Jette E. Kristiansen

Clinical Concentrations of Thioridazine Kill Intracellular Multidrug-Resistant Mycobacterium tuberculosis

ABSTRACT The phenothiazines chlorpromazine (CPZ) and thioridazine (TZ) have equal in vitro activities against antibiotic-sensitive and -resistant Mycobacterium tuberculosis. These compounds have not been used as anti-M. tuberculosis agents because their in vitro activities take place at concentrations which are beyond those that are clinically achievable. In addition, chronic administration of CPZ produces frequent severe side effects. Because CPZ has been shown to enhance the killing of intracellular M. tuberculosis at concentrations in the medium that are clinically relevant, we have investigated whether TZ, a phenothiazine whose negative side effects are less frequent and serious than those associated with CPZ, kills M. tuberculosis organisms that have been phagocytosed by human macrophages, which have nominal killing activities against these bacteria. Both CPZ and TZ killed intracellular antibiotic-sensitive and -resistant M. tuberculosis organisms when they were used at concentrations in the medium well below those present in the plasma of patients treated with these agents. These concentrations in vitro were not toxic to the macrophage, nor did they affect in vitro cellular immune processes. TZ thus appears to be a serious candidate for the management of a freshly diagnosed infection of pulmonary tuberculosis or as an adjunct to conventional antituberculosis therapy if the patient originates from an area known to have a high prevalence of multidrug-resistant M. tuberculosis isolates. Nevertheless, we must await the outcomes of clinical trials to determine whether TZ itself may be safely and effectively used as an antituberculosis agent.

Phenothiazines and Thioxanthenes Inhibit Multidrug Efflux Pump Activity in Staphylococcus aureus

ABSTRACT Efflux-related multidrug resistance (MDR) is a significant means by which bacteria can evade the effects of selected antimicrobial agents. Genome sequencing data suggest that Staphylococcus aureus may possess numerous chromosomally encoded MDR efflux pumps, most of which have not been characterized. Inhibition of these pumps, which may restore clinically relevant activity of antimicrobial agents that are substrates for them, may be an effective alternative to the search for new antimicrobial agents that are not substrates. The inhibitory effects of selected phenothiazines and two geometric stereoisomers of the thioxanthene flupentixol were studied using strains of S. aureus possessing unique efflux-related MDR phenotypes. These compounds had some intrinsic antimicrobial activity and, when combined with common MDR efflux pump substrates, resulted in additive or synergistic interactions. For S. aureus SA-1199B, which overexpresses the NorA MDR efflux pump, and for two additional strains of S. aureus having non-NorA-mediated MDR phenotypes, the 50% inhibitory concentration (IC50) for ethidium efflux for all tested compounds was between 4 and 15% of their respective MICs. Transport of other substrates was less susceptible to inhibition; the prochlorperazine IC50 for acriflavine and pyronin Y efflux by SA-1199B was more than 60% of its MIC. Prochlorperazine and trans(E)-flupentixol were found to reduce the proton motive force (PMF) of S. aureus by way of a reduction in the transmembrane potential. We conclude that the mechanism by which phenothiazines and thioxanthenes inhibit efflux by PMF-dependent pumps is multifactorial and, because of the unbalanced effect of these compounds on the MICs and the efflux of different substrates, may involve an interaction with the pump itself and, to a lesser extent, a reduction in the transmembrane potential.

Phenothiazines: an alternative to conventional therapy for the initial management of suspected multidrug resistant tuberculosis. A call for studies.

