Friday, January 22, 2021

Helicobacter pylori Eradication & Breastfeeding


 

LactMed

UptoDate

Briggs 10th Edi, 2015

Pantoprazole

Maternal pantoprazole doses of 40 mg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants.

·       Pantoprazole is present in breast milk (Plante 2004).

·       The relative infant dose (RID) of pantoprazole was determined to be 0.14% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 40 mg/day.*

·       The RID of pantoprazole was calculated using a milk concentration of 0.036 mg/L, providing an estimated infant dose via breast milk of 7.3 mcg; the authors calculated the estimated infant dose by assuming 200 mL of breast milk would be ingested around the time of the peak breast milk concentration. This milk concentration was obtained following administration of a single maternal dose of oral pantoprazole 40 mg. Peak concentrations appeared in the breast milk 2 hours after the dose; pantoprazole was undetectable in breast milk by 5 hours postadministration. No adverse events were reported in the mother or infant for the 2 weeks following administration (Plante 2004).

·       The acidic content of a breastfed infant's stomach may potentially inactivate any pantoprazole ingested via breast milk (Plante 2004). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Limited Human DataProbably Compatible

 

·        Small amounts of pantoprazole are excreted into breast milk. A 43-year-old mother, partially nursing a healthy 10-month-old, 8.2-kg, female infant was

given a single 40-mg enteric-coated pantoprazole tablet (16). Breastfeeding was held while nine samples of maternal serum and six of breast milk were obtained over a 24-hour interval. The milk samples, about 10 mL each, were obtained at 0, 2, 4, 6, 8, and 24 hours postdose. Pantoprazole was detected only in the 2-hour (0.036 mg/L) and 4-hour (0.024 mg/L) samples, resulting in an estimated AUC of 0.103 mg·hr/L. The milk AUC was about 2.8% of the AUC for plasma. The peak maternal plasma concentration, 1.65 mg/L, occurred at 2 hours, but the levels were <0.025 mg/L at 8 and 24 hours postdose. If the infant had been nursing, the authors estimated that the infant dose would have been 0.14% of the weight-adjusted maternal dose (16).

·        The results of the above case are consistent with the relatively low molecular weight (about 432 for the hydrated form) that suggests pantoprazole will be excreted into breast milk.

·        In addition, pantoprazole is unstable at acidic pH so the amount actually absorbed by the infant may have been less than estimated.

Omeprazole

Limited information indicates that maternal omeprazole doses of 20 mg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants.

·        Omeprazole is present in breast milk.

·        The relative infant dose (RID) of omeprazole is 0.2% to 0.43% when calculated using the highest average breast milk concentration located and compared to an infant therapeutic dose of 0.7 to 1.5 mg/kg/day.*

·        The RID of omeprazole was calculated using the highest average milk concentration located (20.03 mcg/L), providing an estimated daily infant dose via breast milk of 0.003 mg/kg/day. This milk concentration was obtained following maternal chronic administration of oral omeprazole 20 mg/day; the peak breast milk concentration occurred 3 hours after the dose (Marshall 1998).

·        No adverse effects were noted in one infant exposed to omeprazole following maternal administration of oral omeprazole 20 mg/day for 3 months; the authors of this case report noted that the acidic content of a breastfed infants' stomach may potentially inactivate any ingested omeprazole (Marshall 1998).

·        According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Limited Human DataPotential Toxicity

 

·       Only one report describing the use of omeprazole during human lactation has been located. A woman with refractory GERD was treated with omeprazole (20 mg/day) for 78 weeks before delivering a premature male infant (birth weight not given) at 36 weeks’ gestation. Treatment was continued during breastfeeding. During this time, she fed her infant son just before taking her dose at 8 AM, refrained from nursing for 4 hours, then expressed and discarded her milk at 12 noon. At 3 weeks postpartum, blood and milk samples were obtained at 8 AM and then every 30 minutes for 4 hours (i.e., until 12 noon). The milk was obtained by expressing but the volume of the samples was not specified. Maternal serum concentrations began to rise 90 minutes after the dose, reached 950 nM at 12 noon, and appeared to be still rising. Breast milk levels also began to rise at 90 minutes and peaked at 180 minutes at 58 nM. The infant was doing well at 1 year of age (13).

