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Antibiotics and lactationvan Wattum, J J; Leferink, T M; Wilffert, B; Ter Horst, P G J

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DOI:10.1111/bcpt.13098

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Article Type: Mini-Review MiniReview

Antibiotics and lactation: An overview of relative infant doses and a systematic assessment of clinical studies

J.J. van Wattum1, T.M. Leferink2, Dr. B. Wilffert2 and P.G.J. ter Horst1

1 Isala, Department of Clinical Pharmacy, Zwolle, The Netherlands.

2 Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen and Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands

(Received 18 April 2018; Accepted 11 July 2018)

Correspondence: P.G.J. ter Horst, Isala, Department of Clinical Pharmacy, PO Box 10400, Dr van Heesweg 2, 8025 AB, Zwolle, The Netherlands

Email: p.g.j.ter.horst@isala.nl

Abstract

Breastfeeding is important for the development of the child. Many antibiotics are

considered safe during breastfeeding. The aim of the study was to assess the quality of

lactation studies with antibiotics using the FDA and International Lacation Consultant

Association (ILCA) quality guidelines for lactation studies. The secondary goal was to

determine the exposure of the breastfed infant to antibiotics in relation to bacterial

resistance and the developing microbiome.

A literature search was performed and the included studies were scored on

methodology, parameters concerning maternal exposure to antibiotics, maternal plasma

and milk sampling. The infant exposure has been calculated and expressed as a

percentage of a normal infant therapeutic dose.

Sixty-six studies were included in 5 antibiotic groups (broad-spectrum penicillin,

cephalosporins, macrolides and lincosamides, quinolones and sulfonamides).

Cephalosporins were the most studied group of antibiotics (n=21). Fifteen studies met all

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the criteria of ‘mother exposure to antibiotic’. Six studies met every criterion related to

‘plasma sampling’. Only one case-report met all listed criteria for lactation studies. The

correct calculation of infant exposure to antibiotics via the milk:plasma ratio (AUC)

varies between 13% for macrolides and 38% for broad-spectrum penicillin. The highest

assessed exposure as a percentage of infant therapeutic dose was for metronidazole

(11%).

The studies meet to a limited extent with the quality standards for lactation research. The

breastfed infants are exposed to a sub-therapeutic concentration of antibiotics.

Keywords: Infancy • Antibiotics • Breastfeeding • Microbiome

Introduction

Breastfeeding has numerous advantages over infant formula milk for the development of the

neonate and decreases health risks of the nursing mother. Breastfeeding protects the

neonate against child infections and malocclusions, increased intelligence at later age and

protects against overweight and diabetes. For the mother, breastfeeding protects against

breast cancer, ovarian cancer and type II diabetes (1).

The World Health Organization recommends breastfeeding exclusively during the first six

months and as a supplement up to 2 years. This is due to the earlier mentioned benefits and

the low costs for the developing world. In the United States, 75% of mothers breastfeed their

infants in the early post-partum period and 36% are exclusively breastfeeding at 3 months

(2). One of the concerns in the lactation period is the safety of drugs being used by mothers,

because transfer of the drug over the mammary gland may lead to side effects in the

suckling infant.

Antibiotics are probably among the most prescribed drugs during lactation. The prevalence

of mastitis treated with antibiotics in lactating women is estimated between 16 and 49%

(3,4). Most antibiotics are considered to be safe during breastfeeding, except quinolones,

chloramphenicol, aminoglycosides during early postnatal period and possibly metronidazole

(5,6).

Nowadays, resistance to antibiotic drugs forms a great problem. Studies in both humans and

animals show that low-dose exposure or inadequate exposure time to antibiotics correlates

to the development of resistant microbes (7-9). Therefore, (long-term) sub-therapeutic

transmission of antibiotics via breast milk to the infant could possibly contribute to antibiotic

resistance in the infant. However, no data establishing this relation could be found.

Furthermore, recent research shows that the neonatal microbiome is affected by intrapartum

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antibiotics (10-13) and maternal use of antibiotics in the lactation period (14). In turn, the

microbiome may affect brain development, behaviour and obesity (15-17).

To assess the safety of antibiotics in the light of the developing microbiome, it is of

paramount importance to know the amount of antibiotics transferred into breast milk which

reaches the neonatal gastrointestinal tract. The most important parameter for the exposure

of an infant to maternal use of antibiotics is the Absolut Infant Dose (AID) of which the

formula is described in fig. 1. By calculating the AID, the infant dose per kilogram per day is

known. Furthermore, the AID can be compared with the therapeutic infant dose.

