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Chapter 6. Monographs on individual drugs

Chapter 6. Monographs on individual drugs

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Antimicrobial drugs, pp. 75-203



1.0% (1.06 x 900/1000)* and a maximum of 1.3% (1.45 x 900/1000)* of the

weight-adjusted maternal daily oral dose (1). Alternatively, a suckling infant would

ingest in a feed at maximum 1.5% (7.3 x 180/900)* and on average 4.9% (4.88 x

900/900)* of the weight-adjusted maternal daily i.v. dose (2).

DATA ON THE INFANT

No data are available.

ASSESSMENT AND RECOMMENDATIONS

Data from two mothers suggests that the risk to the suckling infant of administering

aciclovir to its mother is low on the basis that the quantity of drug that passes into

milk is small. Breast feeding can probably be regarded as safe.

REFERENCES

1. Myer LJ, de Miranda P, Sheth N, Spruance S (1988) Acyclovir in human breast milk. Am. J.

Obstet. Gynecol., 158, 586-588.

2. Bork K, Benes (1995) Concentration and kinetic studies of intravenous acyclovir in serum and

breast milk of a patient with eczema herpeticum. J. Am. Acad. Derm., 32, 1053-1055.



* An explanation of the calculation (s) appears on pp. 71-72.



76



Antimicrobial drugs, pp. 75-203



AMIKACIN

GENERAL

Amikacin is an aminoglycoside antibiotic. It is poorly absorbed from the adult gastrointestinal tract and is given by i.m or i.v. injection or by i.v. infusion. It is negligibly bound to plasma proteins. Amikacin is eliminated unchanged in the urine and

the plasma half-life is 2 h. Renal excretion of aminoglycosides is generally slower

in neonates.

EVALUATION OF DATA

Passage of amikacin into human milk has been reported as follows"

Treatment conditions

Dose x Frequency x

Duration; Route; No.

of patients; Lactation

stage

100 mg x 1/d x 1 d;

i.m." 2-3; 5-7 d



Concentration

(mg/1)



Milk/

plasma

ratio



Milk



Plasma



Trace



1.93



.



Maximum

observed

milk conc.

(mg/1)



.



.



Absolute dose

to infant (mg/kg/day)

Ave



Ref.



Max



.



(1)



The table gives average plasma concentration based in the area under the concentration-time curve, the peak concentration being 4.2 mg/1. Only trace amounts were found in milk but the lower limit of sensitivity of the assay is

not stated.



RELATIVE DOSE IN MILK

As the amount in milk was not quantified, a relative dose cannot be calculated.

DATA ON THE INFANT

No data are available.

ASSESSMENT AND RECOMMENDATIONS

The quantity of amikacin in milk after a single dose to the mother was too small to

quantify. There are no data on which to base an estimate of the amount ingested by

the infant under steady-state conditions at an appropriate maternal dose. In common with other aminoglycosides, amikacin may be eliminated more slowly by the

infant, especially the neonate, in which it may thus accumulate. Use of amikacin is

best avoided when breast-feeding a neonate but is probably safe when the infant is

older.

77



Antimicrobial drugs, pp. 75-203

REFERENCE

1. Matsuda T (1984) Transfer of antibiotics into maternal milk. Biol. Res. Preg., 5, 57-60.



78



Antimicrobial drugs, pp. 75-203



AMOXICILLIN

GENERAL

Amoxicillin (amoxycillin) is a penicillin antibiotic closely related to ampicillin (see

p. 81) in its antibacterial spectrum, but more lipid soluble. After oral administration

peak concentrations are attained in 1-2 h in the adult and absorption is little affected by food. Plasma protein binding is 20% and it is eliminated by the kidney.

The plasma half-life is 1 h.

EVALUATION OF DATA

Passage of amoxicillin into human milk has been reported as follows:

Treatment conditions

Dose • Frequency x

Duration; Route; No.

of patients; Lactation

stage

1000 mg • 1/d • 0.43;

p.o.; 6; 3 d



Concentration

(mg/1)



Milk/

plasma

ratio



Milk



Plasma



0.43



8.75



0.05



Maximum

observed

milk conc.

(mg/l)



1.3



Absolute dose

to infant (mg/kg/day)

Ave



Max



0.45



1.29



Ref.



(1)



Concentration-time profiles were defined for 3 h (serum) and 6 h (milk) after dosing. The peak concentration was

observed at 2 h in serum and after 4-5 h in milk. The quoted milk and serum concentrations are average values

over these times based on area measurements; the maximum concentration is the highest value recorded in an

individual.



RELATIVE DOSE IN MILK

The amount of amoxicillin which a suckling infant would ingest in a feed is at

maximum 0.2% (1.3 x 180/1000)* of the weight-adjusted maternal single dose (1).

DATA ON THE INFANT

No adverse effects were recorded in infants nursed by mothers taking amoxicillin

in the quoted study.

ASSESSMENT AND RECOMMENDATIONS

Only single dose data are available, but the risk to the suckling infant of administering amoxicillin to its mother would appear to be low on the basis that the

* An explanation of the calculation (s) appears on pp. 71-72.



