**18. Pharmacodynamics of antimicrobials used in eye coinfections**

explained the immune mechanisms implicated, because there is considerable variability in

The immunological mechanisms that occur in the eye are similar to the rest of the immune system. However, there is more regulation in the silencing response in order to prevent damage from infection and inflammation, and immune mechanisms preserve the functionality of the

In the following, studies that investigated the most common corneal coinfections are reviewed. These reports show the critical role of pathogens and the pathogenesis generated by the host

Vernal conjunctivitis is an example of how the immune phenotype affects the response to the infection. Patients with vernal keratoconjunctivitis have a family history of atopic diseases such as allergic rhinitis, asthma, and eczema [64]. A theory suggests that patients with a history of atopy are susceptible to intracellular infections because they have a Th2 immune phenotype [65, 66]. Kerr and Stern showed a polymicrobial infection in two patients with vernal kerato‐

Although regulation of the immune response in the eye is controlled locally, in immunocom‐ promised patients with human immunodeficiency virus (HIV), it is evident that the privilege is broken by the depletion of T CD4+ cells, and infections can occur. In addition, several pathogens can remain latent (herpes virus, bacteria, fungi, parasites). The clinical manifesta‐ tion produced by the herpes virus can be conjunctivitis, blepharitis, intraocular inflammation, retinitis, or keratitis [68]. In particular, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2] infect 50 % to 90 % of the population infected with HIV, causing ocular herpes and genital orofacial herpes in different geographic regions [69]. Herpetic retinitis has a high incidence; however, few cases have been reported. Faber *et. al*., studied eyes from 25 cases with AIDS with an immunohistochemical test. *Cytomegalovirus* was found in 60 % of the cases and was related to retinitis, while in another case series, 36.64 % of 131 patients were diagnosed with *Cytomegalovirus* retinitis [70, 71]. Freigassner *et. al*., documented a case with the Epstein-Barr virus and *Cytomegalovirus* in a patient with AIDS [72]. Other studies showed *Cytomegalovirus*

Opportunistic microorganisms such as *Toxoplasma* spp., herpes zoster virus (HZV), and

*Burkholderia ambifaria*, *Enterococcus*, and *Staphylococcus aureus* were found in a patient with herpetic stromal keratitis. *Burkholderia ambifaria* is a Proteobacteria, which comprises strains with a virulence potential toward immunocompromised patients [76]. In a report on keratitis, *Acanthamoeba* spp., *Fusarium solani*, and Gram-negative cocci were identified in a patient who

**17. Coinfections produced by strange conjunction of pathogens**

had unprotected sexual contact with multiple commercial sex workers [77].

each combination of microorganisms that produces an infection.

cornea [63].

immune response.

130 Advances in Common Eye Infections

conjunctivitis and corneal ulcers [67].

or herpes in isolated cases [73, 74, 75].

*Pneumocystis* spp., participates the least in coinfections.

There is little information about the pharmacodynamics of antimicrobials used for coinfections of the human eye. The activity of antimicrobial drugs against yeast, bacteria, and fungi has been evaluated with a standardized microdilution assay in a culture medium [78]. The lowest concentration of an antimicrobial that completely inhibits the growth of any microorganism is known as the minimal inhibitory concentration (MIC), which can be used to determine the sensitivity or resistance.

Based on MICs with microdilutions and the growth radial technique on solid medium using Potato Dextrose Agar (PDA) dishes (using the percent mycelial inhibition) [79], our group reported that *S. aureus* cocultured with *F. solani* or *A. fumigatus* (all isolated from patients) significantly inhibited fungal growth (66.5 % and 55.6 %, respectively). gatifloxacin and moxifloxacin in the cocultures eliminated the bacterial effect on both growth fungi (p<0.001). amphotericin B, natamycin, and itraconazole inhibited fungal growth partially or completely, depending on the fungus. In contrast, the effect of amphotericin B or natamycin in the presence of quinolones significantly favored the growth of fungi; this effect was more evident in *F. solani* [80].

Nevertheless, the MIC does not reflect physiological concentrations of drugs because *in vivo* drug concentrations may vary due to many factors such as absorption, metabolism, half-life, elimination, etc. [81, 82, 83]. In addition, in treatments with prophylactic and therapeutic purposes for confections, fortified or coadministered agents are used that may affect the efficacy of the other agent [84, 85].

Attempts to understand the magnitude and type of interactions between drugs have enabled the development in isobolographic analysis of the "gold standard" for drug interactions, which define the interactions as follows: *Additive effect*: The combined effect of two drugs (A and B) equals the sum of the equivalent doses (depending on the relative potency of each drug). *Synergism*: The effect of A and B is greater than that of the two separate drugs. *Antagonism*: The addition of a second drug decreases the effectiveness of the first. *Indifferent*: No interaction between the drugs. The calculation is aided by an isobologram graph. This facilitates visual evaluation of the interaction but requires a separate statistical analysis. The isobolographic analysis for the MIC is more sensitive because the analysis evaluates the dose effects and is the prelude to studies in *in vivo* pharmacodynamics [86].

In coinfections, patients are exposed to simultaneous antifungal and antibacterial therapeutic treatment. Quinolones and antifungals are commonly used in bacteria and fungi or bacteria and yeast coinfections. Nakajima *et. al.,* reported the synergistic effect of DU-9859a fluoroqui‐ nolone enhanced the *in vitro* antifungal activity of amphothericin B and fluconazole against *Candida* spp. growth and decreased the load in mice infected with yeast. The last result was also observed in mice infected with *Aspergillus fumigatus* [87]. Similar results were obtained with ciprofloxacin, amphotericin B, levofloxacin, voriconazole, or caspofungin combinations, which has a synergistic effect against *Candida albicans* and *Aspergillus fumigatus* [88]. In another report, ofloxacin had a synergic effect on fluconazole versus a fluconazole-resistant *Candida albicans* strain [89].

Analysis of drug interactions with simultaneous application is still developing. Modified methods have been proposed related to more accurate isobolographic analysis, and *in vitro* models approach physiological conditions. Animal models have also been used. This area will revolutionize therapeutic interventions.
