Chemoprophylaxis is the administration of drug to prevent the development of a disease. This review will focus on the use of medications to prevent tropical infectious diseases. The use of chemo-prophylactic agents is based on knowledge of the epidemiology and clinical implications of the infectious diseases from which protection is sought. Generally, chemoprophylaxis is taken for diseases that are common, or where the clinical impact of infection is high.

Drugs may be taken before exposure (pre-exposure prophylaxis) or after potential exposure to an infectious agent (post-exposure prophylaxis). In addition to the severity and frequency of the disease, the tolerability, toxicity and ecological implications of the medications being used are important considerations in whether drugs are prescribed and taken. In many instances, vaccines are the most effective and safest means by which to prevent infection. This review will not discuss vaccination as this is well covered elsewhere [1]. Passive immunotherapy is also used to prevent infection either before or after potential exposure to infectious agents. Again this review will not discuss this form of therapy in detail. Immunotherapy is also reviewed elsewhere [2,3]. This review will discuss chemoprophylaxis for specific infections and disease syndromes in the order of how widely used and acceptable their use is. A summary of recommendations is shown in Table 1.

Malaria is blood protozoan parasite which is transmitted by mosquitos. There are four human species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae [4]. A fifth species, Plasmodium knowlesi is also a parasite of several macaque species, and is thus zoonotic. It is a common cause of malaria in Malaysian Borneo, but is also found on the Malay Peninsula, Singapore, the Philippines, Thailand and Myanmar [5,6,7,8,9].

Malaria is endemic in 109 countries and causes an estimated 247 million infections worldwide and about 1 million deaths [10]. Of the estimated 50 million international travelers per year, between 1–5% are ill enough on return to seek medical attention, and up to 3% of short term travelers report fevers [11]. Malaria is the most common cause of fever in returned travelers, but this is strongly related to the travel history. Fever in a traveler returning from Sub-Saharan Africa is almost exclusively due to malaria, whereas visitors to the Caribbean and South East Asia are more likely to have dengue fever than malaria as a cause of their fever [12].

From 1997 through 2006, 10,745 cases of malaria among U.S. residents were reported to CDC. During this period, 54 fatal malaria infections occurred among U.S. residents; 46 (85.2%) were caused by P. falciparum, of which 33 (71.1%) were acquired in sub-Saharan Africa [1]. Drugs used to prevent malaria include chloroquine, hydroxychloroquine, atovaquone/proguanil (Malarone^®), doxycycline, mefloquine, primaquine and tafenoquine. None of the drugs are totally effective at preventing malaria and should always be given in conjunction with general advice on avoidance of mosquito bites through behavioral means, protective clothing and insect repellants.

Diarrhea is the most common affliction for travelers to tropical countries. Between 20–60% of visitors to resource poor countries are affected [12,41]. Prevention is primarily through attention to food and hand hygiene. Vaccination is available for cholera, typhoid, entertoxigenic E. coli (ETEC), and rotavirus. Chemoprophylaxis, using rifaximin has been shown to be effective in reducing the incidence of traveler’s diarrhea [42]. Rifaximin is a semi synthetic derivative of rifamycin. Taken, orally it is not absorbed and achieves high concentrations intraluminally [43]. In a dose of 200 mg/day it reduced traveler’s diarrhea by 72% [44]. It is considered safe in children more than 2 years old but not in pregnancy. Quinolone antibiotics (ciprofloxacin and norfloxacin) are around 90% efficacious in preventing traveler’s diarrhea, but are associated with development of resistant organisms, are not generally recommended as chemoprophylaxis. They do have a role in presumptive treatment of diarrhea episodes [45]. Chemoprophylaxis for traveler’s diarrhea should not be routinely provided but may be useful in circumstances where diarrheal episodes could prove inconvenient or clinically significant for the traveler [43]. Doxycycline was shown to reduce episodes of diarrhea in Peace Corps volunteers in Honduras, however diarrhea episodes in soldiers in Thailand, receiving either mefloquine or doxycycline occurred in nearly 50% with either drug. Both were associated with increased antibiotic resistance [46,47]. There is no evidence to support the choice of an antimalarial drug in the prevention of traveler’s diarrhea.

Scrub typhus is caused by Orientia tsutsugamushi and transmitted to humans via the bite of the mite, Leptotrombidium diliense [48]. Cases of scrub typhus tend to geographically localized and clusters of cases can occur when groups of people are exposed, through close contact with vegetation, in these areas [49]. These exposures can sometimes be predicted and use of doxycycline in a dose of 200 mg weekly has been shown to be effective in field and laboratory experiments at preventing disease, but not infection [50,51]. Azithromycin is effective in the treatment of scrub typhus but there is no evidence to support its’ use in chemoprophylaxis [52,53,54].