·       The above case report estimated a maximum daily omeprazole exposure of 4 mcg, but the calculation was based on a consumption of only 200 mL of milk/day for a 5-kg infant (40 mL/kg/day). A more acceptable value is 150 mL/kg/day (34). Moreover, the milk samples were obtained by expression and the volumes expressed were not given. This is clinically relevant because hindmilk obtained at the end of a feeding is 45 times higher in fat than foremilk (35). For lipid-soluble drugs, such as omeprazole, hindmilk would be expected to contain most of the drug in milk.

·       In concurrence with the above case report, the molecular weight of omeprazole (about 345) suggests that it will be excreted into human milk. One source stated that the safety of a drug during breastfeeding can be arbitrarily defined as no more than 10% of the adult dose standardized by weight if a therapeutic dose for infants is not known (34).

·       Until additional studies show that omeprazole meets this criterion, the use of omeprazole during breastfeeding should probably be avoided. Other concerns, such as the carcinogenicity observed in animals and the potential for suppression of gastric acid secretion in the nursing infant, also warrant further study.

Esomeprazole

Esomeprazole is the S-enantiomer of the proton-pump inhibitor, omeprazole. Limited information indicates that maternal doses of 10 mg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants.

·       Esomeprazole is present in breast milk (Saito 2020).

·       A case report describes maternal use of esomeprazole 10 mg/day throughout pregnancy and postpartum. Breast milk was sampled multiple times between 2 and 4 days after delivery at term. The highest breast milk concentration was 4 hours after the maternal dose (19.6 ng/mL) and esomeprazole was no longer detected in breast milk 10 hours after the maternal dose. Using the highest breast milk concentration, authors of the study determined the estimated daily infant dose via breast milk to be 0.003 mg/kg/day. This infant received >50% of nutrition via breast milk and was developing normally as of 6 months of age (Saito 2020).

·       According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

 

No Human Data - Potential Toxicity

 

·  No reports describing the use of esomeprazole, the S-isomer of omeprazole,

during human lactation have been located.

·  The molecular weight (about 345 for the anhydrous free base) is low enough that excretion into breast milk should be expected.

·  The effect of esomeprazole on a nursing infant is unknown. The potential for toxic effects such as those seen in adults (e.g., headache, diarrhea, and abdominal pain) and the suppression of gastric acid secretion are a concern, as is the potential for the gastric tumors that have been observed in animals after long-term use.

·  Small amounts of omeprazole, a mixture of the S- and R-isomers, are excreted into milk, but the quantity excreted needs further clarification. (See Omeprazole.)

·  If a lactating womass condition requires esomeprazole, consideration of the drug’s properties might allow her to nurse without significantly exposing her infant.

·  Esomeprazole is dosed once daily because the inhibition of gastric acid secretion is prolonged. In contrast, the plasma elimination half-life is short (about 11.5 hours). Thus, waiting 57.5 hours after a dose should eliminate up to 97% of the drug from the plasma. Moreover, the mean peak plasma concentration is reported to occur 1.6 hours after the dose, and waiting 5-7.5 hours would avoid the period when the greatest amount of drug is available to enter milk. Emptying both breasts near the end of the waiting period and discarding the milk completes the strategy to limit the infant’s exposure. This strategy was used in one case involving omeprazole but warrants further study.

Amoxicillin

Limited information indicates that amoxicillin produces low levels in milk that are not expected to cause adverse effects in breastfed infants. Occasionally, rash and disruption of the infant's gastrointestinal flora, resulting in diarrhea or thrush, have been reported, but these effects have not been adequately evaluated. Amoxicillin is acceptable in nursing mothers. Amoxicillin powder for suspension reconstituted with breastmilk is absorbed as well as the powder reconstituted with water.

·        Amoxicillin is present in breast milk (Kafetzis 1981).