Increased frequency of multidrug resistant strains of Mycobacterium tuberculosis results from inappropriate treatment and lack of patient compliance. The Center for Disease Control/American Thoracic Society (CDC/ATS) guidelines issued for the management of newly diagnosed cases of tuberculosis (TB) will not be totally effective regardless of adherence to the guidelines and patient cooperation. The long interim period between the diagnosis of TB and confirmation of antibiotic susceptibility contributes to the infection rate. Consequently, the use of an adjuvant that is known to inhibit all encountered multidrug resistant strains of M. tuberculosis may be helpful until antibiotic susceptibility is known. Phenothiazines such as chlorpromazine, methdilazine and thioridazine are effective against strains of M. tuberculosis in vitro and in vivo. It is recommended that studies be designed and conducted for the purpose of managing new cases of TB that emanate from areas known to harbour multidrug resistant strains of M. tuberculosis, with phenothiazines as adjuvants to the regimen recommended by the CDC/ATS guidelines until antibiotic susceptibility is defined. Because the normal maximum period for obtaining conventional antibiotic susceptibility results is less than 7 or 8 weeks, the probability of serious side effects from the use of a phenothiazine is remote.

Phenothiazines: potential management of Creutzfeldt -Jacob disease and its variants

Creutzfeldt-Jakob disease acquired from bovines (nvCJD) has been responsible for nearly 100 deaths in the UK and thousands more may die in the years to come. New variant CJD (nvCJD) is incurable and although clinical diagnosis is becoming more precise, the diagnosis is only certain at autopsy. Phenothiazine derivatives inhibit production of prions, the disease causing agent, in cultured neuroblastoma cells, and an advanced case of nvCJD was recently brought to remission by the use of these agents in combination with an antimalarial. In this review we present direct and circumstantial evidence in support of a model describing the manner by which the intracellular antimicrobial activity of phenothiazines might cause the destruction of intracellular prions.

Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus

Structural variants of phenylpiperidine selective serotonin reuptake inhibitors (P-SSRIs) inhibited the function of two unique Staphylococcus aureus multidrug efflux pumps. The most active compound was the paroxetine isomer NNC 20-7052, which had an IC(50) for ethidium, acriflavine, and pyronin Y efflux of 9, 53, and 18% of its MIC, respectively, against the NorA pump. The unbalanced effect of NNC 20-7052 on the efflux of different substrates suggests the possibility that P-SSRIs function by a physical interaction with NorA. Under the conditions employed pump inhibition partially extended to the resistance-nodulation-division (RND) pump AcrAB-TolC, but not to the Pseudomonas aeruginosa RND pumps MexAB-OprM or MexCD-OprJ.

Phenothiazines: potential alternatives for the management of antibiotic resistant infections of tuberculosis and malaria in developing countries

The in vitro and in vivo activity of phenothiazines against antibiotic susceptible and antibiotic resistant Mycobacterium tuberculosis and malaria‐causing Plasmodia is reviewed. Given the facts that pulmonary tuberculosis and malaria are the major causes of death in developing countries, that both of these infections continue to escalate in their resistance to antibiotics, that the cost for the management of these infections is beyond that afforded by most developing nations, and lastly, that new and effective agents are not forthcoming from the pharmaceutical industry, the scientific rationale for the potential use of select phenothiazines for the management of these infections is presented.

Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps.

Global rates of pulmonary tuberculosis (TB) continue to increase. Moreover, resistance of the causative organism Mycobacterium tuberculosis to the two most effective anti-TB medications continue to rise. Now, multi-drug resistant TB (MDR-TB) has progressed to extensively drug resistant TB (XDR-TB) - a M. tuberculosis organism that is resistant to the most effective second line drugs available for the treatment of TB. This review provides detailed, significant evidence that supports the use of an old neuroleptic compound, thioridazine (TZ), for the management of MDR-TB and XDR-TB infections and which has been shown to inhibit efflux pumps of bacteria. The argument has been previously presented but no one seems to be listening - and the disease continues unabated when there is a very good probability that the suggested drug will prove to be effective. When the prognosis is poor, available therapy predictably ineffective and death is inevitable, compassionate therapy with TZ should be contemplated. The risks are small and the rewards great.