Objective and rationale

In this study we aimed, using guidelines of the FDA (18) and ILCA (19), to determine the

quality of lactation studies that investigated antibiotics in breast milk and examined the data

regarding absolute infant dose.

Search methods

Antibiotics

A literature search was performed using the PubMed database using the following search

strings: (Milk, Human[MeSH Terms] OR Breast Milk[Title/Abstract] OR Human

Milk[Title/Abstract]) or Lactation AND (a specific antibiotic drug (table 2)). See appendix 1 for

detailed search strings. Cross references were searched for additional studies. An additional

search was performed using the LactMed® database. Antibiotics were categorized in 17

groups based on their chemical and physical properties (table 2).

Inclusion and exclusion criteria

Only articles containing primary data in humans published from 1970 until March 2017 were

included in this study. We excluded studies of languages other than English, German and

Dutch. Studies without reported drug concentrations in the mother’s plasma or mother’s milk

were also excluded.

Guidelines

The FDA (18) and ILCA (19) draft guidelines were used to review the quality of the included

articles. These guidelines provide recommendations on how to conduct clinical lactation

studies. In more detail, information is given about the recommended study design and the

data analysis that is favoured. In this MiniRreview, the recommendations of the FDA and

ILCA were combined to create a checklist (table 1). Due to the limited amount of studies

available per antibiotic, solely the results of antibiotic groups containing a minimum of 5

papers are presented in this study (fig. 3).

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Absolute infant dose

We determined the AIDs that are known for each group of antibiotics, by using the reported

values or by calculating using the formula provided in fig. 1, using 150ml/kg/day as a

standard for daily milk intake (20). We used a mean value for the AID for two published

reports and a median value for three or more reports. The AID as a percentage of the

Therapeutic Infant Dose (mg/kg/day) was calculated using the pediatric drug formulary of the

Netherlands (21).

Outcomes

Using the search strings, we found 229 articles in the LactMed database and 808 articles in

PubMed. In total, 174 articles and 797 articles were excluded in LactMed and PubMed,

respectively. Reasons for exclusion were different language (n=127), no concentrations

(n=254), review (n=169), animal study (n=258), paper published before 1970 (n=38), already

in LactMed database (n=76) and duplicates (n=49) (fig. 2). We found no studies that met the

inclusion criteria for the antibiotics of the groups ‘Trimethoprim and similar compounds’ and

‘Polymixins’ (table 2). In total, 66 studies were assessed using the checklist based on FDA

(18) and ILCA (19,22) guidelines (table 1). For five antibiotic groups, only 1 study (23-27)

was included and for three antibiotic groups, 2 studies (28-31) were included. The results of

the quality determination of the different parameters (table 1) of 6 antibiotic groups with at

least 5 studies are shown in fig. 3A-D.

The parameters (table 1) that most frequently met the quality criteria set by combining the

FDA and ILCA guidelines are the reported daily dose and dose regimen, see fig. 3A.

Shortcomings of most studies were the absence of whole milk portions, see fig. 3B.

Fifteen studies (23,27,29,32-43) met all the criteria of ‘mother exposure to drug’; this

includes the presence of the administered daily dose and dose regimen, the analysis of

concentrations during steady state and the use of longitudinal data (table 1). In only one

case-report study with cephalexin (32), the breast milk sampling met all listed criteria. In six

of the 66 assessed studies (37,38,42,44-46), every criterion related to ‘plasma sampling’

(table 1) was present. Only one study with cephalexin (32) met all the criteria of ‘method /

data analysis’, including M:P, RID and AID are correctly measured and a validated method

of analysis is used. Infant’s plasma concentrations or the occurrence of adverse reactions in

the breastfeeding infant were only addressed in 10 of the 66 assessed studies

(23,31,32,42,45,47-51).

Next to the quality determination, we also assessed the potential infant risk based on the

Absolute Infant Dose (AID) for different antibiotic drugs (fig. 4A). The highest AID

corresponded to sulfapyridin (median AID: 2.68 mg/kg/day (N=4)) (37,45,52,53). The infant

risk as a percentage of the daily therapeutic infant dose (fig. 4B) was the highest for

metronidazole (11% based on a median AID: 1.59 mg/kg/day (N=4)) (42,43,54,55).

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Wider implications

Of all assessed antibiotic groups, cephalosporins was the most documented group, with 21

different studies, including 226 patients (table 2). The data on the quality determination (fig.

