PHMB: the safe approach of infection management

Mar 24, 2021

Nowadays the increase in resistance of bacteria to antibiotics complicates the treatment of infections. Fortunately, new, highly effective antiseptics are available that lack the drawbacks of the old ones from the past. Modern antiseptics can therefore be the alternative to antibiotic treatment that is so much needed, provided that they combine a broad antimicrobial spectrum with low toxicity, high tissue compatibility. Since 1956, Rose et al. demonstrated that biguanide compounds have antimicrobial activity. The most common biguanide widely used is chlorhexidine, because of its broad-spectrum activity and low toxicity. Further studies demonstrated that the longer is the chain of the polybiguanide the more bacteriostatic is the product. New polybiguanide drugs have been developed as polyhexamethylene biguanide (PHMB) that resulted in being more effective and tolerated than chlorhexidine. Research on PHMB from the 20th century has shown in the fact that poly-biguanides are strongly antibacterial, compared to molar particles carrying only one group of biguanide. In polyhexane, the number of biguanide residues is n = 2-40, and an optimal number of methylene groups in the walk between the biguanide residues is m = 6. The terminal groups of this chemical compound are amine and cyanoguanidine. PHMB is commercially available in many formulations and for different indications, including wound and burns care management, eye drops, and contact lens antisepsis as well as bacterial vaginosis. Both a PHMB-based vaginal solution and a dermatologic gel are used in gynecology, clinical trials have shown the high efficacy against bacteria, and yeasts as well as human papillomavirus-infected genital warts.

Gynecological infections

The vaginal flora of healthy women consists mainly of Lactobacilli (or Doderlein’s bacilli), which regulate the growth of the remaining bacterial flora and prevent the colonization of the vagina by hostile germs acidifying the vaginal environment to pH 4-4.5 by the production of lactic acid. In addition to Lactobacilli, the vaginal bacterial flora consists to a lesser extent of other microorganisms, such as Streptococci, Enterobacteria, anaerobic microorganisms, Gardnerella, Candida, and Mycoplasma. Some of these, although potentially pathogenic, are not able to carry out their damaging action (precisely because they are maintained in limited numbers by the lactobacilli and the immune system). However, the “good” vaginal flora may become altered, both qualitatively and quantitatively, and is thus overwhelmed by a mixed flora, rich in “bad” germs. This condition, commonly known as Vaginitis represents one of the most recurrent conditions for which women need medical care and it can be due to a wide variety of causes, often associated with infections or atrophic changes.

 The most common infections include bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis.

Bacterial vaginosis (BV) is the most common vulvovaginal infection and represents 35% of all the infections occurring in women of reproductive age.  Lactobacillus populations, which are usually dominant in healthy women, are replaced by a polymicrobial group of organisms that includes Gardner vaginalis, anaerobic Gram-negative rods such as Prevotella species, Peptostreptococcus species, Mycoplasma hominis, Ureaplasma urealyticum, and often Mobiluncus species. Serious forms of BV can induce complications among women undergoing gynecologic or obstetric surgery, having pelvic inflammatory diseases (PID), temporary or absolute infertility, miscarriage, and abortion. Today, after a BV diagnosis, both in presence of asymptomatic or an asymptomatic form, the clinical treatment of choice is the use of systemic or local (gel or cream) metronidazole and clindamycin. However, there are some limitations to the systemic use of these two drugs, due to side-effects that may occur and contraindications, e.g. pregnancy.

Vulvovaginal candidiasis (VVC) is often related to the vaginal carriage of Candida spp.  Vaginitis is one of the most recurrent conditions that afflict women and require medical care. Vulvovaginal candidiasis (VVC) is frequently related to the vaginal carriage of Candida albicans, an opportunistic polymorphic fungus, which colonizes the human skin, the mucosa, and the reproductive tract.  In fact, standard treatments to counteract vaginitis include several topical and oral treatments. Actually, a variety of oral and topical preparations are available for the treatment of uncomplicated yeast infections: vulvovaginal candidiasis is treated with anti-fungal drugs, administered orally or topically. Nevertheless, it is necessary to keep in mind that oral agents are often associated with a wide range of systemic effects including gastrointestinal disorders and headache, while topical treatments often require long-term therapies and sometimes do not show the desired effect. 

