REFERENCE : ANTIBIOTIC AND BREASTFEEDING

  • Scott A, Forsyth S. Breast feeding and antibiotics. Mod Midwife 1996;6:14–6.
  • Bowes WA Jr. The effects of medications on the lactating mother and her infant. Clin Obstet Gynecol 1980;23:1073–80.[Medline]
  • Rasmussen F. The mechanisms of drug secretion into milk. In: Galli G, Jacini G, Pecile A, eds. Dietary lipids and postnatal development. New York: Raven Press, 1973:231.
  • Bourget P, Quinquis-Desmaris V, Fernandez H. Ceftriaxone distribution and protein binding between maternal blood and milk postpartum. Ann Pharmacother 1993;27:294–7.[Abstract]
  • Miller GE, Banerjee NC, Stowe CM. Diffusion of certain weak organic acids and bases across the bovine mammary gland membrane after systemic administration. J Pharmacol Exp Ther 1967;157:245.[Abstract/Free Full Text]
  • term variations within individuals. Br J Nutr 1981;45:483.[CrossRef][Medline]
  • Rasmussen F, Linzell JL. The acetylation of sulfanilamide by mammary tissue of lactating goats. Biochem Pharmacol 1967;16:918.[Medline]
  • Mann CF. Clindamycin and breast-feeding. Pediatrics 1980;66:1030–1.[Abstract/Free Full Text]
  • Committee on drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.[Abstract/Free Full Text]
  • Gardner DK, Gabbe SG, Harter C. Simultaneous concentrations of ciprofloxacin in breast milk and in serum in mother and breast-fed infant. Clin Pharm 1992;11:352–4.[Medline]
  • Lumbiganon P, Pengsaa K, Sookpranee T. Ciprofloxacin in neonates and its possible effect on the teeth. Pediatr Infect Dis J 1991;10:619–20.[CrossRef][Medline]
  • Snider DE Jr, Powell KE. Should women taking antituberculous drugs breastfeed? Arch Intern Med 1984;144:589–90.[Abstract/Free Full Text]
  • Berlin CM Jr, Lee C. Isoniazid and acetylisoniazid disposition in human milk, saliva and plasma. Fed Proc 1979;38:426.
  • Spencer JP, Gonzalez LS 3rd, Barnhart DJ. edications in the breast-feeding mother. Am Fam Physician 2001;64:119–26.[Medline]
  • Miller GE, Peters RD, Engebretsen RV. Passage of pentobarbital and phenobarbital into bovine and caprine Chin KG, Mactal-Haaf C, McPherson CE. Use of anti-infective agents during lactation: part 1—beta-lactam antibiotics, vancomycin, quinupristin-dalfopristin, and linezolid. J Hum Lact 2000;16:351–8.[Abstract]
  • Thomas M, Jairaj P, Mathew LG. A prospective study in a southern Indian hospital on the prescription of medication during the lying in period following childbirth. Soz Praventivmed 1994;39:273–9.[Medline]
  • Olesen C, Steffensen FH, Nielsen GL, et al. Drug use in first pregnancy and lactation: a population based survey among Danish women. The EUROMAP group. Eur J Clin Pharmacol 1999;55:139–44.[CrossRef][Medline]
  • Uppal R, Karmakar S, Singh MM, et al. Prescription drug use in lactating mothers: an experience at a referral hospital and in a community in India. Int J Clin Pharmacol Ther Toxicol 1993;31:93–5.[Medline]
  • Hoppu K, Kettunen K, Remes R. Maternal drug treatment and human milk banking. Int J Clin Pharmacol Ther 1994;32:488–90.[Medline]
  • milk after systemic administration. J Dairy Sci 1967;50:7692.
  • Taddio A, Ito S. Drug use and lactation. In: Koren G, eds. Maternal-foetal toxicology. 2nd Ed. New York: Dekker, 1994.
  • Wilson JT, Brown RD, Cherek DR. Drug excretion in human breast milk: principles, pharmacokinetics and projected consequences. Clin Pharmacokinet 1980;5:1.[Medline]
  • Wojnar-Horton RE, Hackett LP, Dusci LJ. Distribution and excretion of sumatriptan in human milk. Br J Pharmacol 1996;41:217.
  • Chung AM, Reed MD, Blumer JL. Antibiotics and breast-feeding: a critical review of the literature. Paediatr Drugs 2002;4:817–37.[Medline]
  • Morris FH, Brewer ED, Spedale SB. Relationship of human milk pH during course of lactation to concentrations of citrate and fatty acids. Pediatrics 1986;78:458.[Abstract/Free Full Text]

