antimicrobial peptides (AMPs) on engagement. Excessive signalling of TLR4s plays a significant role in Sepsis, proven when TLR4 knock-out mice were unaffected by lethal doses of Lipopolysaccharides (LPS) [8,9].
The term ‘inflammasome’ describes an intracellular cytoplasmic multiprotein complex with a pathogen recognition receptor [10] including NOD-like Receptors (NLRs) and pyrins which are specifically triggered by ligands. The canonical inflammasome is the part of the intracellular innate immunity that was observed first. It comprised the formation of pores in the cell membrane, followed by the release of caspase 1, then IL-1β and pro-IL18. The non-canonical inflammasome releases Caspase 4 and 5 which act as both sensor to pathogens, and effector in the release of IL-1β, IL-18 and events of pyropoptosis. Another non-canonical pathway has been observed in mice and uses Caspase 11 on exposure to LPS and other toxins [11-13].
Minimum Inhibitory Concentration (MIC) defines levels of susceptibility or resistance of specific bacterial strains to treatment [14]. More specifically, it is the lowest concentration of an antimicrobial (mg/ml) which prevents growth of a test strain of an organism in vitro. The antibiotic resistance status and MICS of a range of microbes can be found on the EUCAST website [15]. The technique comprises the distribution of a specific antibiotic over a petridish and the seeding of a bacterial species on the right-hand side; the leftward proliferation of the microbe suggests it has some resistance to the drug concentration present.
The selective serotonin reuptake inhibitors (SSRIs) have an antibacterial effect when used alone [16]. Additionally, the innate bacterial efflux pumps that can prematurely decrease the intracellular concentration of antibiotics, are blocked by efflux pump inhibitors (EPI’s) like Fluoxetine [17], allowing the medicine to act for longer. However, augmentation of antibiotics by this particular drug depends heavily on dose and regimen [18].
Proteus mirabilis is frequently found in catheter associated urinary tract infection (CAUTI) and is associated with serious clinical complications given its ability to form biofilms on even state-of-the-art indwelling catheters [18]. In vitro, a MIC of 0.26 mg/ml of fluoxetine was found for P. miribilis B4. In vivo, reduced blockage and lower levels of bacteria in residual bladder urine were found using small doses of the drug [18].
When taken alongside sub-inhibitory levels of three different antibiotics, a similar dose of fluoxetine was able to control E. coli, P. aeruginosa, and S. aureus [19]. Conversely, when a petridish of agar was exposed to this small dose of fluoxetine for 30 days prior to E. coli seeding, huge increases in the MIC of three different antibiotics were observed [20]. This study also revealed four different modes of antibiotic efflux and concluded that up-regulation of pumps was caused by ROS-mediated mutagenesis of DNA-binding transcriptional regulators. A lab study of three different antibiotics treating Acinebacter baumanni showed that 30 days prior exposure to fluoxetine also caused Ciprofloxacin resistance given this increase in efflux. Colistin-resistance occurred by a different mechanism, and the status of the antibiotic imipenem did not change [21]. So as a general statement we can say that a patient’s prior exposure to fluoxetine is likely to increase their required dose of antibiotics for bacterial infection.
It is known that the use of antibiotics at sub-inhibitory levels is a cause of antibiotic resistance [22], and we have highlighted here that parallel micro-dosing of SSRIs negates this. Obviously, a patient’s co-morbidity, BMI, and regular medications would also be influential. All modes of resistance are transient [23] and so close monitoring of patient's would allow optimisation of the dose and timing of antibiotics and adjunct drugs.
