• ROHITAS DESHMUKH Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
  • RANJIT K. HARWANSH Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
  • MAYUR SHARMA Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
  • SWARNALI DAS PAUL Faculty of Pharmaceutical Science, Shri Shankaracharya Group of Institution, Shri Shankaracharya Technical Campus, Bhilai, 490020, India


Co-trimoxazole appropriates to category of broad-spectrum antimicrobial. They are active upon administration in vitro against an extensive collection of microorganisms. Their application in medical field has roughly spanned over decade now. There are numerous approaches that were progressed for improving their effectiveness towards their antimicrobial potency. However, routine use of this could accelerate the chance of bacterial resistance, and portrait it ineffective when required to treat infection. Consequently, newer investigations are necessary to keep the drug effective by minimise the development of resistance and maximise its safe use. Safe use is meant by safe delivery of drug in low dose, low frequency at the targeted molecule by effective ways. This can be achieved by using nanocarrier systems as they possess smart characteristics of effective drug delivery. These nanocarrier systems are including nanoparticle, liposomes, nanogels etc. Present review article deals with the historical perspectives with regards to co-trimoxazole, their mechanism of act/resistance and spectrum of activity in first section. In second portion different novel carriers, importance and application of nanogels, rational for co-trimoxazole nanogels are discussed. In conclusion, different literatures have proved the efficacy of nanogels in delivery of antimicrobial drug similar to co-trimoxazole. In the present time very less data is available for delivery of this drug with novel carriers. Therefore, this review aims to encourage researchers for creating some new findings in this perspective.

Keywords: Co-trimoxazole, Nanocarriers, Antimicrobials, Antibiotics and Drug resistance


1. Kulkarni A, Deo A, Nimbarte S. Antibiotic resilience pattern and cetrimide induced ultrastructural changes in multidrug resistant S. aureus. JCR 2020;7:1053-65.
2. Tacconelli E, Carrara E, Savoldi A. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018;18:318-27.
3. Suryana K, Suharsono H, Sindhughosa DA. Co-trimoxazole preventive therapy reduces active pulmonary tuberculosis risk in people living with HIV/AIDS on antiretroviral at wangaya hospital in Benpasar, Bali, Indonesia: a prospective cohort study. Asian J Pharm Clin Res 2020;13:96-100.
4. Patel RB, Welling PG. Clinical pharmacokinetics of co-trimoxazole (trimethoprim-sulphamethoxazole). Clin Pharmacokinet 1980;5:405-23.
5. Masters PA, O’Bryan TA, Zurlo J, Miller DQ, Joshi N. Trimethoprim-sulfamethoxazole revisited. Arch Intern Med 2003;163:402–10.
6. Church JA, Fitzgerald F, Walker AS, Gibb DM. The expanding role of co-trimoxazole in developing countries. Lancet Infect Dis 2015;15:327-39.
7. Hawser S, Lociuro S, Islam K. Dihydrofolate reductase inhibitors as antibacterial agents. Biochem Pharmacol 2006;71:941-8.
8. Swarbrick J, Iliades P, Simpson JS, Macreadie I. Folate biosynthesis–reappraisal of old and novel targets in the search for new antimicrobials. Open Enzyme Inhibition J 2008;1:12-33.
9. Bermingham A, Derrick JP. The folic acid biosynthesis pathway in bacteria: evaluation of the potential for antibacterial drug discovery. Bioessays 2002;24:637-48.
10. Sharma N, Aron N, Agarwal T, Sharma C. Pharmacology of ocular therapeutics. In: Velpandian T. editors. Antimicrobial agents for ocular use: bacterial, fungal, viral, and protozoal infections. 1st ed. Switzerland: Springer International Publisher; 2016. p. 285-32.
11. Helweg Larsen J, Benfield TL, Eugen Olsen J, Lundgren JD, Lundgren B. Effects of mutations in pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia. Lancet 1999;354:1347-51.
12. Alsaad N, Van Altena R, Pranger AD. Evaluation of co-trimoxazole in the treatment of multidrug-resistant tuberculosis. Eur Respir J 2013;42:504-12.
13. Lacey RW, Hawkey PM, Devaraj SK, Millar MR, Inglis TJ, Godwin PG. Co-trimoxazole toxicity. Br Med J (Clin Res Ed) 1985;291:481.
