In vitro pharmacological interaction of caffeine and first-line antibiotics is antagonistic against clinically important bacterial pathogens
The in vitro antibacterial and interaction of pure caffeine powder with first line antibiotic against bacterial isolates was investigated by macrobroth dilution and the checkerboard assay methods. This study showed that caffeine and the antibiotics exhibited varied degree of antibacterial activities. While caffeine had MICs ranging between 67.19 and 268.75 µg/ml, chloramphenicol had MICs of between 0.98 and 31.25 µg/ml, kanamycin (15.63 – 62.5 µg/ml), nalidixic acid (0.49 – 250 µg/ml), erythromycin (0.49 – 62.5 µg/ml), tetracycline (1.99 to 62.5 µg/ml) and metronidazole (15.63 to 31.25 µg/ml). Combining ½ MICs and MICs of caffeine with the antibiotics as well as direct combination of caffeine and the antibiotics resulted in significant reduction of the effectiveness of the antibiotics. The fractional inhibitory concentration index (FICI) of the combination of ½ MICs of caffeine with the different antibiotics showed antagonistic interactions with the antibiotics except kanamycin having additive and indifferent interactions with caffeine. The (FICI) of the MICs of caffeine combined with antibiotics showed a reduction in the number of antagonistic interactions as chloramphenicol, nalidixic acid and erythromycin showed some indifferent interactions while kanamycin showed indifferent interaction alone. The direct combination of caffeine and the antibiotics resulted in significant antagonistic interactions higher than when caffeine, at the ½ MICs and MICs, was combined with the antibiotics. Although caffeine demonstrated significant antibacterial activity against the selected bacterial isolates, its combination with the selected antibiotics resulted in significant antagonistic interactions. Caffeine should not be combined with antibiotics as this could result in serious therapeutic failure and, possibly, drug toxicity in vivo.
Agyemang-Yeboah F, Oppong SY (2013) Caffeine: The wonder compound, chemistry and properties. Ghana: Kwame Nkrumah University, MSc thesis.
Almeida AAP, Farah A, Silva DAM, Nunan EA, Gloria MBA, (2006) Antibacterial activity of coffee extracts and selected coffee chemical compounds against Enterobacteria. J Agric Food Chem 54: 8738-8743. doi: 10.1021/jf0617317
Almeida AAP, Naghetini CC, Santos VR, Antonio AG, Farah A, Glória MBA, (2012) Influence of natural coffee compounds, coffee extracts and increased levels of caffeine on the inhibition of Streptococcus mutans. Food Res Int 49: 459-461. doi: 10.1016/j.foodres.2012.07.026.
Antonio AG, Moraes RS, Perrone D, Maria LC, Santos KRN, Iorio NLP, Farah A, (2010) Species, roasting degree and decaffeination influence the antibacterial activity of coffee against Streptococcus mutans. Food Chem 118: 782-788. doi: 10.1016/j.foodchem.2009.05.063
Ashihara H, (2006) Metabolism of alkaloids in coffee plants. Bra¬zil J Plant Physiol 18: 1–8. doi: 10.1590/S1677- 04202006000100001
Banerjee S, Verma PK, Mitra RK, Basu G, Pal SK, (2012). Probing the interior of self-assembled caffeine dimer at various temperatures. J Fluoresc 22(2): 753–769. doi: 10.1007/s10895-011-1011-3
Bauer AW, Kirby Wm, Sherris JC, Turck M, (1966) Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol 45(4): 493-6.
Belitz HD, Grosch W, Schieberle P (2009) Food Chemistry: Coffee, Tea, Cocoa. Berlin Heidelberg: Springer-Verlag.Cano-Marquina A, Tarín JJ, Cano A (2013) The impact of coffee on health. Maturitas 75: 7–21. doi: 10.1016/j.maturitas.2013.02.002.
Charles BG, Rawal BD, (1979) The combined action of methylxanthines with erythromycin and tetracyclines on Staphylococcus aureus. Microbios Lett 10: 143 – 147.
Chen, J, Zhang S, Yang X, (2013) Control of brown rot on nectarines by tea polyphenol combined with tea saponin. Crop Protection 45: 29-35.
Chou T. (1992). Wake up and smell the coffee: Caffeine, coffee and medical consequences. Western J Med 157(5): 544-553.
Cogo K, Montan MF, Bergamaschi CdeC, Andrade ED, Rosalen PL, Groppo FC, (2008) In vitro evaluation of the effect of nicotine, coti¬nine and caffeine on oral microorganisms. Can J Microbiol 54: 501– 508. doi: 0.1139/W08-032.