·        The relative infant dose (RID) of amoxicillin is 0.15% to 0.54% when calculated using the highest average breast milk concentration located and compared to an infant therapeutic dose of 25 to 90 mg/kg/day.*

·        The RID of amoxicillin was calculated using a milk concentration of 0.9 mcg/mL, providing an estimated daily infant dose via breast milk of 0.135 mg/kg/day. This milk concentration was obtained following maternal administration of a single oral dose of amoxicillin 1,000 mg (Kafetzis 1981).

·        Self-limiting diarrhea, rash, and somnolence have been reported in nursing infants exposed to amoxicillin (Benyamini 2005; Goldstein 2009; Ito 1993); the manufacturer warns of the potential for allergic sensitization in the infant. In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea (WHO 2002).

·        Although the manufacturer recommends that caution be exercised when administering amoxicillin to breastfeeding women, amoxicillin is considered compatible with breastfeeding when used in usual recommended doses (WHO 2002).

·        Amoxicillin may be used to treat mastitis in breastfeeding women. The treatment of mastitis with antibiotics is generally not considered unless symptoms do not improve with conservative management or the woman is acutely ill. When antibiotics are clinically indicated for treatment, amoxicillin is one of the suggested therapies for gram-negative organisms (WHO 2000).

·        Recommendations for using amoxicillin for the treatment of B. anthracis in breastfeeding women are the same as in pregnancy. Exposure to anthrax is not considered a contraindication to breastfeeding. However, if there are active cutaneous lesions on the breast, contact with the infant should be avoided and feeding from the affected breast should not occur until >48 hours of appropriate antibiotic therapy (Meaney-Delman 2014).

 

·   Amoxicillin is excreted into breast milk in low concentrations. Following a 1-g oral dose given to six mothers, peak milk levels occurred at 45 hours, averaging 0.9 mcg/mL (range 0.681.3 mcg/mL) (15). Mean milk:plasma ratios at 1, 2, and 3 hours were 0.014, 0.013, and 0.043, respectively. Although no adverse effects have been observed, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant (e.g., allergy or sensitization), and interference with the interpretation of culture results if a fever workup is required.

·   In a 1993 cohort study, diarrhea was reported in 32 (19.3%) nursing infants of 166 breastfeeding mothers who were taking antibiotics (16). For the 25 women taking amoxicillin, diarrhea was observed in 3 (12%) infants. The diarrhea was considered minor because it did not require medical attention.

·   The American Academy of Pediatrics (2001) classifies amoxicillin as compatible with breastfeeding.

Clarithromycin

Because of the low levels of clarithromycin in breastmilk and safe administration directly to infants, it is acceptable in nursing mothers. The small amounts in milk are unlikely to cause adverse effects in the infant. Monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash). Unconfirmed epidemiologic evidence indicates that the risk of infantile hypertrophic pyloric stenosis might be increased by maternal use of macrolide antibiotics during the first two weeks of breastfeeding, but others have questioned this relationship.

·        Clarithromycin and its active metabolite (14-hydroxy clarithromycin) are present in breast milk.

·        The relative infant dose (RID) of clarithromycin is <1% when calculated using the highest mean breast milk concentration located and compared to an infant therapeutic dose of 15 mg/kg/day.*

·        Using the highest mean milk concentrations (clarithromycin: 0.85 mg/L; 14-hydroxy clarithromycin: 0.63 mg/L), the estimated daily infant dose via breast milk was calculated to be 136 mcg/kg/day. This milk concentration was obtained following maternal administration of oral clarithromycin 250 mg twice daily; the half-lives of clarithromycin and 14-hydroxy clarithromycin in breast milk were 4.3 ± 0.3 hours and 9 ± 1.2 hours, respectively (Sedlmayr 1993).