3) also reveal a prominent place for cephalosporins in relation to the validation criteria (table

1). This could be related to the fact that cephalosporins are frequently used antibiotics in

hospitals and especially in gynaecological care departments (56-58), with attendance of

nursing mothers. Most other antibiotics are poorly studied like broad-spectrum penicillins (8

studies, 78 patients), sulfonamides (5 studies, 27 patients) macrolides and lincosamides (8

studies, 67 patients) and quinolones (7 studies, 59 patients).

Many studies lack information about the sample size, method of collection (electric pump or

‘normal’) and whether foremilk or hindmilk was sampled. Without a standardized method of

collection, it is hard to compare studies examining transfer of drugs into breast milk. A

differentiation between foremilk and hindmilk collection is necessary, which was only

performed in 6 studies (30,32,41,59-61). Hindmilk is more lipophilic than foremilk; therefore,

lipophilic antibiotics like quinolones, macrolides and tetracyclines will probably penetrate

more easily into hindmilk (62-64). This might result in an under- or over-estimation of

antibiotic concentrations in breast milk.

Calculated parameters related to drug transfer into breast milk (M:P ratio, AID, RID) are

poorly studied in the assessed lactation studies. The correct measurement of the M:P ratio

varies between 13% of the studies for macrolides and lincosamides and 38% of the studies

for broad-spectrum penicillin. The M:P ratio is often calculated as single point milk:plasma

concentrations, where whole “area under the curve” of the milk/plasma curve is by far more

accurate. However, the clinical implication of the M:P ratio is over-estimated because a low

absolute dose with a high M:P ratio means that still a small amount of a particular drug can

be found in the milk. The poor establishment of drug transport over the mammary gland

may be related to the absence of measurements in steady-state conditions and concurrent

sampling of plasma and milk in many studies.

In order to assess the infant risk to different antibiotics, when transferred into breast milk, we presented, or when necessary, calculated the Absolut Infant Dose (AID). The highest exposure in breast milk was found for sulfapyridin (2.68 mg/kg/day) based on an average milk intake of 150ml/kg/day. This sulfonamide seems compatible with breastfeeding, when the infant shows no signs of illness, stress or jaundices (5,65,66). However, based on primarily the AID, it is hard to review the risk for the infant. Therefore, we calculated the AID as a percentage of the daily therapeutic dose. The AID in perspective of the therapeutic infant dose for metronidazole (11% of therapeutic dose), ofloxacin (2% of therapeutic dose) and gentamycin (2% of therapeutic dose) (fig. 4B), would relate to the highest risk for the breastfeeding infant. For metronidazole, which is indicated for anaerobic infections, especially for prophylaxis following caesarian section and post-partum infection control (67-69), no breastfeeding is advised upon 12-24 hr after the last metronidazole dose (66). However, only one case-report describes infant diarrhoea after breast milk consumption of a mother exposed to metronidazole (70). Based on these percentages alone, it is hard to predict any infant side effects. Therefore, we would like to emphasize that like for most

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drugs, minimalizing infant exposure also applies for maternal use of antibiotics and monitoring for possible adverse reactions is needed. However, only in 6 studies adverse reactions were documented using standardized methods (23,31,32,42,47,49). General concerns of maternal use of antibiotics for the infant are in potential for allergic reaction, changes in bowel flora, and confounding of culture results by the ingested antibiotic if a fever work-up is performed for the infant.

Specific for ampicillin, diarrhoea and candidiasis have been reported in nursing infants. Moxalactam, a third-generation cephalosporin, may lead to colonization of infant’s bowel with gram-positive organisms is possible, resulting in a risk for enterocolitis. (71)

Diarrhoea, irritability and pyloric stenosis have been reported for erythromycin in nursing infants. Perforated pseudomembranous colitis was reported in a breastfed infant whose mother used ciprofloxacin. For sulfasalazine, there is a risk of bilirubin displacing, and bloody diarrhoea has been reported in the nursing infant of a mother who was a slow acetylator. For chloramphenicol, refusal of the breast, somnolence during feeding, gas and post-feeding emesis have been reported in nursing infants. For metronidazole loose stools, feeding problems, and candidiasis have been reported in nursing infants. (65)

The use of maternal antibiotics could also play a role in bacterial resistance and modification

of the infant microbiome. As mentioned earlier, sub-therapeutic dosing of antibiotics is

associated with the development of resistant microorganisms (7-9). Based on our results, all

assessed antibiotics (fig. 4B) are transferred into breast milk in sub-therapeutic levels

ranging from 0.05% for cefotaxime to 10.61% for metronidazole of the therapeutic infant

dose. This low-dose exposure might induce antibiotic resistance in the infant and might lead

to a reduced diversity of intestinal microbiota during infancy and the occurrence of allergies

later in life (72-74), and contribute to the development of infant diseases, even later in life,

like disturbances in brain development, immunity, behaviour and obesity (15-17,75,76). Also,

the infant colonization rate of microorganisms is affected by maternal use of antibiotics in the

lactation period (77), which is one of the first signs of altered gut microbiota composition.