Conlay LA, Conant JA, DeBros F, Wurtman R, (1997) “Caffeine alters plasma adenosine levels,” Nature 389(6647): 136. doi: 10.1038/38160
Cortez D, (2003). Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases. J Biol Chem 278(39): 37139–37145. doi: 10.1074/jbc.M307088200
Daly JW, (2007) “Caffeine analogs: biomedical impact,” Cellular and Molecular Life Sciences, 64(16): 2153–2169.
Davies DB, Veselkov DA, Djimant LN, Veselkov AN. (2001) Hetero-association of caffeine and aromatic drugs and their competitive binding with a DNA oligomer. Eur Biophys J 30(5): 354–366.
Desbrow B, Hughes R, Leveritt M, Scheelings P (2007) An examination of consumer exposure to caffeine from retail coffee outlets. Food Chem Toxicol 45: 1588-92.
DeVries JW, Johnson KD, Heroff JC, (1981). HPLC determination of caffeine and theobromine content of various natural and red dutch cocoas. Hoppe Seyler’s Z Physiol Chem 358: 807-817.
Eliopoulos GM, Eliopoulos CT, (1988) Antibiotic combinations: should they be tested? Clin Microbiol Rev 1: 139-156.
Esinome CO, Okoye FBC, Nworu CS, Agubata CO, (2008). In vitro interaction between caffeine and come penicillin antibiotics against Staphylococcu aureus. Trop J Pharm Res 7(2): 969-974.
Etherton GM, Kochar MS, (1993) “Coffee facts and controversies,” Arch of Fam Med 2(3): 317–322.
Florey K, (1986). Analytical profiles of drug substances. In: Al-Badr AA, Brewer AG, Brenner SG, Deangelis JN, Mollica AJ (Eds). Analytical profiles of drug substances, p. 71. London: Academic Press.
Funk GD, (2009). Losing sleep over the caffeination of prematurity. J Physiol 587(Pt 22): 5299-300. doi: 10.1113/jphysiol.2009.182303
Furuhata K, Dogazaki C, Hara M, Furuyama M, (2002) Inactivation of Legionella pneumophila by phenol compounds contained in coffee. J Antibact Antifung Agents 30: 291-297.
Arendash GW, Cao C, (2010) Caffeine and coffee as therapeutics against Alzheimer’s disease. J. Alzheimers Dis 20 (Suppl 1): S117-S126. doi: 10.3233/JAD-2010-091249.
Greer F, Hudson R, Ross R, Graham T, (2001) Caffeine ingestion decreases glucose disposal during a hyperinsulinemic – euglycemic clamp in sedentary humans. Diabetes 50: 2349 – 2354. doi: 10.2337/diabetes.50.10.2349
Guo S, Zhu Q, Yang B, Wang J, Ye B, (2011). Determination of caffeine content in tea based on poly(safranine T) electro active film modified electrode. Food Chem 129 (3): 1311-1314. doi: 10.1016/j.foodchem.2011.05.095.
Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK, National Healthcare Safety Network Team & Participating National Healthcare Safety Network Facilities (2008) NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect Contr Hosp Epidemiol 29: 996–1011. doi: 10.1086/591861.
Hill P, (1991) It is not what you eat, but how you eat it digestion, life-style, nutrition. Nutrition 7(6): 385-95.
Hosseinzadeh H, Bazzaz BS, Sadat MM, (2006) In vitro evaluation of methylxanthines and some antibiotics: interaction against Staphylococcus aureus and Pseudomonas aeruginosa. Iranian Biomed J 10: 163-167.
Jacobson BH, Thurman-Lacey SR, (1992) Effect of caffeine on motor performance by caffeine-naive and familiar subjects. Perceptual and Motor Skills 74(1): 151-7.
James JE, Paull I, (1985) Caffeine and human reproduction. Rev Env Health 5: 151–167.
Carrillo JA, Benitez J, (2000) “Clinically significant pharmacokinetic interactions between caffeine and medications,” Clin Pharmacok 39(2): 127-153.
