Author(s): Ilan Youngster, Elizabeth Barnett

During pretravel consultations, travel health providers must consider potential interactions between vaccines and medications, including those already taken by the traveler. A study by S. Steinlauf et al. identified potential drug–drug interactions with travel-related medications in 45% of travelers taking medications for chronic conditions; 3.5% of these interactions were potentially serious.

Vaccine–Vaccine Interactions

Most common vaccines can be given safely and effectively at the same visit, at separate injection sites, without impairing antibody response or increasing rates of adverse reactions. However, certain vaccines, including pneumococcal and meningococcal vaccines and live virus vaccines, require appropriate spacing; further information about vaccine–vaccine interactions is found in Sec. 2, Ch. 3, Vaccination & Immunoprophylaxis—General Principles.

Travel Vaccines & Drugs

Live Attenuated Oral Typhoid & Cholera Vaccines

Live attenuated vaccines generally should be avoided in immunocompromised travelers, including those taking antimetabolites, calcineurin inhibitors, cytotoxic agents, immunomodulators, and high-dose steroids (see Table 3-04).

Antimalarial Drugs

Chloroquine and atovaquone-proguanil at doses used for malaria chemoprophylaxis can be given concurrently with oral typhoid vaccine. Data from an older formulation of the CVD 103-HgR oral cholera vaccine suggest that the immune response to the vaccine might be diminished when given concomitantly with chloroquine. Administer live attenuated oral cholera vaccine ≥10 days before beginning antimalarial prophylaxis with chloroquine. A study in children using oral cholera vaccine suggested no decrease in immunogenicity when given with atovaquone-proguanil.

Antimicrobial Agents

Antimicrobial agents can be active against the vaccine strains in the oral typhoid and cholera vaccines and might prevent adequate immune response to these vaccines. Therefore, delay vaccination with oral typhoid vaccine by >72 hours and delay oral cholera vaccine by >14 days after administration of antimicrobial agents. Parenteral typhoid vaccine is an alternative to the oral typhoid vaccine for travelers who have recently received antibiotics.

Rabies Vaccine

Concomitant use of chloroquine can reduce the antibody response to intradermal rabies vaccine administered as a preexposure vaccination. Use the intramuscular route for people taking chloroquine concurrently. Intradermal administration of rabies vaccine is not currently approved for use in the United States (see Sec. 5, Part 2, Ch. 19, . . . perspectives: Rabies Immunization).

Antimalarial Drugs

Any time a new medication is prescribed, including antimalarial drugs, check for known or possible drug interactions (see Table 2-05) and inform the traveler of potential risks. Online clinical decision support tools (e.g., Micromedex) provide searchable databases of drug interactions.

Atovaquone-Proguanil

Antibiotics

Rifabutin, rifampin, and tetracycline might reduce plasma concentrations of atovaquone and should not be used concurrently with atovaquone-proguanil.

Anticoagulants

Patients on warfarin might need to reduce their anticoagulant dose or monitor their prothrombin time more closely while taking atovaquone-proguanil, although coadministration of these drugs is not contraindicated. The use of novel oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, is not expected to cause significant interactions, and their use has been suggested as an alternative for patients in need of anticoagulation.

Antiemetics

Metoclopramide can reduce bioavailability of atovaquone; unless no other antiemetics are available, this antiemetic should not be used to treat vomiting associated with the use of atovaquone at treatment doses.

Antihistamines

Travelers taking atovaquone-proguanil for malaria prophylaxis should avoid using cimetidine (an H2 receptor antagonist) because this medication interferes with proguanil metabolism.

HIV Medications

Atovaquone-proguanil might interact with the antiretroviral protease inhibitors atazanavir, darunavir, indinavir, lopinavir, and ritonavir, or the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz, etravirine, and nevirapine, resulting in decreased levels of atovaquone-proguanil. For travelers taking any of these medications, consider alternative malaria chemoprophylaxis.

Selective Serotonin Reuptake Inhibitors

Fluvoxamine interferes with the metabolism of proguanil; consider an alternative antimalarial prophylaxis to atovaquone-proguanil for travelers taking this selective serotonin reuptake inhibitor (SSRI).

Chloroquine

Antacids & Antidiarrheals

Chloroquine absorption might be reduced by antacids or kaolin; travelers should wait ≥4 hours between doses of these medications.

Antibiotics

Chloroquine inhibits bioavailability of ampicillin, and travelers should wait ≥2 hours between doses of these medications. Chloroquine should not be coadministered with either clarithromycin or erythromycin; azithromycin is a suggested alternative. Chloroquine also reportedly decreases the bioavailability of ciprofloxacin.

Antihistamines

Concomitant use of cimetidine and chloroquine should be avoided because cimetidine can inhibit the metabolism of chloroquine and increase drug levels.

CYP2D6 Enzyme Substrates

Chloroquine is a CYP2D6 enzyme inhibitor. Monitor patients taking chloroquine concomitantly with other substrates of this enzyme (e.g., flecainide, fluoxetine, metoprolol, paroxetine, propranolol) for side effects.