The safety of maternal use of antibiotics in relation to the infant’s microbiome and its effects

later in life should be further studied.

Conclusion

This MiniReview assessed the quality of lactation studies according to FDA and ILCA

guidelines, and most studies did not comply with these guidelines. Especially, the study

methodology was poorly described. We found that antibiotics like metronidazole with a

relatively high AID of 11% of the therapeutic infant dose, is suspected of antibiotic

resistance and microbiome alterations in the suckling infant. However, further research on

these effects in breastfeeding infants is needed. In the meantime, the benefits of maternal

antibiotic therapy should be weighed against the potential (long-term) risk for the

breastfeeding infant.

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(66) Bethesda M. Drugs and Lactation Database (LactMed). National Library of Medicine (U S ) 2006.

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(73) Riiser A. The human microbiome, asthma, and allergy. Allergy Asthma Clin Immunol 2015;11:10.1186/s13223-015-0102-0.

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(76) Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The Intestinal Microbiome in Early Life: Health and Disease. Front Immunol 2014;5:10.3389/fimmu.2014.00427.

(77) Zwittink RD, van Zoeren-Grobben D, Martin R, van Lingen RA, Groot Jebbink LJ, Boeren S, et al. Metaproteomics reveals functional differences in intestinal microbiota development of preterm infants. Mol Cell Proteomics 2017 Jul 6.

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(79) Kafetzis DA, Siafas CA, Georgakopoulos PA, Papadatos CJ. Passage of cephalosporins and amoxicillin into the breast milk. Acta Paediatr Scand 1981;70(3):285-288.

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(85) Buitrago MI, Crompton JA, Bertolami S, North DS, Nathan RA. Extremely low excretion of daptomycin into breast milk of a nursing mother with methicillin-resistant Staphylococcus aureus pelvic inflammatory disease. Pharmacotherapy 2009 Mar;29(3):347-351.

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(87) Harms ,K., Gerke ,G., Zaloudek ,D. Konzentrationsbestimmungen von Cefotaxim aus der Muttermilch. Infection 1980;8(4):451-453.

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(91) Gerk PM, Kuhn RJ, Desai NS, McNamara PJ. Active transport of nitrofurantoin into human milk. Pharmacotherapy 2001 Jun;21(6):669-675.

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(93) Pons G, Rey E, Richard MO, Vauzelle F, Francoual C, Moran C, et al. Nitrofurantoin excretion in human milk. Dev Pharmacol Ther 1990;14(3):148-152.

(94) Shyu WC, Shah VR, Campbell DA, Venitz J, Jaganathan V, Pittman KA, et al. Excretion of cefprozil into human breast milk. Antimicrob Agents Chemother 1992 May;36(5):938-941.

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(95) Traeger A, Peiker G. Excretion of nalidixic acid via mother's milk. Arch Toxicol Suppl 1980;4:388-390.

(96) Festini F, Ciuti R, Taccetti G, Repetto T, Campana S, De Martino M. Breast-feeding in a woman with cystic fibrosis undergoing antibiotic intravenous treatment. J Matern Fetal Neonatal Med 2006 Jun;19(6):375-376.

(97) Khan AK, Truelove SC. Placental and mammary transfer of sulphasalazine. Br Med J 1979 Dec 15;2(6204):1553.

(98) Lassman HB, Puri SK, Ho I, Sabo R, Mezzino MJ. Pharmacokinetics of roxithromycin (RU 965). J Clin Pharmacol 1988 Feb;28(2):141-152.

(99) Lou MA, Wu YH, Jacob LS, Pitkin DH. Penetration of cefonicid into human breast milk and various body fluids and tissues. Rev Infect Dis 1984 Nov-Dec;6 Suppl 4:S816-20.

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(102) Salman S, Davis TM, Page-Sharp M, Camara B, Oluwalana C, Bojang A, et al. Pharmacokinetics of Transfer of Azithromycin into the Breast Milk of African Mothers. Antimicrob Agents Chemother 2015 Dec 28;60(3):1592-1599.

(103) Kelsey JJ, Moser LR, Jennings JC, Munger MA. Presence of azithromycin breast milk concentrations: a case report. Am J Obstet Gynecol 1994 May;170(5 Pt 1):1375-1376.

(104) Cover DL, Mueller BA. Ciprofloxacin penetration into human breast milk: a case report. DICP 1990 Jul-Aug;24(7-8):703-704.