·        Decreased appetite, diarrhea, rash, and somnolence have been reported in breastfed infants exposed to macrolide antibiotics (Goldstein 2009). In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush and diarrhea (WHO 2002). In addition, an increased risk for infantile hypertrophic pyloric stenosis (IHPS) may be present in infants who are exposed to macrolides via breast milk, especially during the first two weeks of life (Lund 2014); however, data are conflicting (Goldstein 2009). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

 

Compatible

 

·        Clarithromycin is excreted into breast milk. In a 1993 study, 12 mothers were given clarithromycin 250 mg twice daily. Both the parent drug and metabolite were excreted into milk, with peaks levels measured at 2.2 and 2.8 hours, respectively, The half-lives of the drug and metabolite were 4.3 and 9 hours, respectively. The combined exposure for an exclusively breastfed infant was about 2% of the mothers weight-adjusted dose.

·        A 2003 study investigated the association between maternal use of macrolides and infantile hypertrophic pyloric stenosis (11). The Danish population-based cohort study comprised 1166 women who had a prescribed macrolide (azithromycin, clarithromycin, erythromycin, spiramycin, or roxithromycin) from birth to 90 days postnatally compared with up to 41,778 controls. The OR for stenosis was 2.33.0, depending on the postnatal period of exposure (42, 56, 70, or 90 days), but none of the ORs was significant.

·        When stratified by gender, the ORs for males were 1.83.1 and again were not statistically significant. For females, the ORs at 70 and 90 days postbirth were 10.3 and 7.5, but only the former was significant (95% CI 1.292.3) (11).

·        Investigators from Israel examined the possible association between macrolide (azithromycin, clarithromycin, erythromycin, or roxithromycin) exposure in milk and infantile hypertrophic pyloric stenosis in a 2009 study (13).

·        They compared 55 infants exposed to a macrolide antibiotic to 36 infants exposed to amoxicillin. In the macrolide group, 7 (12.7%) had an adverse reaction (rash, diarrhea, loss of appetite, somnolence), whereas 3 infants (8.3%) in the amoxicillin group had an adverse reaction (rashes, somnolence).

·        The rates of adverse reactions were comparable. No cases of infantile hypertrophic pyloric stenosis were observed.

Metronidazole

Because of the well demonstrated genotoxicity and mutagenicity in bacteria, carcinogenicity in animals, and possible mutagenicity in humans, concern has been raised about exposure of healthy infants to metronidazole via breastmilk. The relevance of these findings has been questioned and no definitive study has yet been performed in humans.

Opinions vary among experts on the advisability of using metronidazole during longer-term therapy while breastfeeding, but some sources recommend discontinuing breastfeeding for 12 to 24 hours after single-dose maternal treatment. Other drugs are available for some conditions that metronidazole is used to treat. Topical or vaginal use of metronidazole during breastfeeding is unlikely to be of concern, although the manufacturer of one vaginal product recommends not breastfeeding during treatment and for 2 days after the last dose.

·        Metronidazole and its active hydroxyl metabolite are present in breast milk at concentrations similar to maternal plasma concentrations.

·        The relative infant dose (RID) of metronidazole is 13.7% to 22.9% when calculated using the highest average breast milk concentration reported and compared to an oral infant therapeutic dose of 30 to 50 mg/kg/day. *

·        Using the highest average milk concentration (45.8 mcg/mL), the estimated daily infant dose via breast milk is 6.87 mg/kg/day. This milk concentration was obtained following a single maternal dose of oral metronidazole 2,000 mg; the authors estimated the infant would have been exposed to metronidazole 21.8 mg over the first 24 hours after the dose (Erickson 1981).

·        The highest average milk concentration occurred 2 to 4 hours after a single oral maternal dose; the half-life in breast milk was ~9 to 10 hours (Erickson 1981). Metronidazole and its active metabolite can be detected in the serum of breastfeeding infants (Gray 1961; Heisterberg 1983; Passmore 1988).

·        Loose stools, oral and perianal Candida growth, and oral thrush have been reported in breastfeeding infants exposed to metronidazole (Passmore 1988)

·        The manufacturer warns of the risk of carcinogenicity in patients exposed to metronidazole based on animal studies; theoretically, this risk is also present in breastfeeding infants exposed to metronidazole via breast milk. Therefore, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother. Some guidelines note if metronidazole is given, breastfeeding should be withheld for 12 to 24 hours after a single dose (CDC [Workowski 2015]; WHO 2002); alternatively, the mother may pump and discard breast milk for 24 hours after taking the last metronidazole dose. Breastfeeding should be avoided in women requiring treatment with metronidazole for inflammatory bowel disease (van der Woude 2015). Use of other agents is preferred when treating breastfeeding women for Clostridioides (formerly Clostridiumdifficile infection (Surawicz 2013).

