Chapter 2 Preparing International Travelers
Interactions between Travel Vaccines & Drugs
Potential interactions between vaccines and medications, including those already taken by the traveler, must be considered during pretravel consultations. The importance of this topic is highlighted by a study identifying potential drug–drug interactions with travel-related medications in 45% of travelers using chronic medications, and 3.5% of interactions are potentially serious. Interactions of commonly used travel-related vaccines and medications are discussed here.
INTERACTIONS BETWEEN VACCINES
Concomitant administration of multiple vaccines, including live attenuated vaccines, generally is safe and effective. However, the spacing between the administration of some vaccines that are not given at the same time needs consideration.
A single study suggested that in adults, concomitant administration of the 13-valent pneumococcal conjugate vaccine (PCV13) with the trivalent inactivated influenza vaccine results in lower immunogenicity to the PCV13 components. The clinical significance of this observation is uncertain, as responses still met FDA criteria of noninferiority. Infants given PCV13 and inactivated influenza vaccine concomitantly had a slightly increased risk of fever and febrile seizure, but this risk must be weighed against the need for both vaccines before travel and the time available to separate them.
Administering a live-virus vaccine within 4 weeks after administration of another live-virus vaccine can decrease immunogenicity to the second administered vaccine; therefore, live-virus vaccines should be administered the same day or ≥4 weeks apart. If the 4-week span is not achievable, the second vaccine may be administered sooner to afford some protection, but should be readministered ≥4 weeks later if the traveler is at continued risk. A study examining concurrent administration of the yellow fever vaccine with the measles-mumps-rubella (MMR) vaccine in 12-month-old children showed slightly reduced immunogenicity to yellow fever and mumps components, compared with responses following separate vaccination with MMR and yellow fever vaccines 30 days apart. (See “Simultaneous Administration” in Chapter 4, Yellow Fever.) Similarly, risk for varicella vaccine failure among people who received varicella vaccine within 28 days of MMR vaccination was 3-fold higher than among people who received varicella vaccine >28 days after MMR vaccination.
Concerns about spacing between doses of live vaccines not given at the same visit applies only to live injectable or intranasal vaccines, so live oral cholera vaccine (CVD 103-HgR, Vaxchora, PaxVax) may be administered simultaneously or at any interval before or after administration of most other vaccines. One exception to this rule is the Ty21a oral typhoid vaccine. Oral cholera vaccine should be administered before Ty21a vaccine, and 8 hours should separate the cholera vaccine and the first dose of Ty21a.
INTERACTIONS BETWEEN TRAVEL VACCINES AND DRUGS
Live Attenuated Oral Typhoid and Cholera Vaccines
Live attenuated vaccines generally should be avoided in immunocompromised travelers, including those taking immunomodulators, calcineurin inhibitors, cytotoxic agents, antimetabolites, and high-dose steroids (see Table 5-02).
Antimicrobial agents may be active against the vaccine strains in the oral typhoid and cholera vaccines and may prevent adequate immune response to these vaccines. Vaccination with oral typhoid vaccine should be delayed for >72 hours and with oral cholera vaccine for >14 days after administration of antimicrobial agents. Parenteral typhoid vaccine is an alternative to oral vaccine, but there is no parenteral cholera vaccine currently available, and no killed oral cholera vaccines are licensed in the United States.
Chloroquine and atovaquone-proguanil at doses used for malaria chemoprophylaxis may 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 may be diminished when it is given concomitantly with chloroquine. Live attenuated oral cholera vaccine should be given at least 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.
Concomitant use of chloroquine may reduce the antibody response to intradermal rabies vaccine administered for preexposure vaccination. The intramuscular route should be used for people taking chloroquine concurrently. (Currently, intradermal administration of rabies vaccine is not approved in the United States.)
INTERACTIONS BETWEEN ANTIMALARIALS AND SELECTED OTHER DRUGS
This section describes some of the more commonly encountered drug interactions. Any time a new medication is prescribed, clinicians should check for any interactions and inform the traveler of the potential risk.