CYP3A4 Enzyme Inhibitors

CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, ritonavir) can increase chloroquine levels; concomitant use should be avoided.

Digoxin

Chloroquine can increase digoxin levels; additional monitoring is warranted.

Immunosuppressants

Chloroquine decreases the bioavailability of methotrexate. Chloroquine also can cause increased levels of calcineurin inhibitors; use caution when prescribing chloroquine to travelers taking these agents.

QT-Prolonging Agents

Avoid prescribing chloroquine to anyone taking other QT-prolonging agents (e.g., amiodarone, lumefantrine, sotalol); when taken in combination, chloroquine might increase the risk for prolonged QTc interval. In addition, the antiretroviral rilpivirine has also been shown to prolong QTc, and clinicians should avoid coadministration with chloroquine.

Doxycycline

Antacids, Bismuth Subsalicylate, Iron

Absorption of tetracyclines might be impaired by aluminum-, calcium-, or magnesium-containing antacids, bismuth subsalicylate, and preparations containing iron; advise patients not to take these preparations within 3 hours of taking doxycycline.

Antibiotics

Doxycycline can interfere with the bactericidal activity of penicillin; thus, in general, clinicians should not prescribe these drugs together. Coadministration of doxycycline with rifabutin or rifampin can lower doxycycline levels; monitor doxycycline efficacy closely or consider alternative therapy.

Anticoagulants

Patients on warfarin might need to reduce their anticoagulant dose while taking doxycycline because of its ability to depress plasma prothrombin activity.

Anticonvulsants

Barbiturates, carbamazepine, and phenytoin can decrease the half-life of doxycycline.

Antiretrovirals

Doxycycline has no known interaction with antiretroviral agents.

Immunosuppressants

Concurrent use of doxycycline and calcineurin inhibitors or mTOR inhibitors (sirolimus) can cause increased levels of these immunosuppressant drugs.

Mefloquine

Mefloquine can interact with several categories of drugs, including anticonvulsants, other antimalarial drugs, and drugs that alter cardiac conduction.

Anticonvulsants

Mefloquine can lower plasma levels of several anticonvulsant medications, including carbamazepine, phenobarbital, phenytoin, and valproic acid; avoid concurrent use of mefloquine with these agents.

Antimalarial Drugs

Mefloquine is associated with increased toxicities of the antimalarial drug lumefantrine, which is available in the United States in fixed combination to treat people with uncomplicated Plasmodium falciparum malaria. The combination of mefloquine and lumefantrine can cause potentially fatal QTc interval prolongation. Lumefantrine should therefore be avoided or used with caution in patients taking mefloquine prophylaxis.

CYP3A4 Enzyme Inducers

CYP3A4 inducers include medications used to treat HIV or HIV-associated infections (e.g., efavirenz, etravirine, nevirapine, rifabutin) and tuberculosis (rifampin). St. John’s wort and glucocorticoids are also CYP3A4 inducers. All these drugs (rifabutin and rifampin, in particular) can decrease plasma concentrations of mefloquine, thereby reducing its efficacy as an antimalarial drug.

CYP3A4 Enzyme Inhibitors

Potent CYP3A4 inhibitors (e.g., antiretroviral protease inhibitors, atazanavir, cobicistat [available in combination with elvitegravir], darunavir, lopinavir, ritonavir, saquinavir); azole antifungals (itraconazole, ketoconazole, posaconazole, voriconazole); macrolide antibiotics (azithromycin, clarithromycin, erythromycin); and SSRIs (fluoxetine, fluvoxamine, sertraline), can increase levels of mefloquine and thus increase the risk for QT prolongation.

Although no conclusive data are available regarding coadministration of mefloquine and other drugs that can affect cardiac conduction, avoid mefloquine use, or use it with caution, in patients taking antiarrhythmic or β-blocking agents, antihistamines (H1 receptor antagonists), calcium channel receptor antagonists, phenothiazines, SSRIs, or tricyclic antidepressants.

Immunosuppressants

Concomitant use of mefloquine can cause increased levels of calcineurin inhibitors and mTOR inhibitors (cyclosporine A, sirolimus, tacrolimus).

Anti-Hepatitis C Virus Protease Inhibitors

Avoid concurrent use of mefloquine and direct-acting protease inhibitors (boceprevir and telaprevir) used to treat hepatitis C. Newer direct-acting protease inhibitors (grazoprevir, paritaprevir, simeprevir) are believed to be associated with fewer drug–drug interactions, but safety data are lacking; consider alternatives to mefloquine pending additional data.

Psychiatric Medications

Avoid prescribing mefloquine to travelers with a history of mood disorders or psychiatric disease; this information is included in the US Food and Drug Administration boxed warning for mefloquine.

Drugs Used to Treat Travelers’ Diarrhea

Antimicrobials commonly prescribed as treatment for travelers’ diarrhea have the potential for interacting with several different classes of drugs (Table 2-06). As mentioned previously, online clinical decision support tools provide searchable databases that can help identify interactions with medications a person may already be taking.

