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Use of Anti-Infective Agents During Lactation: Part 2Aminoglycosides, Macrolides, Quinolones,

Sulfonamides, Trimethoprim, Tetracyclines, Chloramphenicol, Clindamycin, and Metronidazole
Karen G. Chin, Charles E. McPherson III, Maria Hoffman, Ann Kuchta and Christina Mactal-Haaf
J Hum Lact 2001 17: 54
DOI: 10.1177/089033440101700111

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Chin et al.J Hum
J Hum LactLact 17(1),
17(1), 2001
2001Anti-Infective Agents

The Galactopharmacopedia

Use of Anti-Infective Agents During Lactation: Part 2Aminoglycosides,

Macrolides, Quinolones, Sulfonamides, Trimethoprim, Tetracyclines,
Chloramphenicol, Clindamycin, and Metronidazole
Karen G. Chin, PharmD, BCPS, Charles E. McPherson III, PharmD, Maria Hoffman, PharmD,
Ann Kuchta, PharmD, and Christina Mactal-Haaf, PharmD, BCPS

Abstract
Because many antibiotics are excreted into breast milk, it can be difficult for a practitioner to
choose an antibiotic for a lactating patient that will have minimal risks to her nursing infant.
This article is the second of a three-part series discussing the use of anti-infective agents dur-
ing lactation. The authors review general information regarding use and common side effects
for several classes of antibiotics. They also summarize information, including documented
milk concentrations, milk-to-plasma ratios, and other pharmacokinetic properties, in a table
that can help practitioners choose antibiotics that may be considered safe to use in the lactating
mother. J Hum Lact 2001;17(1):54-65.
Keywords: lactation, breastfeeding, human milk, anti-infectives

This article is the second of a three-part series discuss- being treated. We have previously discussed some
ing the use of anti-infective agents during lactation. We physiologic and chemical factors that may affect the
1
have reviewed general information regarding usage and excretion of medications into breast milk.
common side effects for several classes of antibiotics.
We have also summarized information, including docu- Aminoglycosides
mented milk concentrations, milk-to-plasma ratios, and
Aminoglycosides are antibiotics used to treat infec-
other pharmacokinetic properties, in a table that can
tions caused by aerobic gram-negative bacteria, such as
help practitioners choose antibiotics that may be con-
Escherichia coli, Klebsiella oxytoca, and Pseudomonas
sidered safe to use in the lactating mother (Table 1). 2
aeruginosa; staphylococci; and certain mycobacteria.
Please note that the table includes varying drug concen-
Aminoglycosides are commonly used to treat a variety
trations measured in breast milk based on the dose 3
of infections in infants and children. Drugs within this
administered, achievement of steady state, and the time
class include amikacin, gentamicin, kanamycin,
of sampling. Also note that the potential infant dosages
neomycin, netilmicin, streptomycin, and tobramycin.
listed may vary widely based on the age and weight of
These antibiotics have a polar structure, resulting in
the infant and on the site and severity of the infection
negligible penetration across biological membranes and
2
poor oral absorption. Therefore, therapeutic serum lev-
Karen G. Chin, Charles E. McPherson III, Maria Hoffman, Ann
Kuchta, and Christina Mactal-Haaf are clinical assistant professors at the els of aminoglycosides are achieved with parenteral
2
University of Illinois at Chicago College of Pharmacy and pharmacothera- administration. Aminoglycosides are usually given in
pists in internal medicine at the University of Illinois at Chicago Hospital. combination with other antibiotics such as beta-lactams
Address correspondence to Karen Chin, PharmD, BCPS, University of Illi- 2
nois at Chicago, Department of Pharmacy Practice, M/C 886, 833 S. Wood
to treat bacterial infections. Because of poor oral
Street, Room 164, Chicago, IL 60612, USA. absorption, some aminoglycosides are used for their
J Hum Lact 17(1), 2001 local effects on the gastrointestinal tract. For example,
Copyright 2001 International Lactation Consultant Association kanamycin and neomycin are used in preoperative aero-

54

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J Hum Lact 17(1), 2001 Anti-Infective Agents 55

