Current Treatments and Future Therapies for Human Acquired Zoonoses

CWD

There have not been any cases of CWD in humans, but if CWD was to manifest in humans as BSE did in the form of vCJD then the various treatments used in vCJD may be of use in CWD patients. As of yet there are no curative treatments for vCJD. Currently the drugs that are used for treatment (quinacrine, chlorpromazine, amphotericin and pentosan polysulphate) although they may have shown promise in animal experiments have no significant impact on vCJD, therefore they are only administered on compassionate grounds (Cashman and Caughey 2004, WHO vCJD 2001 and UK Research and Development of TSEs 2004).

Various compounds that have been shown experimentally to inhibit PrP^sc formation and what the current status of the compound with respect to therapy and problems encountered (Cashman and Caughey 2004). Another possible stratergy being considered is the use of small interfering RNA molecules which would inhibit the production of PrPc therefore removing the possibility of prion protein conversion and also disease manifestation (Research and Development of TSEs 2004).

Ebola and Marburg Viruses

Containment of the disease is essential to prevent spread, barrier nursing is implemented whereby clinical staff wear a number of protective garments to prevent nosocomial transmission. Disinfection and the safe disposal of surgical equipment are vital (Weber et al. 2001 and WHO Ebola Factsheet 2004). To date there is no preexposure prophylaxis and no PEP. Therapy for infected individuals consists of administration of ribavirin and passive antibodies from Ebola survivors, rehydration and the replacement of coagulation factors but this treatment course is futile and does not significantly reduce the fatality rate of the disease (Hassani et al. 2004, Weber et al. 2001 and WHO 1997).

With a mortality rate of 50-90% EBOV is an extremely deadly virus that can be obtained from bushmeat and should be treated with great concern. Also due to the fear of EBOV being used as a biological weapon there has been an increase in research for a vaccine (Hassani et al. 2004). The majority of Ebola vaccine research is focused on the development of DNA vaccines because they are safer alternatives copared to live or live-attenuated vaccines. Three of Ebola's structural proteins; nucleoprotein (NP), glycoprotein (GP) and surface glycoprotein (sGP) are the main focus for scientists because it is these proteins (encoded in the vector DNA) that act as antigens and evoke immunity.

Sullivan et al. (2000) found that protection could be elicited in cynomolgus macaques by priming with a DNA vaccine containing subtypes of GP and NP and boosting using adenovirus vectors containing GP. Sullivan et al. (2003b) produced a "accelerated vaccine", which instead of relying on a prime-boost six month immunisation schedule it evoked protection against a challenge with a single inoculation. This vaccine contained an adenovirus vector containing GP and NP containing vectors.

The first human trail of an EBOV vaccine began in 2004 whereby a DNA vaccine is being tested on 27 volunteers, but this trail is carried out to observe the immune response in individuals to compare with NHP data, the volunteers will not be challenged with live virus (Nierengarten 2004). If this trail is successful then further trails may be carried out in the future but the development of an EBOV vaccine is not imminent.

HIV

Presently there is no preexposure prophylaxis. There are a number of drugs available that can slow the increase in HIV viral loads and the progression to AIDS. The three major classes of drug groups are Nucleoside-Analogue Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) and Protease Inhibitors (PIs). These anti-HIV drugs are administered in combinations of 3 or more as part of Highly Active Retroviral Therapy (HAART). Drug therapy initiates in HIV infected patients when the CD4⁺ cell count reaches 200-350 mL^-1 (depending on whether the patient is symptomatic) it is rarely given to patients with a CD4⁺ cell count of 350 mL^-1. But if clinicians or lab workers are exposed to HIV via a needlestick injury or exposure to the mucous membrane of the eye then PEP is available although the Department of Health have stated "No antiretroviral drug has been licensed for post-exposure prophylaxis. These drugs can be prescribed for PEP only on an "off-label" basis since their use in this context is outside approved indications." The drugs they prescribe for PEP include zidovudine and lamivudine (NRTIs) and either nelfinavir or indinavir (PIs) (BHIVA 2003, Department of Health PEP 2004).

But prevention remains better than a cure. There has been an enormous amount of research into developing a HIV vaccine but an effective vaccine remains elusive because of the number of obstacles researchers need to overcome. For example the HIV genome has a high mutation rate which is due to the error prone reverse transcriptase which is essential in HIV replication. This high mutation rate leads to constant changing of the surface glycoproteins which makes the process of antigen recognition by antibodies and therefore immune cells difficult (Mascola and Montefiori 2003). There are also limitations using animal models for example the parts of a specific strain of HIV used to vaccinate a macaque will also be used to challenge the NHP with, only phase III clinical trails will show the true effectiveness of a HIV vaccine (Burgers and Williamson 2005).