14. Alsaad N, Wilffert B, Van Altena R, De Lange WC, Van der Werf TS, Kosterink JG, et al. Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis. Eur Respir J 2014;43:884-97.
15. Lewin C, Doherty C, Govan. In vitro activities of meropenem, PD 127391, PD 131628, ceftazidime, chloramphenicol, co-trimoxazole, and ciprofloxacin against Pseudomonas cepacia. Antimicrob Agents Chemother 1993;37:123-5.
16. Betriu C, Sanchez A, Palau ML, Gomez M, Picazo JJ. Antibiotic resistance surveillance of Stenotrophomonasmaltophilia, 1993–1999. Antimicrob Agents Chemother 2001;48:152-4.
17. Hahn H, Kirov A. Antibacterial activity of co-trimoxazole and tetroxoprim/sulfadiazine in vitro. Arzneimittel Forschung 1980;30:1047-8.
18. Minkowski P, Staege H, Groscurth P, Schaffner A. Effects of trimethoprim and co-trimoxazole on the morphology of Listeria monocytogenes in culture medium and after phagocytosis. Antimicrob Agents Chemother 2001;48:185–93.
19. Forgacs P, Wengenack NL, Hall L, Zimmerman SK, Silverman ML, Roberts GD. Tuberculosis and trimethoprim-sulfamethoxazole. J Antimicrob Chemother 2009;53:4789-93.
20. Jamil B, Bokhari H, Imran M. Mechanism of action: how nano-antimicrobials. Act. Curr Drug Targets 2017;18:363-73.
21. Beyth N, Houri Haddad Y, Domb A, Khan W, Hazan R. Alternative antimicrobial approach: nano-antimicrobial materials. J Evidence Based Complementary Altern Med 2015;2015:246012.
22. Park K. Facing the truth about nanotechnology in drug delivery. ACS Nano 2013;7:7442-7.
23. Rajendran R, Ganesan N, Balu SK, Alagar S, Thandavamoorthy P, Thiruvengadam D. Green synthesis, characterization, antimicrobial and cytotoxic effects of silver nanoparticles using origanum heracleoticum L. leaf extract. Int J Pharm Pharm Sci 2015;7:288-93.
24. Selvarani M. Investigation of the synergistic antibacterial action of copper nanoparticles on certain antibiotics against human pathogens. Int J Pharm Pharm Sci 2018;10:83-6.
25. Panahi Y, Farshbaf M, Mohammadhosseini M. Recent advances on liposomal nanoparticles: synthesis, characterization and biomedical applications [published correction appears in artif cells nanomed biotechnol 2019 Dec; 47:2306]. Artif Cells Nanomed Biotechnol 2017;45:788-99.
26. Bonde S, Nair S. Advances in liposomal drug delivery system: fascinating types and potential applications. Int J Appl Pharm 2017;9:1-7.
27. Ghafelehbashi R, Akbarzadeh I, Tavakkoli Yaraki M, Lajevardi A, Fatemizadeh M, Heidarpoor Saremi L. Preparation, physicochemical properties, in vitro evaluation and release behavior of cephalexin-loaded niosomes. Int J Pharm 2019;569:118580.
28. Thaya R, Vaseeharan B, Sivakamavalli J, Iswarya A, Govindarajan M, Alharbi NS, et al. Synthesis of chitosan-alginate microspheres with high antimicrobial and antibiofilm activity against multi-drug resistant microbial pathogens. Microb Pathog 2018;114:17-24.
29. Adebisi AO, Conway BR. Lectin-conjugated microspheres for eradication of Helicobacter pylori infection and interaction with mucus. Int J Pharm 2014;470:28-40.
30. Xu W, Dong S, Han Y, Li S, Liu Y. Hydrogels as antibacterial biomaterials. Curr Pharm Des 2018;24:843-54.
31. Kesharwani, Prashant, Jain, Keerti, Jain, Narendra. Dendrimer as nanocarrier for drug delivery. Prog Polym Sci 2014;39:268–307.
32. Li C, Zhou K, Chen D. Solid lipid nanoparticles with enteric coating for improving stability, palatability, and oral bioavailability of enrofloxacin. Int J Nanomed 2019;14:1619-31.