Mefloquine may interact with several categories of drugs, including other antimalarial drugs, drugs that alter cardiac conduction, and anticonvulsants. Mefloquine is associated with increased toxicities of the antimalarial drug lumefantrine (available in the United States in fixed combination to treat people with uncomplicated Plasmodium falciparum malaria), potentially causing fatal prolongation of the QTc interval. Lumefantrine should therefore be avoided or used with caution in patients taking mefloquine prophylaxis. Although no conclusive data are available with regard to coadministration of mefloquine and other drugs that may affect cardiac conduction, mefloquine should be used with caution or avoided in patients taking antiarrhythmic or β-blocking agents, calcium-channel blockers, antihistamines, H1-blocking agents, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or phenothiazines. Mefloquine may also lower plasma levels of a number of anticonvulsants, such as valproic acid, carbamazepine, phenobarbital, and phenytoin; concurrent use of mefloquine with these agents should be avoided. In general, mefloquine should be avoided in travelers with a history of seizures, mood disorders, or psychiatric disease. Mefloquine can also lead to increased levels of calcineurin inhibitors and mTOR inhibitors (tacrolimus, cyclosporine A, and sirolimus). Potent CYP3A4 inhibitors such as macrolides (azithromycin, clarithromycin, erythromycin), azole antifungals (ketoconazole, voriconazole, posaconazole and itraconazole), SSRIs (fluoxetine, sertraline, fluvoxamine), antiretroviral protease inhibitors (ritonavir, lopinavir, darunavir, atazanavir, saquinavir), and cobicistat (available in a combination with elvitegravir) may increase levels of mefloquine, increasing the risk for QT prolongation. CYP3A4 inducers such as efavirenz, nevirapine, etravirine, rifampin, rifabutin, St John’s wort, and glucocorticoids may reduce plasma concentrations of mefloquine, and concurrent use should be avoided. Concurrent use of mefloquine with the direct-acting protease inhibitors boceprevir and telaprevir used to treat hepatitis C should also be avoided. The newer direct-acting protease inhibitors (grazoprevir, paritaprevir, simeprevir) are believed to be associated with fewer drug–drug interactions, but as safety data are lacking, alternatives to mefloquine should be considered pending additional data.
Chloroquine may increase risk of prolonged QTc interval when given with other QT-prolonging agents (such as sotalol, amiodarone, and lumefantrine), and the combination should be avoided. The antiretroviral rilpivirine has also been shown to prolong QTc, and coadministration should be avoided. Chloroquine inhibits CYP2D6; when given concomitantly with substrates of this enzyme (such as metoprolol, propranolol, fluoxetine, paroxetine, flecainide), increased monitoring for side effects may be warranted. Chloroquine absorption may be reduced by antacids or kaolin; ≥4 hours should elapse between doses of these medications. Concomitant use of cimetidine and chloroquine should be avoided, as cimetidine can inhibit the metabolism of chloroquine and may increase drug levels. CYP3A4 inhibitors such as ritonavir, ketoconazole, and erythromycin may also increase chloroquine levels, and concomitant use should be avoided. Chloroquine inhibits bioavailability of ampicillin, and 2 hours should elapse between doses. Chloroquine is also reported to decrease the bioavailability of ciprofloxacin and methotrexate. Chloroquine may increase digoxin levels; increased digoxin monitoring is warranted. Use of chloroquine could possibly also lead to increased levels of calcineurin inhibitors and should be used with caution.
Tetracycline, rifampin, and rifabutin may reduce plasma concentrations of atovaquone and should not be used concurrently with atovaquone-proguanil. Metoclopramide may reduce bioavailability of atovaquone; unless no other antiemetics are available, this antiemetic should not be used to treat the vomiting that may accompany use of atovaquone at treatment doses. Atovaquone-proguanil should not be used with other medications that contain proguanil. Patients on warfarin may 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 (dabigatran, rivaroxaban and apixaban) is not expected to cause significant interactions, and their use has been suggested as an alternative in patients in need of anticoagulation. Atovaquone-proguanil may interact with the antiretroviral protease inhibitors ritonavir, darunavir, atazanavir, indinavir, and lopinavir, in addition to the nonnucleoside reverse transcriptase inhibitors nevirapine, etravirine, and efavirenz, resulting in decreased levels of atovaquone-proguanil. Despite the potential for interactions, atovaquone-proguanil is well tolerated in most patients receiving these antivirals and is the preferred antimalarial for short-term travel. Cimetidine and fluvoxamine interfere with the metabolism of proguanil and should therefore be avoided.
Phenytoin, carbamazepine, and barbiturates may decrease the half-life of doxycycline. Patients on anticoagulants may need to reduce their anticoagulant dose while taking doxycycline because of its ability to depress plasma prothrombin activity. Absorption of tetracyclines may be impaired by bismuth subsalicylate, preparations containing iron, and antacids containing calcium, magnesium, or aluminum; these preparations should not be taken within 3 hours of taking doxycycline. Doxycycline may interfere with the bactericidal activity of penicillin, so in general, these drugs should not be taken together. Doxycycline has no known interaction with antiretroviral agents, but concurrent use may lead to increased levels of calcineurin inhibitors and mTOR inhibitors (sirolimus).