2
bic gut sterilization. Tobramycin administered by inha- Helicobacter pylori, an organism associated with peptic
7
lation is used in patients with cystic fibrosis to improve ulcer disease. Roxithromycin displays no clear clinical
2 8
pulmonary function. Systemic bioavailability of advantage over erythromycin. Troleandomycin, an
inhaled tobramycin is low, with peak serum concentra- older agent, is marketed under an orphan drug status for
9
tions of 0.95 to 1.05 mg/mL reported 1 hour after treatment of severe steroid-requiring asthma.
4
tobramycin inhalation. Clarithromycin, azithromycin, and roxithromycin
Gentamicin, tobramycin, and neomycin are also have increased stability in gastric acid and consequently
10,11
available in ophthalmic dosage forms. Systemic side better absorption. Therefore, the nursing infant may
effects have not been reported with ophthalmic be able to absorb a larger percentage of these drugs.
5
fixed-dose tobramycin-diclofenac use or with ocular Most adverse reactions with the macrolides,
6
gentamicin topical administration. Neomycin is not erythromycin in particular, involve the gastrointestinal
commercially available for parenteral administration. tract, including nausea, vomiting, and diarrhea. Fewer
The drug is administered orally as a solution or in tablets side effects of this nature are reported with clarithro-
or topically as a retention enema. mycin and azithromycin. Both drugs are extensively
Significant adverse effects associated with therapeu- distributed in body tissues with tissue concentration
tic aminoglycoside levels include nephrotoxicity, greatly exceeding plasma levels. Azithromycin concen-
2 12
ototoxicity, and rarely, neuromuscular block. Systemic trates in tissues, particularly white blood cells, to such
adverse reactions, which are similar to those reported in an extent that a 5-day regimen can be given with efficacy
3 7
adults treated with therapeutic aminoglycoside doses, equal to that of a 7- to 10-day course of erythromycin.
are unexpected in the nursing infant due to the fact that Since the plasma concentration of azithromycin
12
aminoglycosides are secreted in breast milk in low con- declines rapidly over time after the last dose, the
centrations and generally have poor oral absorption. amount of drug a nursing infant is exposed to should be
negligible. The nursing infant early in life can be
Macrolides hypochlorhydric, which may result in increased absorp-
1
The macrolides have been widely used for infections tion of weak bases such as macrolides.
since the prototype erythromycin was introduced in Pyloric stenosis has been reported in infants treated
13,14
1952. Erythromycin is the drug of choice for with erythromycin, and there is one case report of its
15
Mycoplasma pneumoniae infections, caused by occurrence in a nursing infant. Topical erythromycin is
16
Legionella pneumoniae, Bordetella pertussis, and Chla- generally regarded as safe. However, gastrointestinal
mydia trachomatis. Other indications include pneumo- motility was increased in neonates receiving
nia caused by penicillin-sensitive streptococci includ- erythromycin ophthalmic ointment as prophylaxis
ing Streptococcus pneumoniae and Staphylococcus against chlamydial eye infections, indicating some
17
aureus. It is also useful against certain gram-negative amount of systemic absorption.
bacteria such as Neisseria meningitidis and gonor- Erythromycin and, to a lesser extent, clarithro-
18
rhoea, Bordetella pertussis, Campylobacter jejuni, and mycin can inhibit the cytochrome-P450 metabolism of
Moraxella catarrhalis. However, its activity against multiple drugs, leading to potential toxicity in the nurs-
Hemophilus influenzae is unreliable. It is a safer alterna- ing infant who may be receiving one of the interacting
tive to tetracycline for pregnant patients with drugs. Among those of possible significance in the
8 7
chlamydial pelvic infections and also an alternative to infant population are theophylline and caffeine, which
7
penicillin G in patients allergic to the latter. are used for neonatal apnea and other respiratory condi-
While erythromycin is safe and effective, the newer, tions. Digoxin concentrations may increase due to an
semisynthetic derivatives have the advantages of better inhibition of the digoxin-metabolizing bacteria in the
8
side-effect profiles, increased spectrum of activity, and large bowel. In these instances, close monitoring of
7
decreased risk for drug interactions. Clarithromycin signs and symptoms of toxicity as well as infant plasma
and azithromycin have increased activity against levels would be prudent. Human studies have shown no
7
Hemophilus influenzae and are effective in the treat- major drug interactions with azithromycin.
ment and prophylaxis of Mycobacterium avium- The individual physical properties of each agent
intracellulare. Clarithromycin is also used as part of a must be taken into account when prescribing for the
number of combination regimens in the eradication of nursing mother. Increased protein binding (clarithro-

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56 Chin et al. J Hum Lact 17(1), 2001