33. Jansook P, Pichayakorn W, Ritthidej GC. Amphotericin B-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): effect of drug loading and biopharmaceutical characterizations. Drug Dev Ind Pharm 2018;44:1693-700.
34. Chokshi NV, Khatri HN, Patel MM. Formulation, optimization, and characterization of rifampicin-loaded solid lipid nanoparticles for the treatment of tuberculosis. Drug Dev Ind Pharm 2018;44:1975-89.
35. Zhou W, Jia Z, Xiong P. Novel pH-responsive tobramycin-embedded micelles in nanostructured multilayer-coatings of chitosan/heparin with efficient and sustained antibacterial properties. Mater Sci Eng C Mater Biol Appl 2018;90:693-705.
36. Harwansh RK, Deshmukh R, Rahman MA. Nanoemulsion: promising nanocarrier system for delivery of herbal bioactives. J Drug Delivery Sci Technol 2019;51:224-33.
37. Wallace SJ, Nation RL, Li J, Boyd BJ. Physicochemical aspects of the coformulation of colistin and azithromycin using liposomes for combination antibiotic therapies. J Pharm Sci 2013;102:1578–87.
38. Alhariri M, Majrashi MA, Bahkali AH. Efficacy of neutral and negatively charged liposome-loaded gentamicin on planktonic bacteria and biofilm communities. Int J Nanomed 2017;12:6949-61.
39. Rotov KA, Tikhonov SN, Alekseev VV, Snatenkov EA. Pharmacokinetics of liposomal gentamicin. Bull Exp Biol Med 2012;153:475–7.
40. Fattal E, Rojas J, Roblot Treupel L, Andremont A, Couvreur P. Ampicillin-loaded liposomes and nanoparticles: comparison of drug loading, drug release and in vitro antimicrobial activity. J Microencapsulation 1991;8:29–36.
41. Fattal E, Rojas J, Youssef M, Couvreur P, Andremont A. Liposome-entrapped ampicillin in the treatment of experimental murine listeriosis and salmonellosis. Antimicrob Agents Chemother 1991;35:770–2.
42. Antonela Antoniu S. Inhaled ciprofloxacin for chronic airways infections caused by Pseudomonas aeruginosa. Expert Rev Anti Infect Ther 2012;10:1439–46.
43. Kadry AA, Al-Suwayeh SA, Abd-Allah ARA, Bayomi MA. Treatment of experimental osteomyelitis by liposomal antibiotics. J Antimicrob Chemother 2004;54:1103–8.
44. Liu C, Shi J, Dai Q, Yin X, Zhang X, Zheng A. In vitro and in vivo evaluation of ciprofloxacin liposomes for pulmonary administration. Drug Dev Ind Pharm 2015;41:272-8.
45. Wong JP, Yang H, Blasetti KL, Schnell G, Conley J, Schofield LN. Liposome delivery of ciprofloxacin against intracellular Francisella tularensis infection. J Controlled Release 2003;92:265–73.
46. Radovic Moreno AF, Lu TK, Puscasu VA, Yoon CJ, Langer R, Farokhzad OC. Surface charge-switching polymeric nanoparticles for bacterial cell wall-targeted delivery of antibiotics. ACS Nano 2012;6:4279–87.
47. Brown AN, Smith K, Samuels TA, Lu J, Obare SO, Scott ME. Nanoparticles functionalized with ampicillin destroy multiple-antibiotic-resistant isolates of Pseudomonas aeruginosa and Enterobacter aerogenes and methicillin-resistant Staphylococcus aureus. Appl Environ Microbiol 2012;78:2768–74.
48. He J, Abdelraouf K, Ledesma KR, Chow DS, Tam VH. Pharmacokinetics and efficacy of liposomal polymyxin B in a murine pneumonia model. Int J Antimicrob Agents 2013;42:559–64.
49. Azhdarzadeh M, Lotfipour F, Zakeri Milani P, Mohammadi G, Valizadeh H. Anti-bacterial performance of azithromycin nanoparticles as colloidal drug delivery system against different gram-negative and gram-positive bacteria. Adv Pharm Bull 2012;2:17–24.
50. Mohammadi G, Valizadeh H, Barzegar Jalali M, Lotfipour F, Adibkia K, Milani M, et al. Development of azithromycin–PLGA nanoparticles: physicochemical characterization and antibacterial effect against Salmonella typhi. Colloids Surf Bio Interfaces 2010;80:34–9.
