-
Applied and Environmental Microbiology Oct 2015Risk assessments of the potential for microbicides to select for reduced bacterial susceptibility have been based largely on data generated through the exposure of...
Risk assessments of the potential for microbicides to select for reduced bacterial susceptibility have been based largely on data generated through the exposure of bacteria to microbicides in aqueous solution. Since microbicides are normally formulated with multiple excipients, we have investigated the effect of formulation on antimicrobial activity and the induction of bacterial insusceptibility. We tested 8 species of bacteria (7 genera) before and after repeated exposure (14 passages), using a previously validated gradient plating system, for their susceptibilities to the microbicides benzalkonium chloride, benzisothiozolinone, chlorhexidine, didecyldimethyl ammonium chloride, DMDM-hydantoin, polyhexamethylene biguanide, thymol, and triclosan in aqueous solution (nonformulated) and in formulation with excipients often deployed in consumer products. Susceptibilities were also assessed following an additional 14 passages without microbicide to determine the stability of any susceptibility changes. MICs and minimum bactericidal concentrations (MBC) were on average 11-fold lower for formulated microbicides than for nonformulated microbicides. After exposure to the antimicrobial compounds, of 72 combinations of microbicide and bacterium there were 19≥4-fold (mean, 8-fold) increases in MIC for nonformulated and 8≥4-fold (mean, 2-fold) increases in MIC for formulated microbicides. Furthermore, there were 20≥4-fold increases in MBC (mean, 8-fold) for nonformulated and 10≥4-fold (mean, 2-fold) increases in MBC for formulated microbicides. Susceptibility decreases fully or partially reverted back to preexposure values for 49% of MICs and 72% of MBCs after further passage. In summary, formulated microbicides exhibited greater antibacterial potency than unformulated actives and susceptibility decreases after repeated exposure were lower in frequency and extent.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Benzalkonium Compounds; Biguanides; Chlorhexidine; Microbial Sensitivity Tests; Triclosan
PubMed: 26253662
DOI: 10.1128/AEM.01985-15 -
Journal of Acquired Immune Deficiency... Feb 2016To determine whether mucosal topical microbicides have any influence on disease progression during subsequent simian immunodeficiency virus (SIV) infection.
OBJECTIVE
To determine whether mucosal topical microbicides have any influence on disease progression during subsequent simian immunodeficiency virus (SIV) infection.
DESIGN
A 2-phase study was performed in primate monkeys. The first phase mimicked microbicide efficacy studies; the second phase served to determine the disease progression in a productive infection model.
METHODS
During the first phase, monkeys were intrarectally pretreated with tenofovir, sifuvirtide (SFT), or maraviroc-formulated microbicides and then challenged with low-dose SHIV-1157ipd3N4. Second, all monkeys were rechallenged with a single high dose of SIVmac239 to generate productive infections. The survival rate, viral loads, CD4(+) T-cell counts, and SIV-specific T-cell responses were determined during the 104-week following up.
RESULTS
Repeated rectal challenges did not result in productive infection in all groups, evidenced by undetectable viral loads with occasional viral blips during the first phase of this study. All monkeys were productively infected after the high-dose rechallenge with SIVmac239. Two groups, including maraviroc-treated and tenofovir-treated groups, experienced 100% mortality during the 104-week following up. In contrast, the SFT-treated group showed significantly higher survival, and only 25% died at week 95. Interestingly, SIV-specific T-cell responses were also significantly higher in the SFT group. Transcriptomic analyses evidenced immune imprint in immune system among different microbicide-treated groups.
CONCLUSIONS
This study provides preliminary but important evidence for the influence of prophylactically applied microbicides on disease progression of subsequent SIV infection and suggests that the long-term immune safety concern for microbicides should be also considered in the effort to develop effective microbicides.
Topics: Administration, Rectal; Animals; Anti-Infective Agents, Local; CD4-Positive T-Lymphocytes; Cyclohexanes; Disease Progression; Gene Expression Profiling; Humans; Immunity, Cellular; Macaca mulatta; Maraviroc; Mucous Membrane; Oligonucleotide Array Sequence Analysis; Peptides; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Survival Rate; Tenofovir; Triazoles; Viral Load
PubMed: 26413849
DOI: 10.1097/QAI.0000000000000851 -
PloS One 2011For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque...
For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field.
Topics: Animals; Anti-Infective Agents, Local; CCR5 Receptor Antagonists; CD4 Lymphocyte Count; Chemistry, Pharmaceutical; Cyclohexanes; DNA-Binding Proteins; Disease Models, Animal; Female; Gels; HIV Infections; HIV-1; Homeodomain Proteins; Humans; Maraviroc; Mice; Placebos; Triazoles; Vagina
PubMed: 21673796
DOI: 10.1371/journal.pone.0020209 -
Current Opinion in Infectious Diseases Feb 2010This review provides an update on developments in HIV microbicide research in the light of recent phase 3 efficacy studies and discusses how lessons learnt from early... (Review)
Review
PURPOSE OF REVIEW
This review provides an update on developments in HIV microbicide research in the light of recent phase 3 efficacy studies and discusses how lessons learnt from early generation microbicide candidates can assist the development of future agents.