 

Supported  by
CLINIC FOR CHILDREN

Yudhasmara Foundation

JL Taman Bendungan Asahan 5 Jakarta Indonesia 102010

phone : 62(021) 70081995 – 5703646

http://childrenclinic.wordpress.com/

 

 

Clinical and Editor in Chief :

DR WIDODO JUDARWANTO

email : judarwanto@gmail.com

 

 

 

 

 

 

Information on this web site is provided for informational purposes only and is not a substitute for professional medical advice. You should not use the information on this web site for diagnosing or treating a medical or health condition. You should carefully read all product packaging. If you have or suspect you have a medical problem, promptly contact your professional healthcare provider.

Copyright © 2009, Clinic For Children Information Education Network. All rights reserved.

TRANSFER OF ANTIBIOTICS THROUGH BREAST MILK

The majority of breast milk components are similar to plasma components and theoretically all drugs have the potential of crossing over from maternal plasma into breast milk. Molecular transfer depends on the usual mechanisms governing transfer of molecules across biological membranes, namely, passive diffusion across a concentration gradient, active transport against a concentration gradient and transcellular diffusion, that is, diffusion between adjacent cells . Of these, the most important routes are passive diffusion of molecules across the endothelial wall of maternal capillaries and active transport. Transcellular diffusion is almost negligible. In order of relative importance, the factors determining the transfer of antibiotics to breast milk include physicochemical properties of antibiotic molecules, individual maternal factors, and infant variations in drug handling capability .

Mechanisms of transfer of antibiotics from maternal plasma to breast milk

  • Passive diffusion across a concentration gradient.
  • Active transport against a concentration gradient.
  • Transcellular diffusion.
Factors determining infant effects of maternal antibioticsPhysicochemical properties of antibiotic molecules:

  • State of ionisation:
    pKa of antibiotic molecule.
    – pH of maternal plasma.
    pH of breast milk.
  • Affinity for proteins:
    – Plasma proteins.
    – Milk proteins.
  • Half life.
  • Molecular weight.
  • Lipid solubility.

Individual maternal factors:

  • Interindividual variations.
  • Intraindividual variations:
    – Variation in composition of breast milk with time.
    – Variation in pH of breast milk with time.
  • Mammary blood flow.
  • Drug metabolism in breast tissue.

Infant factors:

  • Gestational age dependent capacity to handle drugs.
  • Gastrointestinal emptying time.
  • Gastro-oesophageal reflux.
  • Intestinal surface area.
  • Duration and frequency of feeding.
  • Unpredictable idiosyncratic reactions.
(A) Physicochemical properties of antibiotic molecules

Antibiotics can move across biological membranes only in the unionised state; this movement depends on pKa of the molecule, pH of plasma, and pH of breast milk. As for all similar systems, this is governed by the Henderson-Hasselbach equation: pH = pKa + log (base/acid). Since the pH of breast milk is lower than plasma (7.2 compared with 7.4 of plasma),8 weakly acidic drug molecules like sulphonamides and penicillins accumulate in higher concentration in plasma,9 whereas weakly basic drugs such as erythromycin, lincomycin, and metronidazole tend to concentrate in milk. Thus the degree of ionisation of a drug determines to a large extent its propensity for being in plasma or breast milk.