mycin) and decreased oral absorption (dirithromycin, absorption (Alcon, Merck, and Allergan, personal com-
azithromycin) would decrease the risk of absorption by munications, September 2000).
the nursing infant. The molecular weights as well as the The use of fluoroquinolones in children has been lim-
basic pH of most macrolides would favor passage into ited because of the potential to induce arthropathy in
breast milk (Table 1). However, in view of the low esti- juvenile animals, which has resulted in a moratorium
22
mated potential daily dose relative to the therapeutic against their use in children. Therefore, the use of
dose and benign side-effect profiles, maternal ingestion fluoroquinolones is contraindicated in children, grow-
22
of therapeutic doses of macrolides should not pose a ing adolescents, and pregnant and lactating women.
serious risk to most nursing infants. Nevertheless, fairly extensive compassionate use of
ciprofloxacin and other fluoroquinolones (norfloxacin
Quinolones and pefloxacin) have shown that prolonged use is well
tolerated in pediatric patients and that there has been no
The quinolones (nalidixic acid and cinoxacin) are 23
significant evidence of chondrotoxicity in this group.
effective only for the genitourinary and gastrointestinal
During the past 10 years, fluoroquinolones have been
tracts and have activity primarily against aerobic gram-
19 used in pediatric patients in circumstances where they
negative bacteria. The newer quinolones or the fluoro-
were the only antibacterial agents active in infections
quinolones (ciprofloxacin, enoxacin, fleroxacin,
caused by multiresistant organisms. These included
gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin,
children with cystic fibrosis, complicated urinary tract
norfloxacin, ofloxacin, pefloxacin, sparfloxacin, and
infections, enteric infections (in developing countries),
trovafloxacin) have wider potential applications and a 22
19 and chronic ear infections.
broader spectrum of activity. The fluoroquinolones
are active against aerobic gram-positive cocci, gram-
Sulfonamides and Trimethoprim
negative bacilli, H. influenzae, M. catarrhalis, Legion-
20
ella species, M. pneumoniae, and C. pneumoniae. Sulfonamides are a class of antibiotics that are used
Ofloxacin, levofloxacin, sparfloxacin, and trova- primarily for the treatment of infections caused by
floxacin show enhanced activity against S. pneumoniae gram-positive and gram-negative aerobic bacteria.
20
(including penicillin-resistant strains). Ciprofloxacin These agents are commercially available in many differ-
remains the most potent agent against P. aeruginosa but ent dosage forms, including topical, ophthalmic, oral,
19
is not active against S. aureus and S. pneumoniae. and parenteral formulations. Major side effects associ-
20
Trovafloxacin is the most active against anaerobes. ated with sulfonamide use include gastrointestinal
The fluoroquinolones (except norfloxacin) penetrate intolerance, hypersensitivity, rash, bone marrow sup-
24
most tissues well, especially bronchial mucosa, lung, pression, and megaloblastic anemia.
19
gallbladder, kidney, prostate, genital tract, and bone. Controversy surrounds the use of sulfonamides dur-
The fluoroquinolones are generally well tolerated, ing the neonatal period. In general, most of these drugs
with gastrointestinal upset occurring in approximately are highly bound to serum albumin. The affinity of sul-
19
5% of patients. Other adverse effects are allergic reac- fonamides for albumin varies greatly; some are more
tions and photosensitivity, particularly with lome- tightly bound than others. Consequently, these drugs
19
floxacin and sparfloxacin. Trovafloxacin has recently compete for albumin binding sites with bilirubin, in
25
been found to be associated with rare but fatal cases of addition to displacing bilirubin. Increased free, circu-
19
liver toxicity. Sparfloxacin prolongs the QT interval in lating bilirubin in the neonate can readily cross the
the electrocardiogram in approximately 3% of patients, blood-brain barrier and potentially deposit in the brain,
and there have been rare cases of cardiac arrhythmias resulting in a condition known as kernicterus.26 For this
19
(i.e., Torsades de pointe). reason, systemic use of these drugs is avoided in prema-
The fluoroquinolones possess good oral bioavailability ture infants and newborns younger than 2 months of
(except norfloxacin), low protein binding, and good tis- age. Also, there is a risk of hemolytic anemia in infants
sue penetration (except norfloxacin), which enhances who are glucose-6-phosphate-dehydrogenase
21 27
the likelihood of their passage into breast milk. The (G-6-PD) deficient.
topical formulations of ciprofloxacin, norfloxacin, and Knowing the pharmacokinetic properties of sulfona-
ofloxacin have been shown to have minimal systemic mides can assist in making rational decisions about the

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J Hum Lact 17(1), 2001 Anti-Infective Agents 57

