Prevention of Malaria & Bacterial Infections at a population level: “Doxycycline” Vaccine development to provide long-lasting benefits: A promising theory by Gian Maria Pacifici

February 06 07:20 2019

Malaria, a parasite vector-borne disease, is not only one of the greatest health threats in tropical regions but is also a major cause of illness, clinical visits, and hospitalizations in many areas of the world, despite the availability of malaria chemoprophylaxis and the use of insecticide and repellents. Malaria prophylaxis and chemotherapy persists to be a central focus of research, and new chemical molecules are continually being developed before the blossoming of drug-resistant strains of the malaria parasite. The utilization of anti-malarial drugs is governed on the basis of resistance level of Plasmodium falciparum in endemic areas, contraindications, clinical tolerance as well as the costs of these drugs.

Among the compounds prospectively utilized against Plasmodium, antibiotics have been assessed in vitro or in vivo.

Global efforts to combat malaria have moved from the failed elimination attempts of the 1950s to the current Roll Back Malaria program. Propelled by ubiquities publicity and powered by newly deployed resources, current control efforts have elevated the optimism that malaria can be vanquished. Despite that, nothing much have been done till now to prevent malaria, especially in children?

However a subsequent discovery through auditing different clinical trials by Associate Professor of Pharmacology, Pisa, Italy — Gian Maria Pacifici shed light on the potential mode of action of doxycycline in conquering over this parasite.

The objective of this audit is to explain the epidemiology, clinical and lab presentation, and gainful treatment of children and adults with malaria, since she considered it truthful that though malaria is frequent in travelers, but is often misdiagnosed on initial presentation, particularly in children.

While performing a retrospective review of 4,240 participants enrolled in eight trials who were put to atovaquone-proguanil, mefloquine and doxycycline, it was revealed that doxycycline users had fewer reported neuropsychiatric events than mefloquine users (relative risk = 0.84, 95% confidence interval = 0.73-0.96) as well as even both have reported similar adverse events when given as prophylaxis (preventive treatment) to non-immune child and adult travelers who were travelling to areas with Plasmodium falciparum resistant to chloroquine.

Similarly, evidences from another study exhibited 62% positive cases of Malaria smears where American children had visited family and friends in malaria endemic countries, with most cases visited Nigeria or Cameroon and Africa. Following travel, Plasmodium falciparum was diagnosed most frequently (72%) with low level of parasitemia (<1%), while Gametocytes rarely identified.

Treatment was firstly with quinine and either clindamycin or doxycycline. All patients responded rapidly and fairly to treatment. Although (14%) had hyperparasitemia but no fatalities or long-term sequelae were reported.

Elucidating upon a major drawback associated with doxycycline i.e., the need for daily dosing, its contraindication for pregnant women and young children, and its adverse effects, one of the powerful properties of doxycycline i.e., its ability to be quickly absorbed orally; and detectable in the blood 15–30 min after its administration should not be overlooked— says Gian Maria Pacifici.

Further she points out that Chloroquine is only effective a prophylaxis in regions like Central America, the Caribbean, and parts of the Middle East.

Diagnosis of Malaria can be difficult in children travelers because parasitemia is usually below 1%. If atovaquone-proguanil, Mefloquine and tetracyclines are now well known as anti-malarial drugs, other antibiotics (like doxycycline) should also be considered. She is of the opinion that crucial discoveries could arise from chemical modifications of older molecules with anti-plasmodial properties.

An advantage of using antibiotics already approved, like doxycycline, azithromycin tigecycline, or clindamycin, as anti-malarial drugs is basically the reduced cost of clinical development and universally availability. However, another prominent advantage that leaves unnoticed of anti-malarial drugs like doxycycline is the modes of action of on inhibition of P. falciparum bc1 complex, type II topo-isomerase enzyme, PfNDH2, DHODH or HDAC, which differs from those of most currently used drugs. This difference in modes of action signalize that there are no cross-resistance between antibiotics and standard anti-malarial drugs and that antibiotics can be a good partner for combination. That said, Doxycycline remains still effective in combination with artesunate or quinine.

Nonetheless, a larger use of antibiotics against malaria cannot be encouraged without considering the risk of the emergence of resistant bacteria — said Gian Maria. She also added that the impact of chemoprophylaxis by doxycycline on bacterial pathogens is the best documented from a publication study of Campylobacter jejuni gastroenteritis among American soldiers based in Thailand. Use of doxycycline resulted in less exposure to resistant bacteria than the accretion of already resistant, which had long been widespread in this country. 

Malaria parasites remain in the circulation of the host for ∼30 min afyer being bitten by an infective mosquito and before gaining entry into hepatocytes. There, the parasites develop for at least 7-10 days to infect RBCs and cause symptoms of malaria disease.

Investigating the pharmacokinetics properties of doxycycline via numerous studies, one important aspect of doxycycline unearthed by Gian Maria is its ability to be rapidly absorbed orally and be detectable after 30 minutes of administration, making it able to kill the parasites essentially before they return from the liver to the blood system, thus, aborting the infection before symptoms develop.

However, Due to Doxycycline short half-life and slow schizonticide action, it should not be use in monotherapy in the treatment of uncomplicated malaria. The life cycle of malarial parasites is complex, and the human immune response to malaria has not been completely characterized. Thus, dependence on presumptive treatment as a mode of preventing malaria-caused morbidity and mortality needs that diagnostic techniques are accurate and that therapeutic interventions be available and rapidly effective.

In the light of these observations, the author concluded that there are great individual variations, depending on the age of the sufferer and any co-administered substances. Therefore an initial as well as daily dose of Doxycycline to maintain plasma concentrations needs to be prepared keeping in mind individual diagnosis at therapeutic levels during the treatment for malaria infection.

She adds that impediments in individual patient management are delayed diagnosis and impertinent fluid resuscitation in severe malaria. In the absence of drug resistance, parasite can reoccur, owing to high parasite densities, low host immunity, or insignificant drug concentrations. The use of antibiotics should only be contemplated after evaluating the conclusive outcomes of clinical trials conducted on exposed populations from different geographical areas.

Chemoprophylaxis has been used widely for decades, but the growing resistance of Plasmodium to medications has restricted the effectiveness of chemoprophylactic regimens used in the past. In areas of chemoprophylactic, endemicity, efforts have been obstructed by cost and schematic challenges. Nevertheless, mosquito avoidance and chemoprophylaxis is the cornerstone of malaria prevention for children traveling from areas where malaria is not endemic to areas where it is.

She says that the real hope for malaria control rests with the pursuance of an optimal vaccination. Initial attempts were disheartening, but advanced methods of immunization hold potential for success.

Full research can be found here:

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