RECENT FINDINGS
Results of an interim analysis of a phase 3 trial suggested that cellulose sulfate increased the risk of HIV acquisition compared with placebo. Carraguard, SAVVY and Buffergel also failed to show any HIV protection in human efficacy trials. Recent research has focused on elucidating the reasons behind these failures as well as improving the assessment of safety and efficacy for the next generation of microbicide candidates. PRO 2000 0.5% gel is the only HIV microbicide candidate for which there are preliminary data suggesting efficacy in women. Antiretroviral agents and entry inhibitors may provide the key in the future to developing an effective HIV microbicide both for vaginal and rectal use.
SUMMARY
Development of a protective 'barrier' which can be controlled by the receptive partner independent of time of coitus remains a key goal in HIV prevention. A gel or ring-delivered combination of active anti-HIV agents may prove more efficacious than a single agent alone. Challenges in evaluating and manufacturing new candidates must be overcome before a well tolerated, effective, acceptable and affordable microbicide can be produced.
Topics: Anti-Infective Agents, Local; Drug Discovery; HIV Infections; Humans
PubMed: 19918175
DOI: 10.1097/QCO.0b013e328334de6d -
Current Opinion in Molecular... Apr 2010Sexually transmitted infections (STIs) are a major cause of morbidity and mortality worldwide. Although a vaccine is available for HPV, no effective vaccines exist for... (Review)
Review
Sexually transmitted infections (STIs) are a major cause of morbidity and mortality worldwide. Although a vaccine is available for HPV, no effective vaccines exist for the HIV-1 and HSV-2 viral pathogens, and there are no cures for these infections. Furthermore, recent setbacks in clinical trials, such as the failure of the STEP trial to prevent HIV-1 infection, have emphasized the need to develop alternative approaches to interrupt the transmission of these pathogens. One alternative strategy is represented by the use of topically applied microbicides, and such agents are being developed against various viruses. RNAi-based microbicides have recently been demonstrated to prevent HSV-2 transmission, and may be useful for targeting multiple STIs. In this review, microbicides that are under development for the prevention of STIs are described, with a focus on topically applied microbicidal siRNAs.
Topics: Anti-Infective Agents; Disease Transmission, Infectious; HIV Infections; Herpes Genitalis; Humans; Papillomavirus Infections; RNA Interference; RNA, Small Interfering; Sexually Transmitted Diseases
PubMed: 20373263
DOI: No ID Found -
Contraception Dec 2005To evaluate the effect of adherence and condom use on apparent efficacy of microbicides.
OBJECTIVE
To evaluate the effect of adherence and condom use on apparent efficacy of microbicides.
DESIGN
Hypothetical trial designs and scenarios.
METHODS
Mathematical calculations of effectiveness.
RESULTS
In a randomized trial of a candidate microbicide and a placebo, nonuse of the microbicide will result in underestimation of microbicide efficacy, with the magnitude of this difference between effectiveness and efficacy increasing directly with the level of microbicide nonuse. Adding condoms to the trial will not change this expected result as long as use of condoms and microbicide is independent, and microbicide use is the same in the trials with and without condoms. However, if microbicide use is lower in the trial with condoms, then effectiveness will be lower than in the trial without condoms, with the magnitude of the difference between effectiveness and efficacy being even greater. Moreover, condom and microbicide use may not be independent. If participants tend to use condoms rather than nothing, the trial result will more closely approximate microbicide efficacy. If, however, participants substitute condom use for microbicide use, then the expected estimate of effectiveness will less closely approximate microbicide efficacy and could be closer to or further away from the expected estimate of effectiveness than in the trial without condoms. In another trial design, where there is either simultaneous use of microbicide and condoms or no use of either (guaranteed when condoms are packaged with either a microbicidal or a placebo gel), expected effectiveness will fall short of microbicide efficacy. If nonuse is the same in a trial without condoms and a trial with microbicidally lubricated condoms, then the trial with condoms will produce an estimate of effectiveness that less closely approximates microbicide efficacy than would the trial without condoms. If there is less nonuse in the trial with condoms, then the expected estimate of effectiveness will more closely approximate microbicide efficacy and could be closer to or further away from the expected estimate of effectiveness than in the trial without condoms.
CONCLUSIONS
Nonuse of a microbicide and use of condoms may seriously impair our ability to identify an effective microbicide.
Topics: Anti-Infective Agents; Bias; Condoms; Female; Humans; Male; Patient Compliance; Placebos; Randomized Controlled Trials as Topic; Research Design; Sexually Transmitted Diseases
PubMed: 16307961
DOI: 10.1016/j.contraception.2005.06.063 -
Best Practice & Research. Clinical... Aug 2012The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency... (Review)
Review
The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy. Topical products that were ineffective in preventing HIV infection include BufferGel, Carraguard, and PRO 2000. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence.