Kang TM, Yuan J, Nguyen A, Becket E, Yang H, Miller JH (2012)
The aminoglycoside antibiotic kanamycin damages DNA bases in Escherichia coli: caffeine potentiates the DNA-damaging effects of kanamycin while suppressing cell killing by ciprofloxacin in escherichia coli and bacillus anthracis. Antimicrob Agents Chemother 56(6): 3216-23. doi: 10.1128/AAC.00066-12
Kapuscinski J, Kimmel M (1993) Thermodynamic model of mixed aggregation of intercalators with caffeine in aqueous solution. Biophys Chem 46: 153–163. doi: 10.1016/0301-4622(93)85022-A
Kawamukai M, Murao K, Utsumi R, Himeno M, Komano T, (1986) Cell filamentation in an Escherichia coli K-12 fic mutant caused by theophylline or an adenylate cyclase gene (cya)-containing plasmid. FEMS Microb Lett 34(1): 117–20. doi: 10.1111/j.1574-6968.1986.tb01360.x
Kruger A, (1996) Chronic psychiatric patients’ use of caffeine: pharmacological effects and mechanisms. Psychol Reports 78: 915–923. doi: 10.2466/pr0.19188.8.131.525
Lachman LJ, Ravin L, (1959). Complexation of benzocaine, procaine, and teracine with caffeine J Am Pharm Ass; 45: 120 – 123.
Larsen RW, Jasuja R, Hetzler RK, Muraoka PT, Andrada VG, Jameson M, (1996) Spectroscopic and molecular modeling studies of caffeine complexes with DNA intercalators. Biophys J 70(1): 43 – 452. doi: 10.1016/S0006-3495(96)79587-5
Lelo A, Birkett DJ, Robson RA, Miners JO, (1986) Comparative pharmokinectics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man. Br J Clin Pharmacol 22(2): 177-182.
Leonard B, (2000) Stress, depression and the activation of the immune system. World J Biol Psych 1(1): 17-25.
Li Y, Feng Y, Zhu S, Luo C, Ma J, Zhong F, (2012) The effect of alkalization on the bioactive and flavor related components in commercial cocoa powder. J Food Comp Anal 25(1): 17-23.
Lindsay J, Laurin D, Verreault R, Hebert R, Helliwell B, Hill GB, McDowell I, (2002) Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 156: 445–53.
Mandal S, Mandal MD, Pal NK, (2004) Evaluation of combination effect of ciprofloxacin and cefazolin against Salmonella enteric serovar typhi isolates by in vitro methods. Calicut Med J, 2: e2.
Matha A, Adbels OH, (1982) Complex formation between antihistaminic drugs and caffeine. J Am Pharm Ass, 9: 208
Minamisawa M, Yoshida S, Takai N, (2004) Determination of biologically active substances in roasted coffees using a diode-array HPLC system. Anal Sci 20: 325-328. doi: 10.2116/analsci.20.325
Mohammed MJ, Al-Bayati FA, (2009) Isolation, identification and purification of caffeine from Coffea arabica L. and Camellia sinensis L.: A combination antibacterial study. Int J Green Pharm 3(1): 52-57. doi: 10.4103/0973-8258.49375
Mohanpuria P, Kumar V, Yadav SK, (2010) Tea caffeine: metabolism, functions and reduction strategies. J Food Sci Biotech 19(2): 275-287. doi: 10/1007/s10068-010-0041-y
Najafi NM, Hamid AS, Afshin RK, (2003) Determination of caffeine in black tea leaves by fourier transform infrared spectrometry using multiple linear regression. Microchem J 75: 151-158.
Namboodiripad PA, Kori S, (2008) Can coffee prevent caries? J Conserv Dentistry 12: 17-21. doi: 10.4103/0972-0707.53336
Nehlig A, Daval JL, Debry G, (1992) “Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects”. Brain Res Rev. 17(2): 139-170. doi: 10.1016/0165-0173(92)90012-B
Nehlig A, Boyet S, (2000) Dose-response study of caffeine effect of cerebral functional activity with a specific focus on dependence. Brain Res: 858:71-7. doi: 10.1016/S0006-8993(99)02480-4
Olajuyigbe OO, Afolayan AJ, (2012) In vitro antibacterial and time kill assessment of crude methanolic stem bark extract of Acacia mearnsii De Wild against bacteria in shigellosis. Molecules 17(2): 2103-2118. doi: 10.3390/molecules17022103.
Petersen PJ, Labthavikul P, Jones CH, Bradford PA, 2006. In vitro antibacterial activities of tigecycline in combination with other antimicrobial agents determined by chequerboard and time-kill kinetic analysis. J Antimicrob Chemother 57: 573–576. doi: 10.1093/jac/dki477
Pons FW, Muller P, (1990) Induction of frameshift mutations by caffeine in Escherichia coli K12. Mutag 5(2): 173-178. doi: 10.1093/mutage/5.2.173
Prescription drugs/caffeine interactions, 2016. http://www.caffeineinformer.com/caffeine-drug-interactions. Accessed 01-05-2016
Pruthviraj P, Suchita B, Shital K, Shilpa K, (2011) Evaluation of antibacterial activity of caffeine. Int J Res in Ayuveda Pharm 2(1): 1354-1357.