Successful antibacterial activity has been demonstrated in the lab and in patients with indwelling catheters for Fluoxetine used alone, and at micro-doses alongside low-dose antibiotics. A range of common medications with antimicrobial properties are summarised in Table 1, often working symbiotically with antibiotics. Alternatively, potentiation of the innate immune system could prevent or fight infection at an even earlier stage, so long as the risk of sepsis is mitigated. To put these conclusions in context, WHO have stated that carbapenem resistance in A. baumanni, P. aeruginosa and Enterobacteria are now a critical priority, with antibiotic resistant S. aureus making the ‘high priority’ list [24].
|
Drug Dose (mg/ml) |
Molecular Formula |
Molecular Weight (g/mol) |
Ionisation |
Water Solubility (mg/L at 25°C) |
Lipophillic |
Standalone Capability |
Effect in Combination with Antibiotics(abx) |
Ref. |
|
Fluoxetine 0.26 (flx) |
C17H18F3NO |
309.33 |
+ve |
No |
Yes |
Indwelling Catheter Users. P. mirabilis MIC 0.26 mg/ml |
|
[18] |
|
|
Lab Study of successful treatment of bacteria alongside abx under their normal minimum inhibitory dose. E. coli, P. aeruginosa, S. aureus |
[19] |
||||||
|
|
Lab study requiring abx above their normal inhibitory dose after 30 days of fluoxetine. S. aureus |
[20] |
||||||
|
|
|
|
Lab study resulting in increasing MIC for abx A. baumanni flx for 30 days, followed by: Ciproflaxacin >MIC |
[21] |
||||
|
Acetylsalicylic acid/Salicylic Acid
|
C7H6O3 |
138.12 |
-ve |
2240 |
yes |
Inhibition of Campylobacter pylori, Helicobacter pylori, Epidermophyton floccosum, Microsporum spp, Trichophyton spp.
|
Increases the antimicrobial susceptibility of many pathogens, but decreases the effect of aminoglycosides, beta-lactams and fluoroquinolones |
[25-31] |
|
Paracetamol |
C8H9NO2 |
151.16 |
+ve |
14000 |
yes |
|
Induction of beta-lactamase activity in Serratia marcesens |
[32] |
|
Ibuprofen |
C13H18O2 |
206.29 |
+ve |
21 |
yes |
Inhibits E. coli, S. aureus, Trichophytan spp, Microsporun spp |
Reduce the effect of azithromycin and moxifloxacin in humans |
[33-36]
|
|
Diclofenac |
C14H11Cl2NO2 |
2.96 |
+ve |
9 |
yes |
Inhibits E. coli |
|
[35] |
|
Sargassum Polyceratium extracts; Sp-1 (132-hydroxy-(132-R) pheophypin-a; 132-hydroxy-(132-S) pheophytin-a
|
|
|
|
|
|
Lab study of three biocidal agents against S. aureus showed no effect. |
Lab study of antibiotic and three strains of S. aureus. The presence of biocidal agents resulted in a four-fold reduction in microbial resistance to antibiotics. |
[36,37] |
|
Duloxetine 0.20 |
C18H19NOS |
297.4 |
+ve |
3 |
Yes |
Lab study resulting in successful treatment of: S. aureus, E. coli, Candida albicans, Bifidobacterium, E. faecalis, Lactobacillus rhamnosus,
|
|
[38,39] |
|
Venlafaxine 0.20 |
C17H28CINO2 |
313.9 |
+ve |
267 |
Yes |
|
||
|
Fluvoxamine0.20 |
C15H21F3N2O2 |
318.33 |
+ve |
4340 |
Yes |
|
||
|
Escitalopram0.20 |
C20H21FN2O |
324.40 |
+ve |
31.09 |
Yes |
|
||
|
Mirtazapine 0.20 |
C17H19N3 |
265.35 |
+ve |
slightly |
Yes |
|
||
|
Fluoxetine/0.20 |
C17H18F3NO |
309.33 |
+ve |
No |
Yes |
|
||
|
Desipramine/0.00-0.80 |
C18H22N2 |
266.4 |
+ve |
56.8 |
Yes |
Lab study of treatment success proportional to dose: B. animalis B. fragilis F. prausnitzii
|
|
|
|
Aripiprazole/0.00-0.80
|
C23H27Cl2N3O2 |
448.4 |
+ve |
Slightly |
Yes |
|
Acknowledgements
Thank you to my parents for continued support. Also thank you to Ruth Garry for life coaching, and bro-in-law Mike Roberts for helping me with DIY tasks on his rare days off.
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