Leptospirosis is a zoonotic bacterial disease transmitted to humans who come in contact with water that has been contaminated with the urine of infected animals. Certain groups of people, e.g., farmers, or participants in water sporting events, are at higher risk for acquisition of this disease, and floods may be associated with large outbreaks [55,56,57,58,59,60,61]. Treatment of leptospirosis is with penicillin, cefotaxime or doxycycline, which are equally effective [62]. Azithromycin has been shown to be also effective in the treatment of humans and in a lethal guinea pig model [54,63]. Penicillin given as post-exposure prophylaxis has been unsuccessful [64]. The efficacy of doxycycline for chemoprophylaxis of leptospirosis has not been consistent in all trials. A study of US soldiers training in Panama demonstrated a 95% protective efficacy with a weekly dose of 200 mg doxycycline, compared to placebo [65]. Two later placebo controlled studies have shown that although doxycycline modestly reduces the rate of clinical disease, it does not reduce the infection rate [66,67]. A recent Cochrane review highlights that doxycycline side effects of nausea and vomiting should be balanced against the relatively weak evidence of prophylactic efficacy [68].

Schistosomiasis is a common problem in returned travelers, especially after exposure to freshwater in Africa (e.g., Lake Malawi). Longer term travelers, such as missionaries, volunteers and researchers have double the risk of infection [69,70]. Artemether, a methyl ether derivative of quinghaosu, has anti-schistosomal properties, and because it affects the parasite at the larval stage was proposed as a chemo prophylactic agent for this disease [71]. A randomized double blinded placebo controlled study in African children after radical treatment demonstrated a 50% reduction in new infection in children who received a course of artemether every three weeks. Not surprisingly malaria prevalence was also reduced [72]. Chemoprophylaxis against schistosomiasis should only be considered for unavoidable exposure in high risk settings.

Leprosy is a skin and nerve disease caused by Mycobacterium leprae. There are a number of studies now showing that single doses of rifampicin are effective at a population level and amongst close contacts (post-exposure) in preventing leprosy [73,74,75,76,77]. Chemoprophylaxis for leprosy would normally only be considered in special circumstances in travelers, but has a role to play in indigenous populations of endemic areas.

Exposure to HIV is a risk for sexually active people, especially in high prevalence countries. Chemoprophylaxis, using the anti-retroviral drug, tenofovir disoproxil fumarate, has been attempted in women who were HIV negative, but at risk of acquiring HIV. Women took 300 mg of tenofovir daily, and although the infection rate appeared to be lower than in the placebo group, the study finished prematurely and the results were not statistically significant [78,79]. Use of chemoprophylaxis for this indication is not justified currently on the basis of the evidence available, and would only be applicable to people who were powerless to protect themselves in other proven ways, such as the use of condoms.

There are several infectious diseases whose occurrence is uncommon but where an infecting event can be identified and preventative chemotherapy is warranted. Laboratory workers can be accidentally exposed to pathogens that are more common in the tropical environments and imported by travelers who have returned from these environments. Burkholderia pseudomallei is a gram negative organism that can cause a multisystem septic illness called melioidosis. People with underlying medical conditions such as diabetes are particularly at risk [80]. In mouse model of infection, co-trimoxazole was found to offer the greatest protection both before, and within 24 hours of exposure. Amoxicillin/clavulanic acid was the least active agent tested in this model [81]. Co-trimoxazole and doxycycline has been used for 3 weeks as post-exposure prophylaxis after laboratory exposure to Burkholderia pseudomallei, although adverse reactions to this drug can be a problem [82,83]. Brucellosis is a bacterial infection caused by one of several species of Brucella. This organism is notoriously infectious, unless cultures are manipulated in biosafety hoods. Laboratory workers exposed to this organism are usually given a combination of doxycycline and rifampicin for 3 weeks or co-trimoxazole [84,85]. Yersinia pestis, the causative agent of plague, is an extremely rare cause of infection in the modern era, however sporadic cases and outbreaks still occur. The disease is considered a potential bioterrorism threat and chemoprophylaxis with either doxycycline or ciprofloxacin is recommended after exposure [86]. Quinolone antibiotics and doxycycline are similarly recommended as post-exposure prophylaxis for Bacillus anthracis, the causative agent of anthrax [87].

Hendra virus infection is a risk for veterinarians and people who come into contact with sick horses in Australia. On the basis of data that ribavarin, a broad spectrum antiviral, was associated with favorable outcomes in nipah virus infections, the use of this drug has been used as post exposure prophylaxis. The combination of ribavarin and chloroquine was not, however, effective in an in vivo hamster model of infection [88,89,90].

Herpes B virus (Cercopithecine herpesvirus 1) is carried by over 80% of Asian macaque monkeys, and there are rare reports of fatal encephalomyelitis in humans after percutaneous exposures. Valacyclovir is recommended within 24 hours after high risk exposures [91,92,93].

Post-exposure prophylaxis is used for infections such as Influenza, Neisseria meningitidis, Haemophilus influenza type B, and Bordatella pertussis. They are not discussed as they are not considered to be predominantly tropical.

Prophylaxis of an infection with an anti-infective is theoretically possible for any infection that has a satisfactory treatment. Pre-exposure prophylaxis is effective when the risk of acquiring infection is high and the drugs used to prevent the infection are well tolerated and easy to take. This is generally the case for malaria prophylaxis taken by travelers. Chemoprophylaxis for other tropical infections is not as well established but should be considered for the traveler who plans to expose themselves to a higher level of risk. Post-exposure prophylaxis is provided after unforeseen exposure to infectious agents that can have serious consequences. In this situation the drug regimens do not necessarily need to be as convenient, or well tolerated, as medication taken for pre-exposure prophylaxis. In many cases chemoprophylaxis should play a secondary role to other non-drug measures that are known to reduce the risk of infection.