Protein binding of antibiotic molecules is the second most important factor determining transfer to milk. Transfer is greatest in the presence of low maternal plasma protein binding. Some drugs may be poorly bound to plasma proteins but get bound to breast milk proteins, which are qualitatively different from plasma proteins. Hence, although such antibiotics reach the infant, they are of little consequence.10–12 The half life of antibiotics also determines the concentration in plasma; those with longer half life are more likely to accumulate and be transferred than rapidly cleared molecules. The molecular weight of the drug molecule and lipid solubility are relatively minor contributory factors to the overall process of drug transfer.13

It is theoretically possible to calculate the amount of drug that will be transferred from maternal plasma to breast milk; this is conventionally expressed as a ratio of concentration in milk to concentration in plasma (M/P ratio). The M/P ratio has been calculated for several of the commonly used drugs; in general, a lower M/P ratio implies a lesser amount in milk compared with drugs with a higher ratio.However, the M/P ratio often does not accurately correlate with the actual amount of a drug in milk. Its value is improved if calculated from the area under the concentration-time curve of the drug in milk and plasma. The dose of drug received by the suckling infant is then calculated from maternal plasma concentration, area under the curve M/P ratio, and the volume of milk ingested. The infant dose can then be expressed as a percentage of the maternal dose. Conventionally, a cut off of 10% has been used as a rough indicator to guide the prescription of a drug during lactation.

(B) Maternal factors

As mentioned above, the composition of breast milk and its pH influence the amount of drug transfer from plasma. There is remarkable interindividual variation in breast milk that can cause different mothers receiving the same dose of antibiotic to transfer different amounts to their babies. In addition, there is also significant intraindividual variation with time, especially in pH. Milk tends to become more acidic with maturity; colostrum may have a pH of around 7.4 whereas transitional milk about 7.05. Likewise, milk from mothers of preterm babies has higher protein content. Milk expressed from the breast later during suckling (hind milk) has a higher pH and fat content and may concentrate fat soluble drugs. It has also been speculated that increased mammary blood flow could result in delivery of a higher quantity of drug into milk, but its significance has not been established. Breast tissue has the capability to metabolise some drugs, for example sulphonamides, which may alter the exposure to the suckling infant depending on whether or not the metabolites are active.

(C) Infant factors

Infants vary in their drug handing capability due to variations in absorption, distribution, metabolism, and elimination of biochemical molecules. Gestational age is probably the most important factor that determines this and premature babies are significantly limited in this regard. This is primarily due to immature renal and hepatic clearance systems. Babies reach adult metabolic capacity only towards the latter part of infancy. Likewise, enzyme mediated metabolic processes such as oxidation, glucuronidation, etc are also incompletely developed in neonates. Other factors that alter absorption include gastrointestinal emptying time, degree of gastro-oesophageal reflux, and relatively smaller intestinal surface area. For these reasons, term babies and “post-conceptionally term” babies behave entirely differently.

Lastly, it must be remembered that side effects and adverse reactions of drugs are not always dose related. There are often non-predictable idiosyncratic reactions, whereby two babies receiving the same amount of drug behave differently.

 

Supported  by
CLINIC FOR CHILDREN

Yudhasmara Foundation

JL Taman Bendungan Asahan 5 Jakarta Indonesia 102010

phone : 62(021) 70081995 – 5703646

http://childrenclinic.wordpress.com/

 

 

Clinical and Editor in Chief :

DR WIDODO JUDARWANTO

email : judarwanto@gmail.com

 

 

 

 

 

 

Information on this web site is provided for informational purposes only and is not a substitute for professional medical advice. You should not use the information on this web site for diagnosing or treating a medical or health condition. You should carefully read all product packaging. If you have or suspect you have a medical problem, promptly contact your professional healthcare provider.

Copyright © 2009, Clinic For Children Information Education Network. All rights reserved.