(105) Evaldson GR, Lindgren S, Nord CE, Rane AT. Tinidazole milk excretion and pharmacokinetics in lactating women. Br J Clin Pharmacol 1985 Apr;19(4):503-507.

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Figure 1. Formulas for the calculation of M:P, AID and RID, according to the ILCA guidelines. In

this study, the AID calculation is based on a Cmilk of 150ml/kg/day (20).

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Figure 2. Flowchart of included and excluded studies using PubMed and LactMed as database.

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Figure 3. Quality determination of the lactation studies of different antibiotic groups.

For different parameters based on FDA (18) and ILCA (19) guidelines, the percentage of correctly performed studies is presented. Studies are scored based on parameters related to drug exposure of the mother (A), plasma sampling parameters (B), milk sampling parameters (C) and method/analytic parameters (D) (see table 1)

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Figure 4. Absolute Infant Dose for different antibiotic drugs.

Presented is the Absolute Infant Dose (mg/kg/day) for 57 different antibiotic drugs, when a daily infant milk intake of 150ml/kg/day is used (20). (A) and Absolute Infant Dose as a percentage of the Therapeutic Infant Dose (mg/kg/day) for 20 different antibiotic drugs (B). A mean AID based on data from 2 different studies was calculated for Tetracycline, Chloramphenicol, Ceftriaxone, Ciprofloxacin and Tinidazole. A median AID based on data from 3 different studies was calculated for Cefotaxime, Cephalexin, Clindamycin, Azithromycin Metronidazole,and Nitrofurantoin. A median AID based on data from 4 different studies was calculated for Sulfapyridin, Cefoxitin and Ampicillin.

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Table 1. Checklist for the quality of lactation studies involving antibiotic use, based on the ILCA (19)

and FDA (18) guidelines.

Subject Explanation

Study design

Number of patients No FDA and ILCA recommendations

Full article No FDA and ILCA recommendations

Mother exposure to drug

Daily dose given Daily dose exposure to the mother is known

Dose regimen given Dose regimen is known

Steady state Rate of drug absorption is equal to rate of drug

elimination

Longitudinal data Samples are obtained between two postpartum

periods in individual woman for drugs that are

administered chronically in several treatment cycles

Breast milk sampling

Time compared to drug intake

known

Time between administration of the drug and

sampling is known

Multiple measures in dose

interval

Minimum 5 samples are taken more than one hour

from each other

Full method of collection given Method including; how milk is withdrawn (manual or

electric), sample volume, milk type (pre- or

postfeeding)

Representive for for and hind

milk

Samples are taken from for and hindmilk

Both breast Both breast are sampled

Plasma sampling

Plasma levels measured Mothers plasma level of the drug is known

Sampled concomitted with milk Plasma is simultaneously sampled with breast milk

Multiple measures in dose

interval

Minimum 5 samples are taken more than one hour

from each other

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Metabolites taken into account Drug metabolites are analysed

Method / Data analysis

M:P correctly measured The antibiotic concentration in breast milk divided by

the antibiotic concentration in mother’s plasma (fig. 1)

RID and AID correctly

measured

AID: the absolute amount of antibiotic consumed by

the infant per kilogram per day (fig. 1)

RID: infant drug exposure as a percentage of the

maternal dose normalized by the maternal and infant

weight (fig. 1)

Method analysis given,

validated

Method of sample analysis is given and a validated

method is used.

Child observation

Plasma level known in child Drug plasma levels of the infant are known

Behaviour monitored in child Behaviour of the infant is assessed by a validated

method

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Registered and unregistered antibiotics categorized by group (antibiotic group name in bold)

TETRACYCLINS BETALACTMASE SUSCEPTIBLE SULFATHIAZOLE TELITHROMYCIN CEFPODOXIME NORFLOXACIN MURIPOCIN

DEMECLOCYCLINE PENICILLINS SULFAMETHOXAZOLE CLINDAMYCIN (28,59,78) CEFACETRILE LOMEFLOXACIN TEDIZOLID

DOXYCYCLINE (30) BENZYLPENICILLIN (28) SULFADIAZINE LINCOMYCIN CEFROXADINE (28) FLEROXACIN (46) NIFURTOINOL

CHLORTETRACYCLINE PHENOXYMETHYLPENICILLIN (31) SULFAMOXOLE CEPHALOSPORINS CEFTEZOLE SPARFLOXACIN FOSFOMYCIN

LYMECYCLINE PROPICILLIN SULFADIMETHOXINE CEFALOTIN (79) CEFPIROME RUFLOXACIN XIBORNOL

METACYCLINE PENAMECILLIN SULFALENE CEFAZOLIN (80,81) CEFIXIME GREPAFLOXACIN CLOFOCTOL

OXYTETRACYCLINE CLOMETOCILLIN SULFAMETOMIDINE CEFOXITIN (28,49,82-84) CEFEPIME LEVOFLOXACIN (39) SPECTINOMYCIN

TETRACYCLINE (28,30) BENZYLPENICILLINEBENZATHIN SULFAMETHOXYDIAZINE CEFUROXIME CEFODIZIME TROVAFLOXACIN METHENAMINE (61)