Raber J, (1998) Detrimental effects of chronic hypothalamic-pituitary-adrenal axis activation. from obesity to memory deficits. Mol Neurobiol 18(1): 1-22.
Ramanaviciene A, Zukiene V, Acaite J, Ramanavicius A, (2002) Influence of caffeine on lysozyme activity in the blood serum of mice. Acta Med Lituanica 4: 241-4.
Ramanaviciene A, Mostovojus V, Bachmatova I, Ramanavicius A (2003a) Anti-bacterial effect of caffeine on Escherichia coli and Pseudomonas fluorescens. Acta med Lituanica 10:185-188.
Ramanaviciene A, Acaite J, Dringeliene A, Markevicius A, Ramanavicius A, (2003b) Effect of caffeine on mice immunocompetent cells. Acta Med Lituanica 2: 86-89.
Ribeiro JA, Sebastiao AM, (2010). Caffeine and adenosine. J Alzheimers Dis 20Suppl(1): S3-15. doi: 10.3233/JAD-2010-1379
Rodrigues CI, Marta L, Maia R, Miranda M, Ribeirinho M, Máguas C (2007). Application of solid-phase extraction to brewed coffee caffeine and organic acid determination by UV/HPLC. J Food Comp Anal 20(5): 440-448. doi: 10.1016/j.jfca.2006.08.005
Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR, (2000) Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA 283: 2674–9. doi: 10.1001/jama.283.20.2674
Sacks LE, Thompson PA, (1977) Increased spore yields of Clostridium perfringens in the presence of methylxanthines. Appl Environ Microbiol 34: 189–93.
Sakurai H, Mitsuhashi N, Tamaki Y, Akimoto T, Murata O, Kitamoto Y et al. (1999) Interaction between low dose-rate irradiation, mild hyperthermia and low-dose caffeine in a human lung cancer cell line. Int J Radiat Biol 759(6): 739-45. doi: 10.1080/095530099140087
Sandlie I, Solberg K, Kleppe K, (1980) The effect of caffeine on cell growth and metabolism of thymidine in Escherichia coli. Mutat Res 73(1): 29–41. doi: 10.1016/0027-5107(80)90133-5
Sawynok J, (1995) Pharmacological rationale for the clinical use of caffeine. Drugs 49: 37–50.
Selby CP, Sancar A, (1990) Molecular mechanisms of DNA repair inhibition by caffeine. Proc Natl Acad Sci USA 87: 3522–5.
Suárez-Quiroz ML, González-Rios O, Barel M, Guyot B, Schorr-Galindo S, Guiraud JP, (2004) Effect of chemical and environmental factors on Aspergillus ochraceus growth and toxigenesis in green coffee. Food Microbiol 21(6): 629-634.
Traganos F, Kaminska-Eddy B, Darzynkiewicz Z, (1991) Caffeine reverses the cytotoxic and cell kinetic effects of Novantrone (mitoxantrone). Cell Prolif 24(3): 305–319. doi: 10.1111/j.1365-2184.1991.tb01159.x
Veselkov DA, Kodintsev VV, Pakomor VI, Djimant LN, Davies DB, Veselkov AN, (2002) 1H-NMR analysis of heteroassociation of caffeine with antibiotic actinomycin D in aqueous solutions. Biophys 45: 193–202.
Vinod DR, (2004) Pharmacognosy and Phytochemistry, Carrier Publication, 1st edn., Vol II, 311pp
Wilmot M, (2006) In vitro Inhibition of phytopathogenic fungi by caffeine, tea catechins theanine, polyphenon g, black-, green- and rooibos tea extracts. Pretoria, South Africa: Pretoria University, MSc thesis.
Yen WJ, Wang BS, Chang LW, Duh PD, (2005) Antioxidant properties of roasted coffee residues. J Agric Food Chem 53(7): 2658-63. Doi: 10.1021/jf0402429
Youn JH, Gulve EA, Holloszy JO (1991) Calcium stimulates glucose transport in skeletal muscles by a partway independent of contraction. Am J Physiol 260(3 Pt 1): C555 – 561.
Acta Biochimica Polonica is an open access quarterly and publishes four issues a year. All contents are distributed under the Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) license. Everybody may use the content following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made, ShareAlike — If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original. There are no additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Copyright for all published papers © stays with the authors.
Copyright for the journal: © Polish Biochemical Society.