use of these agents in nursing mothers. These agents are, Because of the pharmacokinetic properties of sul-
for the most part, lipophilic and passively diffuse across fonamides, little drug actually passes into breast milk.
biologic membranes and, therefore, into breast milk. Thus, adverse effects associated with their use in the
Sulfisoxazole, however, is one of the most water soluble nursing infant have been minimal (Table 1). There is a
of the sulfonamides and does not cross into breast milk case report of bloody diarrhea in an infant whose mother
25 30
readily. The degree of protein binding also affects the was receiving therapeutic doses of sulfasalazine. In
amount of drug that can transfer into breast milk, as only general, maternal sulfonamide use is considered safe
unbound or free drug will cross. Extensive protein bind- while breastfeeding healthy newborns. However, cau-
ing of sulfonamides limits the amount of free drug that tion should be used in critically ill, preterm, G-6-PD
31
can cross into breast milk, which explains why sulfona- deficient, or hyperbilirubinemic neonates.
mides are excreted in breast milk in low concentrations Trimethoprim is an oral or parenteral antibiotic that is
(Table 1). oftentimes used in combination with sulfonamides,
Oral absorption of sulfonamides in the infant is such as sulfamethoxazole. Although trimethoprim
another property that must be assessed when determin- passes into breast milk in low concentrations, no
31
ing whether or not these drugs should be used in a nurs- adverse effects have been reported with its use. The
ing mother. These agents are readily absorbed from the American Academy of Pediatrics considers trimetho-
28
small intestine. Only sulfasalazine is poorly absorbed, prim, in combination with sulfamethoxazole, to be com-
with only 10% to 15% of a dose reaching the plasma as patible with breastfeeding.32 Therapeutic concentrations
28
unchanged drug. Protein binding of sulfonamides is of trimethoprim, however, have been associated with
28 4
variable, ranging from 32% to 90%. However, it is the megaloblastic anemia and bone marrow suppression.
ability of these agents to displace bilirubin from serum
proteins that is of greatest concern. While all sulfona- Tetracyclines
mides displace bilirubin from albumin-binding sites, The class of antibiotics known as the tetracyclines
26
they do so to varying degrees. Sulfasalazine has the has been in clinical use since the 1940s. Although they
greatest bilirubin-displacing ability. However, since this have activity against a variety of gram-positive and
drug is poorly absorbed from the gastrointestinal tract, gram-negative bacteria, tetracyclines are commonly
low maternal blood concentrations are achieved with used to treat infections caused by atypical organisms,
standard adult doses. The resultant concentration in such as mycoplasma and rickettsia, and sexually trans-
breast milk is not high enough to cause bilirubin dis- mitted diseases, including chlamydia and syphilis.
33
26
placement upon ingestion by the nursing newborn. There are currently six agents that are commercially
Furthermore, sulfapyridine, the active metabolite of available, and each is classified according to its duration
26
sulfasalazine, has minimal displacing ability. of action. Tetracycline and oxytetracycline are
Sulfisoxazole (sulphafurazole) can also markedly dis- short-acting, methacycline and demeclocycline are
place bilirubin from albumin.26 Bilirubin displacement intermediate-acting, and doxycycline and minocycline
does not usually occur when infant sulfisoxazole serum are long-acting agents.
25
drug concentrations are less than 50 mcg/mL. This is Common side effects associated with the use of
greater than the predicted serum sulfizoxazole concen- tetracyclines include gastrointestinal intolerance,
trations in nursing infants absorbing sulfisoxazole-con- photosensitivity, dental staining, hepato-toxicity and
taining breast milk.25 Of all the sulfonamides, however, 34
nephro-toxicity. One important fact about
sulfadiazine and sulphanilamide are least likely to dis- tetracyclines is that they have an increased affinity for
26
place bilirubin. Although specific human data regard- divalent cations, such as calcium. For this reason, these
ing sulfamethoxazole and breastfeeding are limited, agents should not be used within 2 hours of administra-
therapeutic concentrations of sulfamethoxazole and tion of dairy products, antacids, or iron products
trimethoprim (co-trimoxazole) in neonates do not because decreased oral absorption of the antibiotic may
appear to displace bilirubin from albumin-binding 4
occur. Tetracyclines are contraindicated for use during
29
sites. There are no published accounts of adverse pregnancy and in children younger than 8 years of age,
effects in the nursing infant associated with maternal as they have been associated with reduced bone growth
use of topical or ophthalmic sulfonamide preparations. 27
and permanent tooth discoloration. Generally speak-

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58 Chin et al. J Hum Lact 17(1), 2001