 

§  Hold Breastfeeding (Single Dose)

§  Limited Human DataPotential Toxicity (Divided Dose)

 

·        Metronidazole is excreted into breast milk.

·        Following a single 2-g oral dose in three patients, peak milk concentrations in the 5060 mcg/mL range were measured at 24 hours (52). With normal breastfeeding, infants would have received about 25 mg of metronidazole during the next 48 hours. By interrupting feedings for 12 hours, infant exposure to the drug would have been reduced to 9.8 mg, or 3.5 mg if feeding had been stopped for 24 hours (52).

·        In women treated with divided oral doses of either 600 or 1200 mg/day, the mean milk levels were 5.7 and 14.4 mcg/mL, respectively (53). The milk:plasma ratios in both groups were approximately 1.0. The mean plasma concentra-tions in the exposed infants were about 20% of the maternal plasma drug level. Eight women treated with metronidazole rectal suppositories, 1 g every 8 hours, produced a mean milk drug level of 10 mcg/mL with maximum concentrations of 25 mcg/mL (54).

·        One report described diarrhea and secondary lactose intolerance in a breastfed infant whose mother was receiving metronidazole (55). The relationship between the drug and the events is unknown. Except for this one case, no reports of adverse effects in metronidazole-exposed nursing infants have been located. However, because the drug is mutagenic and carcinogenic  in some test species (see Fetal Risk Summary), unnecessary exposure to metronidazole should be avoided.

·        However, topical or vaginal use of metronidazole during breastfeeding does not appear to represent a risk to a nursing infant.

·        A 1988 report analyzed the milk and plasma concentrations of metronidazole and its metabolite (hydroxymetronidazole) in 12 breastfeeding women who had been taking 400 mg 3 times daily for 4 days (56). The mean milk:plasma ratios for the parent drug and metabolite were 0.9 and 0.76, respectively. In seven of the nursing infants, the plasma concentra-tions for the parent drug and metabolite ranged from 1.27 to 2.41 mcg/mL and 1.1 to 2.4

Levofloxacin

Levofloxacin is the S-enantiomer of the fluoroquinolone, ofloxacin. No information is available on the clinical use of levofloxacin during breastfeeding. However, amounts in breastmilk appear to be low and would not be expected to cause any adverse effects in breastfed infants. Fluoroquinolones such as levofloxacin have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk.[1][2] The calcium in milk might prevent absorption of the small amounts of fluoroquinolones in milk,[3] but insufficient data exist to prove or disprove this assertion. Use of levofloxacin is acceptable in nursing mothers with monitoring of the infant for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash). Avoiding breastfeeding for 4 to 6 hours after a dose should decrease the exposure of the infant to levofloxacin in breastmilk. Maternal use of an eye drop that contains levofloxacin presents negligible risk for the nursing infant.

·        Levofloxacin is present in breast milk.

·        The relative infant dose (RID) of levofloxacin is 6% when calculated using the highest breast milk concentration located and compared to a therapeutic infant dose of 20 mg/kg/day. *

·        The RID of levofloxacin was calculated using a milk concentration of 8.2 mcg/mL, providing an estimated daily infant dose via breast milk of 1.23 mg/day. This milk concentration was based on random samples obtained following a maternal dose of IV levofloxacin 500 mg/day for 9 days, followed by oral therapy for a total of 23 days beginning 3 days postpartum; the half-life in the breast milk was ~7 hours (Cahill 2005).

·        Levofloxacin may be considered for use in breastfeeding patients requiring antibiotics for inhalational anthrax (postexposure); according to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. However, patients with active cutaneous anthrax lesions on the breast should avoid direct infant contact; feeding from the affected breast should be avoided until 48 hours after the appropriate antibiotic therapy (Meaney-Delman 2014).