Topics: Adenine; Animals; Anti-HIV Agents; Anti-Infective Agents, Local; Female; HIV; HIV Infections; Humans; Mice; Organophosphonates; Tenofovir; Treatment Outcome; Vaginal Creams, Foams, and Jellies
PubMed: 22306523
DOI: 10.1016/j.bpobgyn.2012.01.004 -
Perspectives on Sexual and Reproductive... Mar 2014In time, microbicides may provide women with dual prevention against pregnancy and STDs. Although several microbicide dimensions have been evaluated, little is known...
CONTEXT
In time, microbicides may provide women with dual prevention against pregnancy and STDs. Although several microbicide dimensions have been evaluated, little is known about women's preferences for contraceptive microbicides and correlates of these preferences.
METHODS
Acceptability of a hypothetical contraceptive microbicide cream or jelly was examined among a -clinic-based sample of 266 women in Indianapolis from 2004 (when participants were aged 14-22) to 2008. Group conjoint analyses and individual conjoint analyses were used to compare preferences with respect to four microbicide -dimensions: contraceptive ability, efficacy in relation to condoms, timing of use and texture. Pearson's product moment correlations were used to examine the relationship between preferences for a contraceptive microbicide and selected characteristics of the women.
RESULTS
Overall, the top-rated microbicide dimensions were efficacy in relation to that of condoms and contraceptive ability (importance scores, 40.0 and 35.4 out of 100.0, respectively). When all dimension levels were compared, contraceptive ability was the most strongly preferred (part-worth utility score, 8.9), and lower efficacy than that of -condoms was the least strongly preferred (-11.9). Preference for contraceptive microbicides was positively -associated with current contraceptive use, sexual agency, partner communication, commitment to avoiding pregnancy and -perceived partner agreement about avoiding pregnancy (coefficients, 0.07-0.18). It was negatively associated with current or past nonuse of contraceptives, seeking pregnancy and perceived partner agreement about seeking -pregnancy (-0.08 to -0.14).
CONCLUSIONS
Microbicides with dual prevention properties may be attractive to young women. Microbicide development and subsequent clinical trials should incorporate contraceptive microbicides.
Topics: Adolescent; Anti-Infective Agents; Contraception Behavior; Female; Humans; Longitudinal Studies; Patient Preference; Sexual Behavior; United States; Young Adult
PubMed: 24325312
DOI: 10.1363/46E0114 -
Annual Review of Medicine Jan 2020HIV topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum... (Review)
Review
HIV topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum have the potential to prevent the sexual acquisition of HIV in women and men. Topical microbicides may meet the prevention needs of individuals and groups for whom oral daily forms of pre-exposure prophylaxis (PrEP) have not been acceptable. Microbicides can provide personal control over HIV prevention and offer the possibility of discreet use, qualities that may be particularly important for receptive partners in sexual relationships such as women and transgender women and men, who together account for the clear majority of new HIV infections worldwide. Although the promise of such a product emerged nearly three decades ago, proof of concept has been demonstrated only within the last decade. A robust pipeline of microbicidal gels, films, inserts, and rings has been evaluated in multiple studies among at-risk women and men, and refinement of products for ease of use, reversibility, and high safety is the priority for the field.
Topics: Adult; Anti-HIV Agents; Anti-Infective Agents, Local; Drug Compounding; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Male; Patient Safety; Pregnancy; Pregnancy Complications, Infectious; Prognosis; Rectum; Sexual Partners; Vagina
PubMed: 31613684
DOI: 10.1146/annurev-med-090518-093731 -
Journal of Pharmaceutical Sciences Feb 2008Microbicides are agents applied topically to the vagina to prevent HIV transmission. Microbicide products formulated as semi-solid dosage forms or "gels" coat vulnerable...
Microbicides are agents applied topically to the vagina to prevent HIV transmission. Microbicide products formulated as semi-solid dosage forms or "gels" coat vulnerable tissue to deliver active ingredients. Effective microbicide delivery vehicles must have appropriate rheological properties to ensure appropriate deployment in vivo. Microbicide products become diluted by fluids in the vagina after application; dilution affects vehicle rheological properties and mechanics of vaginal distribution, thus affecting efficacy. To simulate the changes that might occur after application, this study analyzed the effects of small dilutions (10-30%) with vaginal fluid and semen simulants on three semi-solid vaginal formulations: a cellulose lubricant (KY Jelly), a polyacrylic acid moisturizer (Replens), and a carrageenan prototype microbicide (Carraguard). Rheological behavior was characterized using cone-and-plate rheometry. Data were fitted to either the power-law, Carreau, or Herschel-Bulkley model. Rheological parameters from these fits were input to models of coating flow due squeezing, and the simulated area coated output from these models was used to compare the responses of the different formulations to the two diluents for varying degrees of dilution. There were differences in the responses of the three materials to dilution. Even small dilutions altered the rank order of vaginal coating rates compared to the undiluted formulations.
Topics: Anti-Infective Agents; Chemistry, Pharmaceutical; Drug Delivery Systems; Female; Gels; Humans; Hydrogen-Ion Concentration; Male; Rheology; Semen; Vaginal Creams, Foams, and Jellies; Viscosity
PubMed: 17724667
DOI: 10.1002/jps.21132