Azithromycin

Anticoagulants

Increased anticoagulant effects have been noted when azithromycin is used with warfarin; monitor prothrombin time for people taking these drugs concomitantly.

Antimalarial Drugs

Because additive QTc prolongation can occur when azithromycin is used with the antimalarial artemether, avoid concomitant therapy.

HIV Medications

Drug interactions have been reported with the macrolide antibiotics, clarithromycin and erythromycin; antiretroviral protease inhibitors; and the NNRTIs, efavirenz and nevirapine. Concomitant use of azithromycin and these drugs can increase the risk of QTc prolongation, but a short treatment course is not contraindicated for those without an underlying cardiac abnormality. When azithromycin is used with the protease inhibitor nelfinavir, advise patients about possible drug interactions.

Immunosuppressants

Concurrent use of macrolides with calcineurin inhibitors can cause increased levels of drugs belonging to this class of immunosuppressants.

Fluoroquinolones

Antacids

Concurrent administration of ciprofloxacin and antacids that contain magnesium or aluminum hydroxide can reduce bioavailability of ciprofloxacin.

Anticoagulants

An increase in the international normalized ratio (INR) has been reported when levofloxacin and warfarin are used concurrently.

Asthma Medication

Ciprofloxacin decreases clearance of theophylline and caffeine; clinicians should monitor theophylline levels when ciprofloxacin is used concurrently.

Immunosuppresants

Fluoroquinolones can increase levels of calcineurin inhibitors, and doses should be adjusted for renal function.

Others

Sildenafil should not be used by patients taking ciprofloxacin; concomitant use is associated with increased rates of adverse effects. Ciprofloxacin and other fluoroquinolones should not be used in patients taking tizanidine.

Rifamycins

Rifamycin SV

No clinical drug interactions have been studied. Because of minimal systemic rifamycin concentrations observed after the recommended dose, clinically relevant drug interactions are not expected.

Rifaximin

Rifaximin is not absorbed in appreciable amounts by intact bowel, and no clinically significant drug interactions have been reported to date with rifaximin except for minor changes in INR when used concurrently with warfarin.

Drugs Used for Travel to High Elevations

Before prescribing the carbonic anhydrase inhibitor, acetazolamide, to those planning high elevation travel, carefully review with them the complete list of medications they are already taking (Table 2-07).

Acetazolamide

Acetaminophen & Diclofenac Sodium

Acetaminophen and diclofenac sodium form complex bonds with acetazolamide in the stomach’s acidic environment, impairing absorption. Neither agent should be taken within 30 minutes of acetazolamide. Patients taking acetazolamide also can experience decreased excretion of anticholinergics, dextroamphetamine, ephedrine, mecamylamine, mexiletine, and quinidine.

Anticonvulsants

Acetazolamide should not be given to patients taking the anticonvulsant topiramate because concurrent use is associated with toxicity.

Barbiturates & Salicylates

Acetazolamide causes alkaline urine, which can increase the rate of excretion of barbiturates and salicylates and could cause salicylate toxicity, particularly in patients taking a high dose of aspirin.

Corticosteroids

Hypokalemia caused by corticosteroids could occur when used concurrently with acetazolamide.

Diabetes Medications

Use caution when concurrently administering metformin and acetazolamide because of increased risk for lactic acidosis.

Immunosuppressants

Monitor cyclosporine, sirolimus, and tacrolimus more closely when given with acetazolamide.

Dexamethasone

Using dexamethasone to treat altitude illness can be lifesaving. Dexamethasone interacts with several classes of drugs, however, including: anticholinesterases, anticoagulants, digitalis preparations, hypoglycemic agents, isoniazid, macrolide antibiotics, oral contraceptives, and phenytoin.

HIV Medications

Patients with HIV require additional consideration in the pretravel consultation (see Sec. 3, Ch. 1, Immunocompromised Travelers). A study from Europe showed that ≤29% of HIV-positive travelers disclose their disease and medication status when seeking pretravel advice. Antiretroviral medications have multiple drug interactions, especially through their activation or inhibition of the CYP3A4 and CYP2D6 enzymes.

Several instances of antimalarial prophylaxis and treatment failure in patients taking protease inhibitors and both nucleoside and NNRTIs have been reported. By contrast, entry and integrase inhibitors are not a common cause of drug–drug interactions with commonly administered travel-related medications. Several potential interactions are listed above, and 2 excellent resources for HIV medication interactions can be found at HIV Drug Interactions and HIV.gov. HIV preexposure prophylaxis with emtricitabine/tenofovir is not a contraindication for any of the commonly used travel-related medications.

Herbal & Nutritional Supplements

Up to 30% of travelers take herbal or nutritional supplements. Many travelers consider them to be of no clinical relevance and might not disclose their use unless specifically asked during the pretravel consultation. Clinicians should give special attention to supplements that activate or inhibit CYP2D6 or CYP3A4 enzymes (e.g., ginseng, grapefruit extract, hypericum, St. John’s wort). Advise patients against coadministration of herbal and nutritional supplements with medications that are substrates for CYP2D6 or 3A4 enzymes, including chloroquine, macrolides, and mefloquine.