·        For other indications, the manufacturer does not recommend use of levofloxacin in breastfeeding patients during therapy or for 2 days after the last levofloxacin dose due to concerns of potential serious adverse reactions; alternatively, lactating patients can pump and discard breast milk during therapy and for 2 days after the last levofloxacin dose. The risk of articular damage in breastfed infants exposed to other quinolones (ie, ciprofloxacin) is considered low even in children receiving high therapeutic doses. Therefore, some sources do not consider maternal use of these agents to be a reason to discontinue breastfeeding as long as the infant is monitored for GI symptoms (eg, diarrhea) that could occur following antibiotic exposure (Kaplan 2015). Other sources recommend avoiding quinolone antibiotics if alternative agents are available (WHO 2002).

·        In general, antibiotics that are present in breast milk may cause nondose-related modification of bowel flora. Monitor infants for GI disturbances (WHO 2002).

 

Limited Human DataProbably Compatible

 

·        When first marketed, the use of levofloxacin during lactation was not recommended because of the potential for arthropathy and other serious toxicity in the nursing infant.

·        Phototoxicity has been observed with quinolones when exposure to excessive sunlight (i.e., ultraviolet [UV] light) has occurred. Well-differentiated squamous cell carcinomas of the skin has been produced in mice who were exposed chronically to some fluoroquinolones and periodic UV light (e.g., see Lomefloxacin), but studies to evaluate the carcinogenicity of ofloxacin in this manner have not been conducted.

·        Levofloxacin is excreted into breast milk. A lactating woman received levofloxacin 500 mg/day during the first 23 days postpartum. Milk samples were collected at various times at steady state.

·        The peak concentration in milk, 8.2 mcg/mL, occurred 5 hours after a dose. The pharmaco-kinetics in milk was similar to those in the plasma. Minimal levels of the drug were detectable 65

hours after the last dose. The infant was not allowed to breastfeed.

The effect of this exposure on a nursing infant is unknown, but other fluoroquinolones are classified as compatible with breastfeeding by the American Academy of Pediatrics (see Ofloxacin and Ciprofloxacin).

Doxycycline

A number of reviews have stated that tetracyclines are contraindicated during breast feeding because of possible staining of infants’ dental enamel or bone deposition of tetracyclines. However, a close examination of available literature indicates that there is not likely to be harm in short-term use of doxycycline during lactation because milk levels are low and absorption by the infant is inhibited by the calcium in breastmilk. Doxycycline use in children <8 years is now considered acceptable in courses up to 21 days. As a theoretical precaution, avoid prolonged (>21 days) or repeat courses during nursing. Monitor the infant for rash and for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash).

·        Doxycycline is present in breast milk.

·        The relative infant dose (RID) of doxycycline is 6.14% when calculated using the highest average breast milk concentration located and compared to an infant therapeutic dose of 4.4 mg/kg/day.*

·        Using the highest average milk concentration (1.8 mcg/mL), the estimated daily infant dose via breast milk is 0.27 mg/kg/day. This milk concentration was obtained following maternal administration of a single oral dose of doxycycline 200 mg (Tokuda 1969). Concentrations of doxycycline in breast milk may increase with duration of therapy (Anderson 1991).

·        Oral absorption of doxycycline is not markedly influenced by simultaneous ingestion of milk; therefore, oral absorption of doxycycline by the breastfeeding infant would not be expected to be diminished by the calcium in the maternal milk.

·        The therapeutic use of doxycycline should be avoided during tooth development (children <8 years) unless there are no alternative therapies due to the potential for tissue hyperpigmentation, tooth enamel hypoplasia, or permanent tooth discoloration. Theoretically, this risk is also present in breastfeeding infants exposed to doxycycline via breast milk. Although breastfeeding is not specifically contraindicated, the effects of long-term exposure via breast milk are not known. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. The World Health Organization (WHO) states that maternal use of doxycycline should be avoided if possible but that a single dose or the short-term use of doxycycline is probably safe; there exists a possibility of dental staining and inhibition of bone growth in the infant, especially with prolonged use (WHO 2002). In general, antibiotics that are present in breast milk may cause nondose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush and diarrhea (WHO 2002).