MINOCYCLINE AZIDOCILLIN SULFAMETHOXYPYRIDAZINE CEFAMANDOL CEFETAMET MOXIFLOXACIN NITROXOLIN

ROLITETRACYCLINE FENETICILLIN SULFAPERIN CEFACLOR CEFPIRAMIDE GEMIFLOXACIN LINEZOLID (41)

PENIMEPICYCLINE BETALACTMASE RESISTENT SULFAMERAZINE CEFADROXIL (28,79) CEFAPIRINE (79) GATIFLOXACIN DAPTOMYCIN (85)

CLOMOCYCLINE PENICILLINS SULFAFENAZOLE CEFOTAXIME (28,79,86,87) CEFRADINE (88) PRULIFLOXACIN FIDAXOMICIN

TIGECYCLINE DICLOXACILLIN SULFAMAZONE CEFTIBUTEN (89) CEFOPERAZONE (28) PAZUFLOXACIN ORNIDAZOLE

AMPHENICOLS CLOXACILLIN SULFAMETROLE CEFDINIR AMINOGLYCOSIDEN GARENOXACIN (90) NITROFURANTOIN (91-93)

CHLORAMPHENICOL (28,29) METICILLIN SULFAMETOPYRAZINE CEFMETAZOLE (28) STREPTOMYCIN ROSOXACIN

THIAMPHENICOL (29) OXACILLIN (27) SULFAFURAZOLE CEFPROZIL (94) STREPTODUOCIN NALIDIXIN (95)

BROAD SPECTRUM PENICILLINS FLUCLOXACILLIN SULFANILAMIDE CEFORANID TOBRAMYCIN (96) PIROMIDIN

AMPICILLIN (27,28,44,47) FLOXACILLIN SULFADIMIDINE CEFTIZOXIME (28) GENTAMICIN (50) PIPEMIDIN

PIVAMPICILLIN (48) BETALACTMASE INHIBITORS SULFAPYRIDINE (37,45,52,53,97) CEFDITOREN KANAMYCIN (28) OXOLIN

CARBENICILLIN (28) SULBACTAM (26) MACROLIDES AND CEFTAROLINE NEOMYCIN CINOXACIN

AMOXICILLIN (79) TAZOBACTAM LINCOSAMIDES CEFTOLOZAN AMIKACIN (28) FLUMEQUINE

CARINDACILLIN MONOBACTAM ANTIBIOTICS ERYTHROMYCIN (28) CEFTAZIDIME (34) NETILMICIN GLYCOPEPTIDES

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Table 2. List of included antibiotics in this MiniReview. References of the included antibiotics are presented in brackets. No studies were included for the

antibiotics without references.

BACAMPICILLIN (28) AZTREONAM (25) SPIRAMYCIN LORACARBEF SISOMICIN VANCOMYCIN (23)

EPICILLIN (88) CARBAPENEM-ANTIBIOTICS MIDECAMYCIN CEFSULODIN DIBEKACIN TEICOPLANIN

PIVMECILLINAM MEROPENEM (24) PRISTINAMYCIN CEFTRIAXONE (36,79) RIBOSTAMYCIN TELAVANCIN

AZLOCILLIN ERTAPENEM OLEANDOMYCIN CEFOTETAN (28) ISEPAMICIN DALBAVANCIN

MEZLOCILLIN (28) DORIPENEM ROXITHROMYCIN (98) CEFAZEDON FRAMYCETIN ORITAVANCIN

MECILLINAM IMIPENEM JOSAMYCIN(28) CEFMENOXIME (33) PAROMOMYCIN POLYMYXINS

PIPERACILLIN TRIMETHOPRIM AND SIMILAR TROLEANDOMYCIN CEFONICID (99) STREPTOZOCIN COLISTIN

TICARCILLIN (28,100) COMPOUNDS CLARITHROMYCIN (38) LATAMOXEF QUINOLONES POLYMYXIN B

METAMPICILLIN TRIMETHOPRIM AZITHROMYCIN (101-103) MOXALACTAM (35) OFLOXACIN (40) BACTRACIN

TALAMPICILLIN BRODIMOPRIM MIOCAMYCIN CEFOTIAM (28) CIPROFLOXACIN

(40,51,104)