CLINICAL SIGNIFICANCE OF MATERNALLY TRANSFERRED ANTIBIOTICS

In general, all antibiotics can cause three potential problems for nursing infants. Firstly, they can modify the bowel flora and alter gut defence mechanisms; this can result in diarrhoea and malabsorption of nutrients. Secondly, they may have direct effects that may or may not be dose related. Lastly, and often ignored, is that antibiotics can alter and interfere with microbiological culture resulting in babies being investigated for sepsis. Based on these principles, antibiotics can be categorised under three headings: (1) those that are safe for administration to lactating mothers, (2) those whose effects in breast feeding infants are not known and should be used with caution, and (3) those that are not recommended for breast feeding mothers (box 3Go).

 

Antibacterial antibiotics and breast feeding

  1. Safe for administration:
    – Aminoglycosides.
    – Amoxycillin.
    Amoxycillin-clavulanate.
    – Antitubercular drugs.
    Cephalosporins.
    – Macrolides.
    – Trimethoprim-sulphamethoxazole.
  2. Effects not known/to be used with caution:
    – Chloramphenicol.
    Clindamycin.
    – Dapsone.
    – Mandelic acid.
    Metronidazole (low dose).
    – Nalidixic acid.
    Nitrofurantoin.
    – Penicillins.
    – Tetracyclines.
  3. Not recommended:
    – Metronidazole (single high dose).
    Quinolones.

 

 

As a general rule, drugs of the same class are expected to behave similarly in infants, though safety of one agent may not always imply the same for other members of the class. It must be emphasised that side effects of maternal medication are often not reported; hence lack of information does not imply safety to the suckling baby. On the other hand, the occurrence of side effects in isolated reports may not necessarily warrant discontinuation of breast feeding or altering the maternal antibiotic prescription. Various academic bodies have tried to compile information about the likely risks to infants; such information may guide decisions about antibiotic use.

Among the antibacterial antibiotics, cephalosporins seem to be the safest class. This generalisation seems to hold for all generations and is irrespective of the route of administration. Although third generation cephalosporins have a greater potential to alter bowel flora and individual agents vary with respect to M/P ratio, as a group they are regarded safe. Similarly, macrolides are also “safe” antibiotics, though they can alter infants’ bowel flora adversely.

For entirely different reasons, another relatively safe class of drugs is the aminoglycoside group. This is because although they are transferred to breast milk, they have poor oral bioavailability and are not absorbed by the infant. However, there is the potential risk of some direct effects as evidenced by a case report of bloody diarrhoea in an infant whose mother was receiving gentamicin and clindamicin.19 Both the drugs were found in significant levels in breast milk and diarrhoea subsided when breast feeding was temporarily ceased.

Sulphonamides are excreted into breast milk, but this does not pose a risk for healthy term infants. However, it is recommended that they should be avoided in ill, stressed, or preterm babies as well as infants with hyperbilirubinemia or glucose-6-phosphate deficiency (G6PD) deficiency. Barring these exceptions, the American Academy of Pediatrics considers sulphonamides compatible for use while breast feeding.20 The combination with trimethoprim is also safe.

Although penicillins seem to be commonly prescribed to lactating mothers,there is no hard evidence concerning their safety during breast feeding. They have the potential to alter infant bowel microflora and produce diarrhoea. However, the American Academy of Pediatrics considers them compatible for use during breast feeding.

In contrast, the use of quinolones is not recommended in breast feeding mothers because of the putative risk of arthropathy noted in animal studies. In addition, phototoxicity has been observed with some quinolones on exposure to ultraviolet light or excessive sunlight. There is only a single report of ciprofloxacin administered by a breast feeding mother and it resulted in no adverse effects to the baby. However, the manufacturer recommends that 48 hours be allowed to elapse after the last dose of ciprofloxacin before breast feeding is resumed. There is an unusual incident of greenish staining of teeth reported in two neonates treated with ciprofloxacin whose cause could not be located. The clinical significance of this, if any, in lactating mothers is unclear.  Tetracyclines must be avoided during lactation due to possible risks of dental staining and adverse effects on bone development. Metronidazole in a single, high dose is not advised for lactating women, though conventional doses may be used with caution.