·        Current guidelines note that the short-term use of doxycycline for the treatment of RMSF (rocky mountain spotted fever) is considered compatible with breastfeeding (CDC [Biggs 2016]). If used for the treatment or prophylaxis of malaria, breastfeeding during doxycycline therapy is considered compatible; however, the theoretical risk of dental staining and inhibition of long bone growth in the breastfeeding infant should be considered (WHO 2002). Breastfeeding is not recommended when doxycycline is being used for maternal treatment of acne (AAD [Zaenglein 2016]).

 

Compatible

 

·   Doxycycline is excreted into breast milk.

·   Oral doxycycline, 200 mg, followed after 24 hours by 100 mg, was given to 15 nursing mothers. Milk:plasma ratios determined at 3 and 24 hours after the second dose were 0.3 and 0.4, respectively. Mean milk concentrations were 0.77 and 0.38 mcg/mL.

·   Theoretically, dental staining and inhibition of bone growth could occur in breastfed infants whose mothers were consuming doxycycline. However, this theoretical possibility seems remote, because in infants exposed to a closely related antibiotic, tetracycline, serum levels were undetectable (less than 0.05 mcg/mL).

·   The American Academy of Pediatrics classifies tetracycline as compatible with breastfeeding. Three potential problems may exist for the nursing infant even though there are no reports in this regard: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required.

Bismuth subsalicylate

Because of the possibility of absorption of salicylate from the breastmilk by the infant, alternatives are preferred.

·        Salicylates enter breast milk (Bar-Oz 2004). Following ingestion of bismuth subsalicylate, plasma salicylate concentrations may be comparable to those following ingestion of aspirin (Bierer 1990). Refer to the aspirin monograph for additional information related to salicylates and breastfeeding.

·        It is not known if bismuth is present in breast milk; however, absorption is limited following oral admini-stration of this preparation at usual doses (Bierer 1990).

·        A case report describes bowel obstruction in a breastfed infant whose mother applied a bismuth-containing ointment to her nipples prior to breastfeeding (Ingestion of bismuth-containing 1974).

·        Bismuth subsalicylate should not be used for the treatment or prevention of traveler’s diarrhea in breastfeeding patients (CDC 2018).

 

Under à Uptodate: Aspirin: Drug Information

ü  The WHO considers occasional doses of aspirin to be compatible with breastfeeding but recommends avoiding long-term therapy and consider monitoring the infant for adverse effects (hemolysis, prolonged bleeding, metabolic acidosis) (WHO 2002).

ü  Other sources also suggest avoiding high doses of aspirin while breastfeeding due to the theoretical risk of Reye syndrome (Bar-Oz 2003; Spigset 2000).

No Human DataPotential Toxicity

 

·   The excretion of significant amounts of bismuth obtained from bismuth subsalicylate into breast milk is not expected because of the poor absorption of bismuth into the systemic circulation.

·   Salicylates, however, are excreted in milk and are eliminated more slowly from milk than from plasma with milk:plasma ratios rising from 0.03 to 0.08 at 3 hours to 0.34 at 12 hours (12).

·   Because of the potential for adverse effects in the nursing infant, the American Academy of Pediatrics recommends that salicylates should be used cautiously during breastfeeding (13).

·   A review stated that bismuth subsalicylate should be avoided during lactation because of systemic salicylate absorption (14).

 

*RID = In general, breastfeeding is considered acceptable when the RID is <10%; when an RID is >25% breastfeeding should generally be avoided (Anderson 2016; Ito 2000).

*Author’s Comment: Suggest to find entries in the latest edition of Briggs – especially for PPI.

 

Extra Note:

Metronidazole – is it safe to use with breastfeeding?
Vanessa Chapman, Director, Trent Medicines Information Service & UK Drugs in Lactation Advisory Service · Published 12 October 2020

 

·       The balance of current evidence and clinical experience, and the consensus of specialist opinion, is that there is no established mutagenic or carcinogenic risk to infants breastfeeding from mothers receiving routine short-course treatment with metronidazole by any route.