Phenothiazines alter resistance of methicillin-resistant strains of Staphylococcus aureus (MRSA) to oxacillin in vitro

Mechanisms of antibiotic resistance of bacteria include efflux pumps which extrude the antibiotic prior to reaching its target. Phenothiazines inhibit the activity of some efflux pumps thereby altering the susceptibility of bacteria. This study demonstrated that chlorpromazine and thioridazine reduce the susceptibility of methicillin-resistant strains (MRSA) but not that of methicillin-susceptible Staphylococcus aureus (MSSA) strains to oxacillin (MIC of oxacillin reduced from >500 to 10 mg/l). Reserpine, an inhibitor of antibiotic efflux pumps also reduced the resistance of MRSA strains to oxacillin suggesting the presence of an efflux pump that contributes to antibiotic resistance of MRSA strains.

Non-Antibiotics: alternative therapy for the management of MDRTB and MRSA in economically disadvantaged countries.

The antibiotic resistance is now common place throughout the globe. Two highly problematic antibiotic resistant infections are those produced by multi-drug resistant Mycobacterium tuberculosis (MDRTB) and methicillin resistant Staphylococcus aureus (MRSA). Although vancomycin is useful for therapy of MRSA, there is now evidence that resistance to this antibiotic is taking place. Intracellular infections of MRSA are very difficult to manage and are recurrent especially when invasive prosthetic devices are employed. This mini-review provides cogent evidence that both intracellular MDRTB and intracellular MRSA can be killed by concentrations of the non-antibiotic phenothiazine, Thioridazine, at concentrations in the medium that are below those present in the plasma of patients treated with this agent. Although thioridazine has been claimed to cause arrhythmias and even sudden death, the frequencies of these episodes are rare and when present, they are related to the patients underlying cardiac status as opposed to the direct effect of the agent itself. The authors do not suggest that thioridazine be used indiscriminately for MDRTB or intracellular infections produced by MRSA. However, there are circumstances where there are no alternative forms of therapy and the patient faces an unfavourable prognosis. For these highly selective and controlled situations, the use of thioridazine in the manner employed for the therapy of psychosis is recommended (compassionate therapy).

Methylene Blue halves the long-term recurrence rate in acute pilonidal sinus disease

ObjectiveTo study the potential benefits of intraoperative methylene blue (MB) use in pilonidal sinus surgery, the correlation between long-term recurrence rate and intraoperative MB use in pilonidal sinus surgery was investigated.BackgroundExplicit investigations of MB effects in sinus surgery are scarce and inconclusive; an effect on long-term recurrence rate has never been systematically investigated.Materials and methodsA random selection of 247 patients out of 1,960 patients with primary sinus surgery was drawn, and the patients were subjected to a telephone interview according to a specific questionnaire. The interview covered a recurrence follow-up time of 14.9 years after surgery (mean, standard deviation=3.8 years, range 8.6–25.4 years).ResultsRecurrence was less likely to occur when MB was used intraoperatively (32 of 197, [16% actuarial 20-year recurrence rate, Kaplan–Meier estimate] recurrences with MB vs 15 of 50, 30% [actuarial 20-year recurrence rate, Kaplan–Meier estimate] recurrences without MB; p=0.018; log-rank test). This effect was especially pronounced in acute abscess-forming disease (8 of 46, 17% [actuarial 20-year recurrence rate, Kaplan–Meier estimate] recurrences with MB; 11 of 33, 33% [actuarial 20-year recurrence rate, Kaplan–Meier estimate] recurrences without MB; p=0.078; log-rank test) compared to chronic disease (24 of 151, 16% [actuarial 20-year recurrence rate, Kaplan–Meier estimate]) recurrences with MB; 4 of 17, 24% [actuarial 20-year recurrence rate, Kaplan–Meier estimate] recurrences without MB; p=0.35; log-rank test).ConclusionsMB application halves the long-term risk of recurrence for pilonidal sinus patients. This significant reduction in recurrence rate can be achieved by a single careful injection of non toxic inexpensive dye into the sinus at the start of the operation. MB application should therefore be considered as an integral part of pilonidal sinus surgery.