A group of drugs that may be of importance, particularly in developing countries, are those used for antitubercular therapy. Unfortunately, not much is known about many of these drugs, though the American Academy of Pediatrics categorises them as compatible with breast feeding. However, isoniazid has the potential for interference with nucleic acid metabolism and can cause hepatotoxicity in the infant. Hence, in mothers taking isoniazid, it is suggested that infants be regularly examined for peripheral neuritis and hepatotoxicity. Streptomycin does not carry the risk of ototoxicity in suckling babies because it is poorly absorbed from the gut. There are few data available on ethambutol, rifampicin and pyrazinamide, but their use is regarded as compatible with breast feeding.

Among the antiviral antibiotics, acyclovir is transferred in significant amounts to breast milk, but its poor absorption through the oral route makes it compatible with breast feeding. Since acyclovir is the active metabolite of valacyclovir, the latter also is regarded safe, although no human studies are available. The current recommendation of the Centers for Disease Control and Prevention restricts HIV infected women in developed countries from breast feeding; hence there is no information on the infant effects of maternal antiretroviral antibiotics. Likewise, there is no information available with regard to ganciclovir. Although famciclovir and foscarnet are detectable in significant amounts in breast milk, there are no data on the effects in sucking infants.

Amphotericin B is an antifungal agent that has been well studied in infants, however the effects on maternally transferred drug are not known. Similarly, fluconazole is transferred to milk, but effects on babies are not documented. Flucytosine, itraconazole, ketoconazole, and terbinafine are other antifungal antibiotics that are transferred in varying amounts to breast milk, but their potential effects on nursing infants are unknown.

Among the antimalarials, chloroquine, hydroxychloroquine, and quinine are found in variable quantities in breast milk, but all three are regarded as compatible with breast feeding. However, quinine is advised to be withheld in mothers with G6PD deficient infants. Insufficient information is currently available to make specific recommendations about the use of pentamidine, proguanil, primaquine, and mefloquine. Pyrimethamine can result in serious side effects such as bone marrow suppression; however it is regarded as compatible with breast feeding.

The usual antihelminthic drugs include mebendazole, pyrantel pamoate, praziquantel, thiabendazole, and piperazine. No information is available on the infant effects of these drugs in lactating mothers; however, mebendazole has been shown to decrease milk output in some women.

Other antibiotics and breast feeding
  1. Antiviral
    • Compatible with breast feeding:
      – Acyclovir.
      – Amantadine.
      Valacyclovir.
    • Effects during breast feeding are not known:
      Antiretrovirals.
      – Famciclovir.
      – Foscarnet.
      Ganciclovir.
  2. Antifungal
    • Compatible with breast feeding:
      Ketoconazole.
    • Effects during breast feeding are not known:
      Amphotericin.
      – Fluconazole.
      – Flucytosine.
      Itraconazole.
  3. Antimalarial
    • Compatible with breast feeding:
      Chloroquine.
      – Hydroxychloroquine.
      – Quinine.
    • Effects during breast feeding are not known:
      – Mefloquine.
      Pentamidine.
      – Proguanil.
      – Primaquine.
      Pyrimethamine.
  4. Antihelminthic
    • Effects during breast feeding are not known:
      – Mebendazole.
      – Pyrantel pamoate.
      Praziquantel.
      – Quinacrine antihelminth.
      – Thiabendazole.
      Piperazine.

 

 

Supported  by
CLINIC FOR CHILDREN

Yudhasmara Foundation

JL Taman Bendungan Asahan 5 Jakarta Indonesia 102010

phone : 62(021) 70081995 – 5703646

http://childrenclinic.wordpress.com/

 

 Clinical and Editor in Chief :

DR WIDODO JUDARWANTO

email : judarwanto@gmail.com

 

  

  1.  

     

     

    Information on this web site is provided for informational purposes only and is not a substitute for professional medical advice. You should not use the information on this web site for diagnosing or treating a medical or health condition. You should carefully read all product packaging. If you have or suspect you have a medical problem, promptly contact your professional healthcare provider.

    Copyright © 2009, Clinic For Children Information Education Network. All rights reserved.