·       Low-dose oral metronidazole, 200-400 mg three times daily, produces milk levels only slightly lower than corresponding levels in maternal plasma (76 to 99%). However, doses up to 500 mg three times daily for a 7 to 10 day course are considered to be compatible with breastfeeding.

·       Single, 2 g high-dose oral metronidazole produces significantly higher levels in milk than low-dose oral therapy. However, the estimated total ingestion is still lower than the daily infant dose given directly. Daily 2 g oral doses, normally given for 3 days, are considered to be compatible with breastfeeding.

·       Intravenous administration produces similar maternal plasma and milk levels to equivalent oral doses, although the data are limited. Short-course IV metronidazole is considered to be compatible with breastfeeding.

·       Administration of metronidazole by rectal, vaginal, or topical routes produces significantly lower plasma levels, and would therefore be expected to produce correspondingly lower milk levels than after oral administration, and is considered to be compatible with breastfeeding.

·       Adverse effects in breastfed infants whose mothers have been treated with metronidazole are rare and unsubstantiated, and include loose stools, candidiasis and lactose intolerance.

·       Anecdotal reports of infants rejecting milk at the start of feeds may be due to a metallic/bitter taste imparted to foremilk by a water soluble metabolite, although this again has not been substantiated.

·       If an infant is exposed to metronidazole via breast feeding they may experience alteration of the oral and gut flora, therefore monitor the infant for oral candida infections and The infant should also be monitored for rash due to the theoretical concern of hypersensitivity.

·       The concentrations of metronidazole seen in breast milk are too low to have a bactericidal effect in the infant; therefore an infant with an active infection needs independently treating in their own right.

·       There are no data relating to the effects of metronidazole exposure in preterm breastfed infants. Special consideration should be given to the use of metronidazole by any route in preterm or low-birth-weight infants, or in infants with compromised renal or hepatic function.

 


UptoDate: Treatment regimens for Helicobacter pylori

TREATMENT DURING PREGNANCY AND LACTATION

When peptic ulcer disease is diagnosed in a woman who is pregnant, the mainstay of treatment is typically acid suppression. If H. pylori is present, treatment is typically deferred until after delivery. However, with the exception of bismuth, fluoroquinolones, and tetracycline, the other medications used for H. pylori eradication are low risk in pregnancy, especially after 14 weeks. This includes clarithromycinamoxicillin, and probably metronidazole. Moreover, there is some evidence that H. pylori can cause severe nausea and vomiting in pregnancy, including hyperemesis gravidarum [66,67]. Thus, if indicated, H. pylori treatment should be considered in pregnancy.

Some of the medications typically used for the treatment of H. pylori are possibly unsafe for nursing infants (eg, bismuth, metronidazolelevofloxacin).

Treatment of Helicobacter pylori infection in adults 

(Conseil National Professionnel d’Hépato-Gastroentérologie, France ; May 2017)

Treatment is not urgent: in case of pregnancy or breastfeeding, the treatment must be deferred.

 https://www.has-sante.fr/upload/docs/application/pdf/2017-09/helicobacter_pylori_-_tool_for_appropriate_treatment.pdf

Treatment of Helicobacter pylori in Special Patient Populations 

(by Andrea Richard, Minnesota Direct Care and Treatment, 2020)

·         In asymptomatic patients who are pregnant or breastfeeding, it is recommended to delay treatment until delivery or cessation of breastfeeding due to lack of safety data for any of the regimens.

·         In symptomatic patients, such as those with hyperemesis gravidarum, a risk vs. benefit conversation with the patient must occur.

·         If the decision to pursue treatment is made, clarithromycin triple therapy is recommended.

https://www.pharmacy.umn.edu/degrees-and-programs/postgraduate-pharmacy-residency-program/news-events-and-publications/curbside-consult-volume-17-issue-4-fourth-quarter-2019/treatment-helicobacter-pylori-special-patient-populations

 All references accessed on 20 Jan 2021 by JCK Ho