GRAMICIDIN

SULBENICILLIN (28) SULFONAMIDES ROKITAMYCIN CEFATRIZINE PEFLOXACIN (40) OTHERS ANTIBIOTICS

TEMOCILLIN SULFISOMIDINE DIRITHROMYCIN CEPHALEXIN (28,32,79) ENOXACIN METRONIDAZOLE

(42,43,54,55)[42, 43, 55,

56][42, 43, 55, 56](Passmore

et al., 1988; Heisterberg and

Branebjerg, 1983; Erickson et

al., 1981; A. T. Willis, I. R.

Ferguson, P. H. Jones, K. D.

Phillips, P. V. Tearle, 1978)

HETACILLIN SULFAMETHIZOL FLURITHROMYCIN CEPHALORDINE (28) TEMAFLOXACIN TINIDAZOLE (60,105)

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Appendix 1 – detailed search parameters

("Milk, Human"[Mesh] OR "Breast Milk"[title/abstract] OR "Human Milk"[title/abstract] OR

LACTATION [TITLE/ABSTRACT]) AND

TETRACYCLINES

(DEMECLOCYCLIN* OR DOXYCYCLIN* OR CHLORTETRACYCLIN* OR LYMECYCLIN* OR

METACYCLIN* OR OXYTETRACYCLIN* TETRACYCLIN* OR MINOCYCLIN* OR

ROLITETRACYCLIN* OR PENIMEPICYCLIN* OR CLOMOCYCLIN* TIGECYCLIN*)

AMPHENICOLES

(CHLORAMPHENICOL* OR THIAMPHENICOL*)

BROAD SPECTRUM PENICILLIN

(AMPICILLIN* OR PIVAMPICILLIN* OR CARBENICILLIN* OR AMOXICILLIN* OR CARINDACILLIN*

OR BACAMPICILLIN* OR EPICILLIN* OR PIVMECILLINAM* OR AZLOCILLIN* OR MEZLOCILLIN*

OR MECILLINAM* OR PIPERACILLIN* OR TICARCILLIN* OR METAMPICILLIN* OR

TALAMPICILLIN* OR SULBENICILLIN* OR TEMOCILLIN* OR HETACILLIN*)

BETA-LACTAMASE-SENSITIVE PENICILLIN

(BENZYLPENICILLIN* OR FENOXYMETHYLPENICILLIN* OR PHENOXYMETHYLPENICILLIN* OR

PROPICILLIN* OR AZIDOCILLIN* OR FENETICILLIN* OR PENAMECILLIN* OR CLOMETOCILLIN*

OR BENZYLPENICILLINEBENZATHIN* OR (PENICILLIN* V) OR (PENICILLIN* G))

BETA-LACTAMASE-RESISTENT PENICILLIN

(DICLOXACILLIN* OR CLOXACILLIN* OR METICILLIN* OR OXACILLIN* OR FLUCLOXACILLIN*

OR FLOXACILLIN*)

BETA-LACTAMASE-INHIBITORS

(SULBACTAM OR TAZOBACTAM)

CEFALOSPORINS

(CEFALEXIN* OR CEFALORIDIN* OR CEFALOTIN* OR CEFAZOLIN* OR CEFOXITIN* OR

CEFUROXIM* OR CEFAMANDOL* OR CEFACLOR* OR CEFADROXIL* OR CEFOTAXIM* OR

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CEFTAZIDIM* OR CEFSULODIN* OR CEFTRIAXON* OR CEFOTETAN* OR CEFAZEDON* OR

CEFMENOXIM* OR CEFONICID* OR LATAMOXEF* OR MOXALACTAM OR CEFOTIAM* OR

CEFATRIZIN* OR CEFIXIM* OR CEFEPIM* OR CEFODIZIM* OR CEFETAMET* OR CEFPIRAMID*

OR CEFAPIRIN* OR CEFRADIN* OR CEFOPERAZON* OR CEFPODOXIM* OR CEFACETRIL* OR

CEFROXADIN* OR CEFTEZOL* OR CEFPIROM* OR LORACARBEF* OR CEFTIBUTEN OR

CEFDINIR* OR CEFMETAZOL* OR CEFPROZIL* OR CEFORANID* OR CEFTIZOXIM* OR

CEFDITOREN* OR CEFTAROLIN* OR CEFTOLOZAN*)