There has been little success with subunit vaccines instead DNA vaccines are the main area of research with a couple of vaccines even reaching phase II clinical trails (Ahmed 2005 and Karnasuta 2005). Although millions of pounds of research are being spent on the development of HIV vaccines each year we are still finding it difficult to catch up with and stop the HIV pandemic.

HTLV

At present there is no preexposure prophylaxis or PEP, there is no PEP because HTLV only manifests in 5% of those infected, the rest are asymptomatic carriers. Treatment is available for the different diseases HTLV manifests for example zidovudine, lamivudine and reverse transcriptase inhibitors are used to treat patients with TSP/HAM (Machuca et al. 2001). HTLV causes ATL currently conventional chemotherapy and high-dose chemotherapy with a bone marrow transplant only prolongs the inevitable fatal outcome (Bazarbachi et al. 2004). Arsenic trioxide is one of the more exciting prospects because it can inhibit various pathways that lead to cell transformation (Bazarbachi et al. 2004). Bortezomib, a proteosome inhibitor has been shown to be experimentally effective at inhibiting the growth of ATL cells by inducing their apoptosis (Satou et al. 2004).

Haematopoietic stem cell transplantation (HSCT) have been given to some ATL patients but unfortunately ATL persisted. HTLV tax is a therapeutic target because silencing of this viral protein would stop cell transformation. Kannagi et al. (2004) found that the T cells from rats vaccinated with tax oligopeptides prevented the growth of experimentally-induced tumours. They also found that a DNA vaccine containing tax cDNA induced anti-tumour T cell immunity. Bazarbachi et al. (2004) also mentioned the development of HTLV vaccines in Japan. Hence steps are being taken to develop preexposure and PEP HTLV vaccines and prevent the development of ATL.

Monkeypox Virus

Preexposure prophylaxis and PEP is available in the form of the vaccinia virus (smallpox) vaccine. The smallpox vaccine should be given as a pre-exposure prophylaxis (because it is >85% effective) The vaccinia vaccine is effective against MPV because there is 96.3% homology between the two species and they only differ in the end regions of the genomes. Although they probably originated from a common ancestor both viruses have evolved separately (Douglass and Dumbell, 1992). It should be given to individuals who are most likely to come into contact with MPV for example clinicians, veterinarians, laboratory workers and those who are likely to come into contact with infected animals or people. The smallpox vaccine should be given as a PEP to individuals who have come into contact with a person or animal infected with MPV in the last four days. The CDC recommends that vaccinated individuals should receive a second vaccination within two weeks of the initial exposure (CDC Interim Guidelines for prevention and treatment of MPV and Di Giulio et al. 2004).

Cidofovir (anti-viral agent) and vaccinia immune globulin (VIG) can be used both as a prophylactic treatment and in the treatment of a MPV infected individual. But their clinical effectiveness has yet to be fully accessed (CDC Interim Guidelines for prevention and treatment of MPV and Di Giulio et al. 2004).

Plague

PEP for individuals exposed to Y. pestis consisted of antibiotic therapy in particular the administration of doxycycline, chloramphenicol or ciprofloxacin. Administration of doxycycline, chloramphenicol, gentamicin or streptomycin is given to patients with a bubonic, septecemic or pneumonic plague. Fritz et al. (1996) described PEP (antibiotic therapy) as a major part of public safety plans if a plague epidemic was ever to occur.

Vaccines (live attenuated and whole cell) providing preexposure prophylaxis have been used in the pass but their use was discontinued because in murine models 1% of mice died and in humans 10% suffered from severe side effects for example fever and lymphadenopathy (Hassani 2004). The development of novel vaccines is important because antibiotic therapy although effective against bubonic plague it is not so efficient in treating pneumonic plague (Titball and Williamson 2001).

Improved live vaccines and subunit vaccines have been developed and are being tested to provide immunity for those living or traveling to endemic areas. A number of research groups are looking into the efficiency of sub-unit vaccines containing F1 and V antigens in providing immunity as of yet their research is ongoing (Eyles et al. 2004, Garmory et al. 2003, Griffin et al. 2002 and Sabhnani et al. 2003).