ing, because these drugs bind to calcium in maternal published reports of breastfeeding mothers who have
breast milk, there is little concern for oral absorption in received ophthalmic chloramphenicol; thus, the effect
31
the nursing infant. Doxycycline and minocycline, of these preparations on the nursing infant is unclear.
however, have a decreased affinity for calcium com- Gray baby syndrome, which primarily affects neo-
pared to the older tetracyclines and, therefore, have an nates, has also been associated with the therapeutic use
21
increased likelihood for oral absorption. Though they of chloramphenicol in infants. Symptoms include
are not contraindicated for use during breastfeeding, tet- abdominal distention, vomiting, cyanosis, irregular res-
racycline use generally is not recommended, as there piration, flaccidity, and circulatory collapse. Gray baby
exist other classes of antibiotics with similar spectrums syndrome is dose related, generally occurs with serum
of activity that have a better safety profile. chloramphenicol levels higher than 50 mcg/ml, and is
35
potentially fatal.
Miscellaneous Chloramphenicol may also reduce vitamin K synthe-
sis, leading to coagulation disorders. It may also inhibit
Chloramphenicol the metabolism of some drugs that are metabolized via
Chloramphenicol possesses a broad spectrum of the cytochrome P-450 system such as phenytoin and
activity against most aerobic and anaerobic bacteria. It warfarin. In addition, drugs that induce the cytochrome
also possesses activity against rickettsia, chlamydia, P-450 system, such as phenobarbital, phenytoin, and
35
mycoplasma, and spirochetes. Chloramphenicol is rifampin, may decrease serum chloramphenicol con-
available in several formulations, including oral cap- centrations. Chloramphenicol should not be used in
sules, an oral suspension, a parenteral preparation, and combination with clindamycin since these agents com-
topical agents for ophthalmic and otic use. Both the oral petitively inhibit each other.35
suspension and the parenteral preparation require While the drug is not contraindicated in breastfeed-
hydrolysis in order to be activated. Malnourished chil- ing, the American Academy of Pediatrics suggests cau-
dren and neonates may be unable to hydrolyze the drug tion when prescribing chloramphenicol to breastfeed-
32
and thus be unable to achieve therapeutic serum ing mothers. Based on the drugs potential to cause
35
chloramphenicol concentrations. Unlike the systemic potentially life-threatening side effects as well as its
formulations, ophthalmic preparations of chloram- ability to cross into breast milk, anti-infective therapy
phenicol do not provide measurable systemic drug con- with systemic chloramphenicol should be reserved for
36,37
centrations. Chloramphenicol is highly lipid soluble patients with severe infections or those who cannot tol-
and distributes well in most body fluids, including the erate or have failed therapy with other anti-infective
35
central nervous system and breast milk (Table 1). agents. Recommendations for the use of topical
Despite its broad spectrum of activity, the therapeutic chloramphenicol are less clear however, as previously
use of chloramphenicol has fallen out of favor due to its mentioned; the practitioner may choose to avoid its use
side-effect profile. Chloramphenicol has been associ- in lactating mothers with risk factors for blood
ated with a 13-fold increase in the risk of aplastic ane- dyscrasias.
mia that is generally fatal and does not appear to be dose
35
related. Bone marrow suppression (anemia, Clindamycin
leukopenia, and/or thrombocytopenia), optic neuritis, Clindamycin is active against most anaerobic organ-
peripheral neuropathy, headache, confusion, and gas- isms as well as most gram-positive aerobic organisms
35
trointestinal complaints may also occur. Despite the with the exceptions of Enterococcus and methicillin-
observation that ophthalmic preparations do not achieve resistant S. Aureus. It has negligible activity against
35
measurable systemic drug concentrations, reports exist gram-negative aerobic organisms. Clindamycin also
of bone marrow suppression following the use of oph- possesses some antiparasitic activity and has been used
36,37
thalmic preparations. Because of these reports, it is in conjunction with other agents for the prophylaxis and
38
reasonable to use caution when prescribing topical treatment of toxoplasmosis and pneumocystis carinii.
chloramphenicol products to patients with other predis- Topical preparations of clindamycin are often used in
posing factors for blood dyscrasias (i.e., personal or the treatment of dermatologic disorders such as acne
family history of blood dyscrasias, concomitant use of vulgaris and rosacea. Intravaginal clindamycin is used
35
other marrow-suppressive medications). There are no for the treatment of bacterial vaginosis. Clindamycin

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J Hum Lact 17(1), 2001 Anti-Infective Agents 59