51. Gajendiran M, Gopi V, Elangovan V, Murali RV, Balasubramanian S. Isoniazid loaded core-shell nanoparticles derived from PLGA-PEG-PLGA tri-blockcopolymers: in vitro and in vivo drug release. Colloids Surf B 2013;104:107–15.
52. Kalluru R, Fenaroli F, Westmoreland D, Ulanova L, Maleki A, Roos N, et al. Poly(lactide-co-glycolide)–rifampicin nanoparticles efficiently clear Mycobacterium bovis BCG infection in macrophages and remain membrane-bound in phago-lysosomes. J Cell Sci 2013;126:3043–54.
53. Ghaffari S, Varshosaz J, Saadat A, Atyabi F. Stability and antimicrobial effect of amikacin-loaded solid lipid nanoparticles. Int J Nanomed 2011;6:35–43.
54. Abul Kalam M, Sultana Y, Ali A, Aqil M, Mishra AK, Chuttani K, et al. Part II: enhancement of transcorneal delivery of gatifloxacin by solid lipid nanoparticles in comparison to commercial aqueous eye drops. J Biomed Mater Res A 2013;101:1828–36.
55. Wang Y, Zhu L, Dong Z, Xie S, Chen X, Lu M, et al. Preparation and stability study of norfloxacin-loaded solid lipid nanoparticle suspensions. Colloids Surf Bio Interfaces 2012;98:105–11.
56. Kumar PV, Asthana A, Dutta T, Jain NK. Intracellular macrophage uptake of rifampicin loaded mannosylated dendrimers. J Drug Target 2006;14:546–56.
57. Choi SK, Myc A, Silpe JE, Sumit M, Wong PT, McCarthy K, et al. Dendrimer-based multivalent vancomycin nano platform for targeting the drug-resistant bacterial surface. ACS Nano 2013;7:214–28.
58. Navath RS, Menjoge AR, Dai H, Romero R, Kannan S, Kannan RM. Injectable PAMAM dendrimer–PEG hydrogels for the treatment of genital infections: formulation and in vitro and in vivo evaluation. Mol Pharm 2011;8:1209–23.
59. Kumar P, Narang RK, Swamy S. Development and evaluation of nanoparticle-loaded hydrogel of co-trimoxazole. Int J Pharm Sci Nanotechnol 2016;9:3131-41.
60. Attama AA, Onuigbo EB. Properties of co-trimoxazole microparticles prepared with carbopol 941 and exogenous mucin. Sci Res Essays 2007;2:421-5.
61. Amaral AC, Marques AF, Munoz JE. Poly (lactic acid-glycolic acid) nanoparticles markedly improve immunological protection provided by peptide P10 against murine paracoccidioidomycosis. Br J Pharmacol 2010;159:1126-32.
62. Bottari NB, Baldissera MD, Tonin AA, Rech VC, Alves CB, DAvila F, et al. Synergistic effects of resveratrol (free and inclusion complex) and sulfamethoxazole-trimetropim treatment on pathology, oxidant/antioxidant status and behavior of mice infected with Toxoplasma gondii. Microb Pathog 2016;95:166-74.
63. Mendes C, Valentini G, Chamorro Rengifo AF, Pinto JMO, Silva MAS, Parize AL. Supersaturating drug delivery system of fixed drug combination: sulfamethoxazole and trimethoprim. Expert Rev Anti Infect Ther 2019;17:841-50.
64. Gurbuz MU, Erturk AS, Tulu M. Synthesis of surface-modified TREN-cored PAMAM dendrimers and their effects on the solubility of sulfamethoxazole (SMZ) as an analog antibiotic drug. Pharm Dev Technol 2017;22:678-89.
65. Gokturk S, Çal??kan E, Talman RY, Var U. A study on solubilization of poorly soluble drugs by cyclodextrins and micelles: complexation and binding characteristics of sulfamethoxazole and trimethoprim. Sci World J 2012;2012:718791.
66. Bodaghabadi N, Hajigholami S, Malekshahi ZV, Entezari M, Najafi F, Shirzad H, et al. Preparation and evaluation of rifampicin and co-trimoxazole-loaded nanocarrier against Brucellamelitensis infection. Iranian Biomed J 2018;22:275-82.
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