This particular piece is triggered by a recent discussion. Does paracetamol have antimicrobial properties? The response is going to cover other agents used as antipyretics. I will be using materials by Zimmermann P, Curtis N. 2017.Antimicrobial effects of antipyretics. Antimicrob Agents Chemother 61:e02268-16. An antipyretic reduces fever.

Acetaminophen (paracetamol), acetylsalicylic acid (ASA, Aspirin, which is rapidly
degraded to salicylic acid [SAL] in vivo) and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, flurbiprofen, ibuprofen, and indomethacin, are
some of the most commonly used drugs. They have antipyretic, analgesic, and apart
from paracetamol, anti-inflammatory activities through the inhibition of prostaglandin synthesis. In addition to these activities, it has been known, for several years, that antipyretic drugs also have direct and indirect antimicrobial effects.

Antipyretics can inhibit and promote thegrowth or replication of bacteria and fungi. At therapeutic plasma levels, SAL and ASAinhibit the growth of Campylobacter pylori, Helicobacter pylori, and Klebsiellapneumoniae, as well as Epidermophyton floccosum, Microsporum spp., and Trichophyton spp.. Ibuprofen at therapeutic levels inhibits the growth of Escherichia coli and, at low pH, also Staphylococcus aureus, Microsporum spp., and
Trichophyton spp. Diclofenac inhibits the growth of E. coli, and flurbiprofen
inhibits Trichophyton spp.Theinhibitory activity of SAL, ibuprofen, diclofenac, and flurbiprofen can occur at concentrations that are achieved with normal therapeutic doses. In contrast, the usual therapeutic plasma levels of acetaminophen (paracetamol) are lower than the concentration at which inhibition of bacterial growth has been shown.

SAL reduces the motility of E. coli, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Pseudomonas aeruginosa.  Celecoxib, a nonselective COX-2 inhibitor, reduces flagellar motility in H. pylori.

Ibuprofen at a very low concentration significantly decreases the adhesion of E. coli to uroepithelial cells. Ibuprofen also reduces the adherence of E. coli to silastic catheters. Ibuprofen and diclofenac inhibit the adherence of Candida albicans, C. glabrata,
and C. krusei.

SAL at therapeutic levels reduces fibronectin binding in S. aureus and the adherence
of E. coli to silastic catheters. At concentrations slightly above the usual therapeutic plasma level, SAL reduces the production of adhesin in Staphylococcusepidermidis and fimbria production in E. coli. SAL also prevents the adhesion of P. aeruginosa and S. epidermidis to human corneal epithelial cells and the adherenceof P. aeruginosa, Haemophilus influenzae, S. epidermidis, and Streptococcus pneumonia to contact lenses.

SAL at therapeutic levels decreases biofilm production byCandida spp., E. coli, P. aeruginosa, and S. epidermidis.

In K.pneumoniae, SAL at very low concentrations reduces the production of the polysaccharide capsule by more than 50%. In P. aeruginosa, SAL and ASA decrease the production of hemolysin, elastase, protease, and pyocyanin by about 55%. Ibuprofen, at low concentrations, reduces hemolysin production in E. coli.

SAL at a concentration above therapeutic plasma levels leads tothe downregulation of gluconeogenesis and glycolysis in S. aureus and to activation of sugar transport (sorbitol and mannose) in E. coli. Ibuprofen and indomethacin induce cytochrome P450 (CYP) production in Bacillus megaterium, which renders the bacteria considerably more sensitive to oxidant insults. Ibuprofen at high concentrations induces metabolic alternation and also damages the cytoplasmic membrane in Candida spp.. It also inhibits the transition from yeast to hyphae and, therefore, germ tube formation in Candida spp..

SAL increases the antimicrobial susceptibility of many pathogens. Less commonly, it leads to decreased susceptibility, mainly to aminoglycosides but also to beta-lactams and fluoroquinolones. When H.pylori is exposed to ASA and other COX inhibitors, its susceptibility to amoxicillin, clarithromycin, and metronidazole increases.  In Candida spp., ibuprofen or ASA in combination with azoles and amphotericin B leads to synergistic effects.The MICs of Candida spp. Tofluconazole decrease up to 128-fold in the presence of ibuprofen.

ASA/SAL inhibit the cell entry and replication of hepatitis C virus, as well as the replication of flavivirus and influenza virus. The inhibition of replication mostly occurs at therapeutic levels. One of the underlying mechanisms is inhibition of the transcription factor nuclear factor-kappa B, which is critical for the
inducible expression of multiple cellular and viral genes involved in inflammation, including
interleukin-1 (IL-1), IL-6, and adhesion molecules. Another mechanism is the
activation of p38 mitogen-activated protein kinase and mitogen-activated protein kinase/
extracellular signal-regulated kinase kinase 1/2.

As antipyretics are commonly coadministered with antimicrobial therapy, it is important
to understand the interactions between these two classes of drugs. Antipyretics primarily
act by inhibiting prostaglandin synthesis. Fungi (unlike bacteria and viruses) produce
prostaglandins, and influence virulence, in particular controlling the yeast-to-hypha transition and biofilm production. Aside from prostaglandin inhibition, other mechanisms by which antipyretic drugs influence pathogens include inhibiting virus replication, inhibiting or promoting bacterial and fungal growth, altering the expression of virulence factors, changing the surface hydrophobicity of microbes, influencing biofilm
production, affecting motility, adherence, and metabolism, interacting with the transport and release of antibiotics by polymorphonuclear leukocytes (PMNL), modifying the susceptibility of microbes to antimicrobial therapy, and inducing or reducing the frequency of mutations leading to antimicrobial resistance.

Although many of the MICs for antipyretic drugs are above the therapeutic plasma
levels normally attained, higher drug concentrations might be reached in urine, synovia, or with topical therapy. Topical ibuprofen, for example, is more effective in suppressing
the growth of Trichophyton than topical clotrimazole. About two-thirds of women with uncomplicated urinary tract infections (80% with E. coli) treated with ibuprofen recover without antibiotics. Although this finding is considered to result from the anti-inflammatory effects of ibuprofen, it might also be attributable to the antimicrobial effects of ibuprofen, which include blocking of adherence to uroepithelial cells, reduced motility, and reduced toxin and biofilm production, as well as inhibition of growth. Diclofenac and other NSAIDs inhibit bacterial DNA
synthesis (10, 91) in E. coli; this was shown to be through the inhibition of a DNA polymerase.

Changes in susceptibility mostly result from a change in direct antimicrobial penetration through cell membranes of bacteria or from an increase or decrease in efflux through the membranes. However, decreased susceptibility can also result from induced beta-lactamase activity. By understanding these mechanisms, these synergistic effects can be exploited in the
treatment of infectious diseases and the potential compromising effects on antimicrobial
efficacy can be avoided. Antipyretics could be useful in the management of
biofilm-associated infections, as adjuvant therapy in viral, bacterial, and fungal infections, or in reducing antimicrobial resistance.




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