MONOBACTAM-ANTIBIOTICS

(AZTREONAM)

CARBAPENES

(MEROPENEM OR ERTAPENEM OR DORIPENEM OR IMIPENEM)

TRIMETHOPRIM AND DERIVATIVES

(TRIMETHOPRIM OR BRODIMOPRIM)

SULFONAMIDES

(SULFISOMIDIN* OR SULFAMETHIZOL* OR SULFADIMIDIN* OR SULFAPYRIDIN* OR

SULFAFURAZOL* OR SULFANILAMID* OR SULFATHIAZOL* OR SULFAMETHOXAZOL* OR

SULFADIAZIN* OR SULFAMOXOL* OR SULFADIMETHOXIN* OR SULFALEEN OR

SULFAMETOMIDIN* OR SULFAMETHOXYDIAZIN* OR SULFAMETHOXYPYRIDAZIN* OR

SULFAPERIN* OR SULFAMERAZIN* OR SULFAFENAZOL* OR SULFAMAZON* OR

SULFAMETROL* OR SULFAMETOPYRAZIN*)

MACROLIDE ANTIBIOTICS AND LINCOSAMIDE

(ERYTHROMYCIN* OR SPIRAMYCIN* OR MIDECAMYCIN* OR PRISTINAMYCIN* OR

OLEANDOMYCIN* OR ROXITHROMYCIN* OR JOSAMYCIN* OR TROLEANDOMYCIN* OR

CLARITHROMYCIN* OR AZITHROMYCIN* OR MIOCAMYCIN* OR ROKITAMYCIN* OR

DIRITHROMYCIN* OR FLURITHROMYCIN* OR TELITHROMYCIN* OR CLINDAMYCIN* OR

LINCOMYCIN*)

AMINOGLYCOSIDES

(STREPTOMYCIN* OR STREPTODUOCIN* OR TOBRAMYCIN* OR GENTAMICIN* OR

KANAMYCIN* OR NEOMYCIN* OR AMIKACIN* OR NETILMICIN* OR SISOMICIN* OR DIBEKACIN*

OR RIBOSTAMYCIN* OR ISEPAMICIN* OR FRAMYCETIN* OR PAROMOMYCIN* OR

STREPTOZOCIN*)

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QUINOLONES

(OFLOXACIN* OR CIPROFLOXACIN* OR PEFLOXACIN* OR ENOXACIN* OR TEMAFLOXACIN*

OR NORFLOXACIN* OR LOMEFLOXACIN* OR FLEROXACIN* OR SPARFLOXACIN* OR

RUFLOXACIN* OR GREPAFLOXACIN* OR LEVOFLOXACIN* OR TROVAFLOXACIN* OR

MOXIFLOXACIN* OR GEMIFLOXACIN* OR GATIFLOXACIN* OR PRULIFLOXACIN* OR

PAZUFLOXACIN* OR GARENOXACIN* OR ROSOXACIN* OR NALIDIXIN* OR PIROMIDIN* OR

PIPEMIDIN* OR OXOLIN* OR CINOXACIN* OR FLUMEQUIN* OR PIPEMIDIC* OR NALIDIXIC* OR

PIROMIDIC*)

GLYCOPEPTIDES

(VANCOMYCIN* OR TEICOPLANIN* OR TELAVANCIN* OR DALBAVANCIN* OR ORITAVANCIN*)

POLYMYXINS

(COLISTIN* OR “POLYMYXIN B” OR BACTRACIN* OR GRAMICIDIN*)

ADDITIONAL ANTIBIOTICS

(METRONIDAZOL* OR TINIDAZOL* OR ORNIDAZOL* OR NITROFURANTOIN* OR NIFURTOINOL

OR FOSFOMYCIN* OR PHOSPHOMYCIN* OR XIBORNOL* OR CLOFOCTOL* OR

SPECTINOMYCIN* OR METHENAMIN* OR NITROXOLIN* OR LINEZOLID OR DAPTOMYCIN* OR

FIDAXOMICIN* OR MURIPOCIN* OR TEDIZOLID)

ANTITUBERCULOUS DRUGS

(AMINOSALICYL* OR CYCLOSERIN* OR RIFAMPICIN* OR RIFAMYCIN* OR RIFABUTIN* OR

RIFAPENTIN* OR RIFAXIMIN* OR CAPREOMYCIN* OR ISONIAZID* OR PROTIONAMID* OR

TIOCARLID* OR ETHIONAMID* OR PYRAZINAMID* OR ETHAMBUTOL OR TERIZIDON* OR

MORINAMID* OR BEDAQUILIN* OR DELAMANID)