has rapid and near complete absorption following oral It has also been associated with the disulfiram reaction
35
administration. In contrast, 1.7% to 7.5% of the dose when taken concomitantly with alcohol. This reaction
of topical clindamycin may be systemically absorbed may be of concern if the nursing infant is prescribed
39,40
depending on the vehicle used. An average of 4% medications that are solubilized with alcohol (i.e., phe-
(range 2.7-4.7%) of a 100-mg dose is systemically nobarbital, theophylline elixir). Other severe though
absorbed following the administration of clindamycin less common side effects include seizures, cerebellar
41 35
intravaginal cream. Clindamycin should not be used in dysfunction, and peripheral neuropathy. Since
combination with macrolide antibiotics or chloram- high-dose metronidazole has been associated with
phenicol because these agents competitively inhibit tumorigenic effects in mice and rats, concerns exist for
35 35
each other. its carcinogenic and mutagenic potential in humans.
Common side effects of clindamycin include nausea, Thus far, there is no documented evidence that
vomiting, flatulence, and diarrhea. The incidence of metronidazole possesses carcinogenic effects in
clindamycin-induced C. difficile colitis with associated humans. Metronidazole may also inhibit the metabo-
35
diarrhea has been reported from 0.01% to 10%. While lism of certain drugs metabolized via the cytochrome
35
C. difficile colitis is often mild and self-limiting, it can P-450 pathway, such as warfarin. However, these
be a potentially life-threatening reaction. Other reac- drugs are generally not administered in the neonatal and
tions can include increased liver function tests and infancy periods.
35
hypersensitivity reactions. Though rare, reports of Based on the concerns for carcinogenic potential in
42
diarrhea following use of topical clindamycin exist. humans, the American Academy of Pediatrics suggests
There are no published reports regarding the use of topi- caution regarding the therapeutic use of systemic
cal clindamycin in breastfeeding mothers; thus, the metronidazole in lactating mothers, including the tem-
32
effect of the drug on the nursing infant is unclear. porary cessation of breastfeeding ( Table 1). There is
Although clindamycin does cross into breast milk no documented evidence to either support or oppose the
(Table 1), the American Academy of Pediatrics consid- use of topical or intravaginal metronidazole therapy in
ers clindamycin a safe anti-infective agent to use in the the nursing mother. However, as intravaginal
32
lactating mother. metronidazole does have limited systemic absorption, it
is possible for the nursing infant to ingest a small
Metronidazole amount of the drug that crosses into the breast milk.
Metronidazole is active against most gram-negative
References
anaerobic and some gram-positive anaerobic organ-
isms. It also possesses activity against H. pylori and 1. Chin KG, Mactal-Haaf C, McPherson CE III. Use of anti-infective agents
during lactation: Part 1beta-lactam antibiotics, vancomycin,
some protozoa. Most aerobic organisms are resistant to quinupristin-dalfopristin, and linezolid. J Hum Lact. 2000;16:351-358.
35
metronidazole. Topical preparations of metronidazole 2. Edson RS, Terrell CL. Symposium on antimicrobial agentsPart VIII:
can be used for the treatment of acne rosacea. the aminoglycosides. Mayo Clin Proc. 1999;74:519-528.
Intravaginal metronidazole is used for the treatment of 3. Henry NK, Hoecker JL, Rhodes KH. Antimicrobial therapy for infants
35 and children: guidelines for the inpatient and outpatient practice of pedi-
bacterial vaginosis. Metronidazole has rapid and atric infectious diseases. Mayo Clin Proc. 2000;75:86-97.
near-complete oral absorption and penetrates well into 4. Takemoto CK, Hodding JH, Kraus DM. Pediatric Dosage Handbook. 6th
35 ed. Cleveland, Ohio: Lexi-Comp; 1999.
all tissues, including the central nervous system. In
5. Salva P, Costa J, Andreu D, Notivol R, Martinez M. Tolerability and
contrast, an average of 56% of a 37.5-mg dose is sys- safety of 0.1% diclofenac plus 0.3% tobramycin fixed-dose ophthalmic
temically absorbed following intravaginal gel adminis- solution: a randomized, comparative, controlled study in healthy volun-
43
tration, whereas an average of 19% of the dose of intra- teers. Methods Find Exp Clin Pharmacol. 1999;21:203-208.
44 6. Trope GE, Lawrence JR, Hind VM, Everden A. Systemic absorption of
vaginal tablets may be absorbed. Metronidazole also topical and subconjunctival gentamicin. Br J Ophthalmol. 1979;
appears to cross readily into breast milk following sys- 63:692-693.
temic administration to the lactating mother (Table 1). 7. Alvarez-Elcoro S, Enzler MJ. Symposium on antimicrobial agentspart
Common side effects of metronidazole include nau- IX: the macrolides: erythromycin, clarithromycin and azithromycin.
Mayo Clin Proc. 1999;74:613-634.
sea, diarrhea, dry mouth, stomatitis, and metallic taste.

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 60
Table 1. Anti-Infective Agents and Their Effect on Lactation.
American
Potential Therapeutic Academy of
Milk Milk-to- Infant Infant Pediatrics
Generic Name Dosage Concentrations Plasma Dose Dose (AAP)
Antibiotic Class (brand name) Forms* (mcg/ml) Ratio (mg/kg/d) **
(mg/kg/d) Compatible