Rabies

There are various types of vaccines that are used in preexposure prophylaxis. In developing countries vaccines derived from neural tissue (suckling mouse brain Fuenzalida vaccine or sheep, goat brain, Semple vaccine) are used in a painful 14 day immunization schedule but in these countries a less painful 5 inoculation-schedule is available but is more expensive. Neural derived vaccines have a number of severe side effects which include meningoencephalitis and mononeuritis multiplex and can be lethal in up to 14% of vaccinated individuals. But in industrialized countries there are a number of rabies vaccines that have been produced, tested and used for immunization. Examples include human diploid cells rabies vaccine (HDCV), Vero cell rabies vaccines and purified chick embryo rabies vaccine. These vaccines have a reduced number of severe side effects compared to the neural tissue derived vaccines (WHO Rabies 2001 and WHO Rabies 2002).

In the UK at risk individuals, veterinarians, zoo workers, and travelers to high risk rabies endemic areas are advised to have a HDCV, which consists of two-three inoculations followed up by a booster 6 months later (Department of Health Rabies 2000).

Roughly 10 million people are inoculated with a post-exposure vaccine annually (WHO Rabies 2001 and WHO Rabies 2002) and roughly 16,000 to 39,000 courses of PEP are given in the USA annually (Morrison 2001). Before PEP can begin the wound should be cleaned with soap, water and alcohol. Vaccines used in PEP are the same as those used in preexposure prophylaxis and the rabies immunoglobulin is administered into and around the site of exposure.

The length of incubation of rabies depends on the site of the bite and the size of the inoculation, therefore incubation can last up to 3 weeks to a year, but this does not mean that treatment can be delayed, once clinical symptoms have begun then death is inevitable or so it was believed. In October 2004 a 15 year old girl was bitten by a rabid bat, she received no PEP. One month after exposure the girl started to exhibit some symptoms of rabies; fatigue, diplopia (double vision), nausea, slurred speech, a high temperature and hypersalivation. After rabies specific antibodies were detected in her CSF and blood serum clinical treatment began. The girl was placed in a drug induced coma and was given ribavirin, comprehensive details of the treatment have yet to be released (March 2005). She was kept in a coma for 7 days and successive lumber punctures during this period showed an increase of antirabies IgG. By December the girl had started to show signs of recovery. This is a landmark case and may lead to a novel course of therapy of individuals who have not received PEP (Willoughby et al. 2004).

Salmonella

There are no vaccines to provide PEP against the serotypes of Salmonella spp acquired from exotic pets and bushmeat. Clinicians treat Salmonellosis via rehydration, Stam et al. (2003) described the treatment of a patient with intravenous rehydration with isotonic saline and potassium. Sanyal et al. (1997) described the treatment of a Salmonellosis patient, treatment consisted of oral rehydration and a course of ciprofloxacin. Sometimes antibiotic therapy can be detrimental as it can increase the duration of the carrier state (Bell et al. 1988 and Sanyal et al. 1997).

SARS

During the SARS outbreak in 2002-2003, preexposure prophylaxes and PEP were none existent due to the novelty of the syndrome. When the patients first arrived in the hospitals presenting with atypical pneumonia they were given a combination of antibiotics but this therapy had no effect on SARS (Schlagenhauf and Ashraf 2003, WHO SARS 2004). Once SARS was identified barrier nursing was put into place and a combination of anti-viral agents such as ribavirin and oseltamivir and steroids were used to treat patients (WHO SARS 2004). Zhao et al. 2004 described how during the epidemic SARS patients were separated into four groups and underwent four different treatment regimes. The most effective regime consisted of levofloxacin, azithromycin, CPAP (continuous airway positive pressure, nasal supply of oxygen) and high levels of the steroid methyl prednisolone.

Overview of the types of clinical treatments that were given to SARS patients and the various experimental anti-viral and immunizing agents that are being developed to treat patients in a future possible epidemic (Groneberg et al. 2005).

Development of preexposure prophylaxes against SARS is of the utmost importance. There have been a number of DNA vaccines containing various amino acids and structural proteins; spike protein (S), envelope protein (E) and membrane protein (M) that have evoked immunity in a number of experimental animals researched groups responsible for these imperative results include Gao et al. (2003), Keng et al. (2005) Okada et al. (2005), Zhi-Yong et al. (2004).

SFV

SFV viral titres of infected people have risen over 20-30 decades in some cases but yet SFV causes no visible clinical manifestations (Switzer et al. 2004). Therefore with no clinical manifestations there is no need for prophylaxis or treatment.