For that reason, some alternative approaches have been investigated as preventive agents in the past. Since it was demonstrated that biguanide have antimicrobic activity and PHBM is more tolerated and effective than chlorhexidine, in this scenario it was evaluated PHMB efficacy also in the treatment of gynecological infections and proved as the therapy of choice for BV, using clindamycin and metronidazole only for relapses treatment, but also the effective and safe for vaginal candidiasis and HPV infections.

Supporting these evidences are several studies:  Gerli et al. demonstrated that pharmaceutical formulations containing PHMB and clindamycin for topical use in BV treatment exhibit a similar efficacy but instead of Clyndamicin, that was found to have a bactericidal activity also against Lattobacilli and consequently reduced self-defense ability of the vaginal ecosystem and then higher frequency of secondary infections, PHMB has both a direct antimicrobial action against microbes and both an indirect action of restarting of lactobacilli growth which induces a fast restoration of the vaginal ecosystem through vaginal pH reduction ad so secondary protection to secondary infections. PHMB, however, provides equivalent efficacy and safety in a single dose, compared with a 7-dose regimen of Clindamycin. This is comparable to the results obtained by a study conducted by Minozzi et aL., again a single-dose regimen of PHMB was shown to be comparable concerning both efficacy and safety to Clindamycin. It has been shown that reducing dose frequency increases the patient’s compliance with treatment, symptom control, satisfaction with treatment, and quality of life in a number of disease states. Furthermore, it was demonstrated that for indications such treatment of mucosal infections, where a prolonged contact time for antiseptic treatment is feasible, the following ranking for the investigated antiseptic agents regarding their effective microbistatic and microbicidal concentration was found: polyhexanide= octenidine > chlorhexidine >triclosan >PVP >iodine, so PHMB seems to be preferable due to its higher tolerability [33]. Biamonti et Al. also reported the efficacy of a single PHMB dose of the vaginal solution in women affected by vaginal candidiasis; within the patients treated with a single dose of PHMB solution, 80% of them experienced a complete resolution of the fungal infection. Moreover, all of them complained of typical clinical mycotic signs like itching, burning, inflammation and presented typical symptoms (as edema, erythema, and excoriation) at baseline and, after 21 days of treatment with PHMB, it has been registered a statistically significant reduction of all signs, symptoms and no yeast infection was found in the microscopic analysis with a score’s reduction of 50%.

Conclusion

Finally, Gentile et Al. reported also that the topical treatment with PHMB is a preliminary safe, and promising approach for patients with detected HPV infection increasing the chance of clearance and avoiding the use of invasive treatments when not strictly necessary.  Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Marelli et Al. confirmed the precedent data because they evaluated the efficacy and safety of daily patient-applied polyhexamethylene biguanide for up to 16-weeks for the treatment of external genital warts. In the intent-to-treat analysis, baseline warts cleared in 52% of patients treated with polyhexamethylene biguanide cream versus 4% placebo patients, so the differences between the groups treated with placebo and polyhexamethylene biguanide were significant. PHMB treatment also didn’t cause systemic reactions, so patient-applied polyhexamethylene biguanide cream confirmed to be effective for the treatment of external genital warts and has a favorable safety profile. Post recovery surgical and destructive treatments of this infection generally consist of analgesic, anti-inflammatory, and topical antimicrobial agents to reduce the risk of local infections, among them PHMB-based vaginal suppositories in the post-recovery regimen after surgical treatment of cervical lesions showed improved efficacy compared to chlorhexidine, in terms of healing process and prevention of bacterial infections. In conclusion due to its safety and effectiveness, the PHMB results in a valid solution as a first approach to manage infection, avoiding side effects, and preventing antibiotic resistance.

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