Special Considerations

General concerns for infant ingestion include potential for allergic re-
action, changes in bowel flora, and confounding of culture results by
the ingested antibiotic if a fever workup is done in the nursing
infant.
2
Aminoglycosides All aminoglycosides have negligible protein binding.
21,31
Amikacin (Amikin) P Trace Unknown Unknown 1522.5 NR Concentration during 6 h following 100- and 200-mg IM doses in 2 of
21,31
4 patients.
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Gentamicin Op, Ot, P 0.41-0.4945 0.11-0.4421,31 0.074 7.50 NR Two bloody stools were reported in a breastfed infant; the nursing
(Garamycin) mother was on clindamycin and gentamicin. Causal relationship is
unknown.46
Kanamycin (Kantrex) O, P 18.447 0.05-0.4048 2.76 1549 Y Milk concentration following a 1-g IM dose.47
Neomycin O, Op, Ot, T Unknown Unknown Unknown 50 NR
(Neo-Fradin)
Netilmicin P Unknown Unknown Unknown NR
(Netromycin)
50
Streptomycin P 0.3-0.6 0.12-1.0 21,31 0.09 10-20 Y
21,31
Tobramycin (Nebsin) I, Op, P 0.52 Unknown 0.08 7.5 NR
Macrolides
51 51
Azithromycin O, P 0.64-2.8 Unknown 0.42 15-50 (in- NR 37% oral absorption. Protein binding is concentration dependent,
11
(Zithromax) fant age > decreasing with increasing concentration (15-50%).
6 mo)
Clarithromycin O Unknown Unknown Unknown 15 (infant NR MW 748.0, 50% oral absorption.52 72% protein binding, which de-
53
(Biaxin) age > 6 creases with increasing concentration.
mo)
Dirithromycin O Unknown Unknown Unknown Efficacy and NR MW 835, 6-14% bioavailable, protein binding 15-30%.55 Excreted in
54
(Dynabac) safety not milk of lactating rodents.
established
in patients
< 12
years.54
56,57 56,57 58
Erythromycin (various) O, Op, P, T 0.4-3.2 0.51.3 0.06-0.48 15-50 Y Diarrhea and irritability have been reported in nursing infants. Py-
15
loric stenosis has been reported in one breastfed infant.
59 60 11
Roxithromycin O Unknown 0.04 0.06 5-10 NR MW 837. Protein binding is also concentration dependent (80-96%).
(Assoral) Less than 0.05% of a 300 mg dose is excreted in breast milk over
59
12 h.
 || || 9
Troleandomycin (TAO) O, P 0.38 0.5 0.057 3.5-14 NR
Quinolones
Cinoxacin (Cinobac) O Unknown Unknown Unknown Unknown NR
61 61 61
Ciprofloxacin (Cipro, O, Op, Ot, P 0.98 4.67 0.147 7-40 NR Infant serum concentration was below assay limit (< 0.03 mcg/ml),
Ciloxan, Cipro HC but infant was breastfed 8 hours after single daily dose of
Otic) ciprofloxacin.61 Mother recovering from acute renal failure and had
received a single dose of ciprofloxacin; infant not allowed to breast-
feed.62 Case report of perforated pseudomembranous colitis in a
64
breastfed infant whose mother self-administered ciprofloxacin.
1.98-3.062 1.7 (mean)62 0.4562
63 61 63
0.02-3.79 0.85-2.14 0.57
Enoxacin (Penetrex) O Unknown Unknown Unknown Unknown NR
65
Fleroxacin (Megalocin, O, P 3.5 (mean) 0.625 0.525 Unknown NR Not commercially available in the US.
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65 65
Quinodis, others) (mean) (mean)
Gatifloxacin (Tequin) O, P Unknown Unknown Unknown Unknown NR
Levofloxacin O, P (see (see (see Unknown NR Levofloxacin is the optical isomer of ofloxacin, and its passage into
(Levaquin) ofloxacin ofloxacin ofloxacin milk should be similar; the milk concentrations of ofloxacin are sim-
31
data) data) data) ilar to those in serum.
Lomefloxacin O Unknown Unknown Unknown Unknown NR
(Maxaquin)
Moxifloxacin (Avelox) O Unknown Unknown Unknown Unknown NR
21 21 21 4 67
Nalidixic Acid O 5 0.08-0.13 0.75 55 Y Single case report of hemolytic anemia in an infant. Retrospective
(Negram) review of 63 women treated with nalidixic acid during pregnancy,
and none of the infants developed congenital deformity of
intracranial hypertension.68
0.3-1.166 0.06166 0.16566
Norfloxacin (Noroxin, O, Op Unknown Unknown Unknown Unknown NR Limited data available regarding secretion into breast milk, but it has
69
Chibroxin) been suggested that it is not secreted into breast milk. Package in-
70
sert states 200-mg dose not detectable in breast milk. Widely used
71
in the pediatric patient population in Japan.
63 63 63
Ofloxacin (Floxin, O, Op, Ot, P 0.05-2.41 0.98-1.66 0.36 Unknown NR
Ocuflox, Oculfox
Otic)
63
Pefloxacin (Abaktal, O, P 0.88-3.54 0.74-163 0.53163 PO: 12 mg NR Not commercially available in the US. Several case reports of
Azuben, others) (for salmo- pefloxacin-induced arthropathy in children.73,74,75
nella)72;
IV: 400mg
Q12H (for
meningitis
in children
6 mo to 12
yr)72
61

(continued)
 62
Table 1 Continued
American
Potential Therapeutic Academy of
Milk Milk-to- Infant Infant Pediatrics
Generic Name Dosage Concentrations Plasma Dose Dose (AAP)
Antibiotic Class (brand name) Forms* (mcg/ml) Ratio (mg/kg/d)** (mg/kg/d) Compatible Special Considerations