INTERACTIONS WITH DRUGS USED TO TREAT TRAVELERS’ DIARRHEA
Close monitoring for side effects of azithromycin is recommended when azithromycin is used with nelfinavir. Increased anticoagulant effects have been noted when azithromycin is used with warfarin; monitoring prothrombin time is recommended for people taking these drugs concomitantly. Additive QTc prolongation may occur when azithromycin is used with the antimalarial artemether, and concomitant therapy should be avoided. Drug interactions have been reported with macrolides and antiretroviral protease inhibitors, as well as efavirenz and nevirapine, and can increase risk of QTc prolongation, though a short treatment course is not contraindicated for those without an underlying cardiac abnormality. Concurrent use with macrolides may lead to increased levels of calcineurin inhibitors.
Increase in the international normalized ratio (INR) has been reported when levofloxacin and warfarin are used concurrently. Concurrent administration of ciprofloxacin and antacids that contain magnesium or aluminum hydroxide may reduce bioavailability of ciprofloxacin. Ciprofloxacin decreases clearance of theophylline and caffeine; theophylline levels should be monitored when ciprofloxacin is used concurrently. Ciprofloxacin and other fluoroquinolones should not be used with tizanidine. Sildenafil should not be used in patients on ciprofloxacin, as concomitant use is associated with increased rates of adverse effects. Fluoroquinolones have no known interaction with antiretroviral agents, but concurrent use may increase levels of calcineurin inhibitors and fluoroquinolone levels, and use should reflect renal function.
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.
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.
INTERACTIONS WITH DRUGS USED FOR TRAVEL TO HIGH ALTITUDES
Acetazolamide produces alkaline urine that can increase the rate of excretion of barbiturates and salicylates and may potentiate salicylate toxicity, particularly if taking a high dose of aspirin. Decreased excretion of dextroamphetamine, anticholinergics, mecamylamine, ephedrine, mexiletine, or quinidine may also occur. Hypokalemia caused by corticosteroids may be potentiated by concurrent use of acetazolamide. Acetazolamide should not be given to patients taking the anticonvulsant topiramate, as concurrent use is associated with increased toxicity. Increased monitoring of cyclosporine, tacrolimus, and sirolimus is warranted if these drugs are given with acetazolamide. Concurrent administration of metformin and acetazolamide should be done with caution, as there may be an additive risk for lactic acidosis. Acetaminophen and diclofenac sodium form complex bonds with acetazolamide in the stomach’s acidic environment, impairing absorption. These agents should not be taken within 30 minutes of acetazolamide.
Dexamethasone interacts with multiple classes of drugs. Using this drug to treat altitude illness may, however, be lifesaving. Interactions may occur with dexamethasone and the following drugs and drug classes: macrolide antibiotics, anticholinesterases, anticoagulants, hypoglycemic agents, isoniazid, digitalis preparations, oral contraceptives, and phenytoin.
DRUG INTERACTIONS IN PATIENTS ON HIV MEDICATIONS
Patients with HIV can be a challenge in the pretravel consultation (See Chapter 5, Immunocompromised Travelers). A study in Europe showed that as many as 29% of HIV-positive travelers do not disclose their disease and medication status when seeking pretravel advice. Antiretroviral medications have multiple drug interactions, especially through activation or inhibition of CYP3A4 and CYP2D6. There are several reports of antimalarial treatment failure and prophylaxis failure in patients on protease inhibitors and both nucleoside and nonnucleoside reverse transcriptase inhibitors, whereas entry and integrase inhibitors are not a common cause of drug–drug interactions with commonly administered travel-related medications. A number of the potential interactions are listed above, and 2 excellent resources for HIV medication interactions can be found at www.hiv-druginteractions.org and at www.aidsinfo.nih.gov. Preexposure prophylaxis with emtricitabine/tenofovir is not a contraindication for any of the commonly used travel-related medications.
INTERACTIONS WITH HERBAL OR NUTRITIONAL SUPPLEMENTS
As many as 30% of travelers take herbal or nutritional supplements, and many consider them to be of no clinical relevance and will not disclose their use unless specifically asked during the pretravel consultation. Special attention should be given to supplements that activate or inhibit CYP2D6 or CYP3A4 like ginseng, hypericum, St. John’s wort, and grapefruit extract. Coadministration with medications that are substrates of CYP2D6 or 3A4 should be avoided (chloroquine, mefloquine, macrolides).
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