Tuberculosis

There is a global preexposure prophylactic vaccine that has helped to reduce the number of cases of tuberculosis (TB) worldwide. Before the vaccine is administered a Heaf test is used to check whether the individual has previously been infected with tuberculosis and has developed some immunity. If positive then the individual is usually given a course of antibiotics (PEP), in the UK they are either given isoniazid or a combination of isoniazid and rifampicin to prevent the clinical manifestations of tuberculosis from developing. If the Heaf test is negative then patients are inoculated with Bacillus Calmette-Guerin (BCG) which is a vaccine containing a live attenuated strain of M. tuberculosis (Collins and Kaufmann 2001 and NHS TB webpage 2005).

Patients with a tuberculosis infection are treated with a combination of antibiotics. In the UK isoniazid, rifampicin, ethambutol and pyrazinamide are used to treat infections. But where a multidrug-resistant form of M. tuberculosis (MDR-TB) has been isolated from the patient treatment will consist of second-line drugs such as capreomycin, cycloserine, rifabutin, streptomycin and quinolones (Michalak et al. 1998, Mukherjee et al. 2004 and NHS TB webpage 2005). WHO has setup DOTS (directly observed therapy short-course), which is a recommend drug regime that is used to treat TB patients globally, it is via DOTS that WHO hopes to decrease global fatalities from TB but at the moment only 43% of people worldwide have access to DOTS (Collins and Kaufmann 2001).

The NHS has stated that only 70% of those vaccinated with BCG are immune to TB for 15 years (NHS TB webpage 2005). In 2000 there were 36 million people infected with HIV and 12 million were co-infected with M. tuberculosis (Godfrey-Faussett et al. 2002), which makes it an opportunistic disease. Due to the development of MDR-TB, new antibiotics used for treatment are expensive therefore the need for a new vaccine is paramount.

Smith et al. (2004) have researched alternative targets for TB treatment, during the chronic phase of a TB infection there is a metabolic shift in the carbon source. Instead of TB receiving its energy via glycolysis the "glyoxylate shunt" is activated, isocitrate is converted into malate via enzymic activity, furthermore one of these enzymes isocitrate lyase is used to essential in keeping the bacteria alive inside activated macrophages. Smith et al. hypothesized that enzymes in this metabolic pathways are attractive drug targets in TB therapy.

Tularemia

There have been a number of vaccines developed for F. tularensis. The former USSR developed a number of live attenuated strains of vaccines and in the US a live vaccine strain (LVS) of a type B strain of F. tularensis has been investigated but not given a licence for general use (Elkins et al. 2003). Antibiotics are used to treat an active tularemia infection specifically ciprofloxacin, gentamicin and streptomycin (Ellis et al. 2002). Research into novel vaccines for tularemia is being carried out due to a risk of F. tularensis being used as a bioweapon and because the LVS is produced from a strain B F. tularensis individuals are still at risk from strain A F. tularensis (Shen et al. 2004). There has been development of subunit vaccines using purified sections of lipopolysaccharide from LVS but research is still ongoing (Ellis et al. 2002).

Chlamydia

Antibiotic therapy (PEP) consists of the administration of tetracyclines such as tetracycline hydrochloride and doxycycline. Erythromycin and macrolides have also been used to treat Chlamydia psittaci infection (Morrison 2001 and Smith et al. 2005).

Leptospirosis

A number of different types of antibiotics are being used to treat patients with leptospirosis. PEP depends upon the stage of infection, the types of antibiotics used include; penicillin G, doxycycline, ampicillin, amoxicillin and ceftriaxone. With leptospirosis causing nephritis which leads to renal failure sometimes dialysis is needed during treatment (Bell et al. 1988, Bharti et al. 2003 and Cetin et al. 2004). Vaccines for leptospirosis are in use in some countries such as China and Russia but there have been a number of problems associated with it for example severe side effects and the problem of providing short-term immunity only.

Q Fever

There is currently a vaccine for C. burnetii (Q-Vax) but it is only licensed in Australia. This vaccine has been problematic in the past because it produces a severe reaction in individuals who have previously been infected by C. burnetii (CDC Q Fever webpage 2003). Mills et al. (2003) reported that a small number of men developed lesions in their deltoid regions. Research is ongoing to discover an improved vaccine with fewer side effects, Waag et al. (2002) has developed a phase I chloroform:methanol residue (CMR) extracted vaccine, results from animal experimentation has been promising. Doxycycline is used in PEP and a combination of doxycycline and chloroquine has been used to treat endocarditis brought about via Q fever (Calza et al. 2002 and Weber et al. 2001).

© MicrobiologyBytes 2007.