Sparfloxacin (Zagam) O Unknown Unknown Unknown Unknown NR

Trovafloxacin/Alatro- O, P Unknown Unknown Unknown Unknown NR Alatrofloxacin is the intravenous formulation that is metabolized to
floxacin (Trovan) trovafloxacin.
Sulfonamides and
Trimethoprim
Sulfabenzamide T Unknown Unknown Unknown Unknown NR
Sulfacetamide O, Op, T Unknown Unknown Unknown Unknown NR
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(Sulamyd and others)

21
Sulfadiazine (Silvadene O, T Unknown Unknown Unknown 100 NR Absorption is complete after oral administration ; 32-56% protein
28
and others) binding.
28
Sulfamethizole O Unknown Unknown Unknown Unknown NR Readily absorbed after oral administration; 90% protein binding.
(Thiosulfil forte)
Sulfamethoxazole O Unknown 0.0621 Unknown 50-75 Y (in com- 50-70% protein bound.28
(Gantanol, Urobak) bination
with
trimetho-
prim)
Sulfanilamide (Vagitrol T Unknown Unknown Unknown Unknown NR
and others)
76,77 77
Sulfapyridine O 10.3 0.5 1.54 Y
21 21
Sulfasalazine O 0.5-2 0.09-0.17 0.3 Contraindi- Y 10-15% oral absorption as unchanged drug. Poor bilirubin displacing
(Azulfidine) cated in ability; one episode of bloody diarrhea reported in the nursing infant
children < of a mother who was a slow acetylator.30
2 yrs
Sulfathiazole O, T Unknown unknown unknown unknown NR
25 28
Sulfisoxazole (Gantri- O, Op 0.45% of 0.06 Unknown 120-150 in Y Readily absorbed; 88% protein bound.
sin) maternal infants 2
dose found mos
in breast
25
milk
21 21 58
Trimethoprim O 2 1.25 0.3 4-6 Y (in com- Co-trimoxazole: poor feeding has been reported in nursing infants.
(Proloprim, Trimpex) bination
with
sulfameth-
oxazole)
 4
Tetracyclines Tetracyclines are contraindicated for oral use in children < 8 yrs.
Demeclocycline O Unknown Unknown Unknown Unknown NR
(Declomycin)
21 31
Doxycycline O, P 0.38-0.77 0.3-0.4 0.115 Unknown NR
(Vibramycin and oth-
ers)
Methacycline Unknown Unknown Unknown Unknown NR
Minocycline (Minocin, O, P Unknown Unknown Unknown Unknown NR
Dynacin)
Oxytetracycline (Terra- O, P Unknown Unknown Unknown Unknown NR
mycin and others)
21 21
Tetracycline (Sumycin O, Op, T 0.43-2.58 0.6-0.8 0.39 Unknown Y
and others)
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Miscellaneous
77
Chloramphenicol O, Op, Ot, P, 16-25 0.51-0.6277 3.75 20-100 U Refusal of the breast, somnolence during feeding, gas, and
(Chloromycetin and T postfeeding emesis has been reported in nursing infants.31 Lactating
others) mothers received multiple doses of chloramphenicol in references
77 and 78 versus single-dose therapy in reference 57.
78
0.54-6.10 NA
57
trace-4.2
79 79 46
Clindamycin (Cleocin O, P, T, V < 0.5-3.1 0.08-3.1 0.570 10-40 Y Bloody stools in a nursing infant has occurred. Lactating mothers
and others) received multiple doses of clindamycin in references 79 and 80 ver-
sus single dose therapy in reference 57.
80
0.74-3.8 NA
57
trace-1.2
Metronidazole (Flagyl O, P, T, V 3.5-45.881 NA 6.87 7.5-50 U Loose stools, feeding problems, and candidiasis have been reported in
82
and others) nursing infants. One report of diarrhea and secondary lactose intol-
83
erance in a nursing infant exists. Lactating mothers received multi-
ple doses of metronidazole in reference 82 versus single-dose ther-
apy in reference 81.
82 82
8.99-15.52 0.88-0.96

* I = inhalation, O = oral, Op = ophthalmic, Ot = otic, P = parenteral, T = topical, V = vaginal.

** Calculated by multiplying maximum known concentration achieved in breast milk by average milk intake (150 ml/kg/day).
Obtained from reference 4, unless otherwise specified.
Obtained from reference 32: Y = yes, NR = not reviewed, U = effect in nursing infants unknown but may be of concern.
Percentage oral absorption and percentage protein binding noted in adult patients.
|| Pfizer, personal communication, October 2000.
AAP suggests cessation of breastfeeding for 12-24 h after single-dose therapy is given to the mother to allow for clearance of the drug.
63
64 Chin et al. J Hum Lact 17(1), 2001

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