79



Antimicrobial drugs, pp. 75-203



quantity of drug that passes into milk is small. Breast feeding may be regarded as

safe.

REFERENCE

1. Kafetzis DA, Siafas CA, Georgakopoulos PA, Papadatos CJ (1981) Passage of cephalosporins

and amoxycillin into the breast milk. Acta Paediatr. Scand., 70, 285-288.



80



Antimicrobial drugs, pp. 75-203



AMPICILLIN



GENERAL

Ampicillin is a aminopenicillin antibiotic. It is rapidly absorbed from the adult

gastrointestinal tract, is 20% bound to plasma proteins and is eliminated largely

unchanged in the urine. The plasma elimination half-life is 1 h.

EVALUATION OF DATA

Passage of ampicillin into human milk has been reported as follows:

Treatment conditions

Dose x Frequency x

Duration; Route; No.

of patients; Lactation

stage

500 mg x 1/d x 1 d;

p.o.; 2-3; 5-7 d

4 g/d x 5 d; p.o.; 13; ?

350 mg x 3/d x ?; p.o.;

12; 0-22 d

700 mg x 3/d x ?; p.o.;

2; 0-22 d



Concentration

(mg/1)



Milk/

plasma

ratio



Maximum

observed

milk conc.

(mg/l)



Milk



Plasma



0.11



2.21



0.05



0.91 (ave.)

0.034-0.082



8.60 (ave.)

006-8.2



0.03-0.11

0.01-0.58



0.25-1.02



0.74-13.83



0.027-0.52 1.02



Absolute dose

to infant (mg/kg/day)



Ref.



Ave



Max



0.02



0.03



1



(1)



2.74

0.082



0.66

0.01



-



(2)

(3)



0.15



-



(3)



Average values based on the areas under the milk amd plasma concentration-time curves for 6 h are given for (1).

The maximum milk concentration is the highest value recorded in an individual. In reference (3) pivampicillin

was administered to mothers with puerperal infections and ampicillin was assayed. Steady-state dosing conditions

are assumed to apply. A further study (4) reported milk to plasma ratios consistent with those in the table.



RELATIVE DOSE IN MILK



A suckling infant would ingest in a feed at maximum 0.1% (0.2 x 180/500)* of the

maternal single dose (1) and at maximum 0.6 % (2.74 x 900/4000) of the weightadjusted maternal daily dose (2).

DATA ON THE INFANT

Six infants whose mothers took pivampicillin for puerperal infection were

estimated to have received in milk 0.06-0.37% of the maternal daily dose (5).



* An explanation of the calculation (s) appears on pp. 71-72.



81



Antimicrobial drugs, pp. 75-203



ASSESSMENT AND RECOMMENDATIONS

The risk to the suckling infant of administering ampicillin to its m o t h e r is low on

the basis that the quantity of drug that passes into milk is small. Breastfeeding

should be regarded as safe.

REFERENCES

1. Matsuda T (1984) Transfer of antibiotics into matemal milk. Biol. Res. Pregnancy Perinatol., 5,

57-60.

2. Peiker G, SchrcSder S (1986) Investigations concerning concentrations of oxacillin and ampicillin

Penstabil| in the serum and milk of mothers suffering from mastitis puerperalis. Pharmazie, 41,

793-795.

3. Branebjerg PE, Heisterberg L (1987) Blood and milk concentrations of ampicillin in mothers

treated with pivampicillin and in their infants. J. Perinatol. Med., 15, 555-558.

4. Amiraslanova LA, Emelyanova AI, Fursova SA, Rukhadze TG (1985). Some aspects of

ampicillin, kanamycin and cerufoxim pharmacokinetics in puerperant patients with endometritis.

Akush. Ginekol. (Mosk.), 1O, 14-17.

5. Matheson I, Samseth M, Sande HA (1988) Ampicillin in breast milk during puerperal infections.

Eur. J. Clin. Pharmacol., 34, 657-659.



82



Antimicrobial drugs, pp. 75-203



AZTREONAM

GENERAL

Aztreonam is a fl-lactam antibiotic. It is poorly absorbed from the gastrointestinal

tract and is administered by i.m. injection or i.v. infusion. Aztreonam is 56% bound

to plasma proteins and 65% of the dose appears in the urine unchanged. The plasma

half-life is 2 h in adults.

EVALUATION OF DATA

Passage of aztreonam into human milk has been reported as follows"

Treatment conditions

Dose x Frequency x

Duration; Route; No.

of patients; Lactation

stage

1000mg x 1 x I/d;

i.v." 10; colostrum



Concentration

(mg/1)



Milk/

plasma

ratio



Milk



Plasma



<0.4-1.0

(3 h)



2.5-32.4

(1.5-2 h)



Maximum

observed

milk conc.

(mg/l)



1.0



Absolute dose

to infant (mg/kg/day)

Ave



Max



-



0.15



Ref.



(1)



The milk and serum values while not concurrent indicate a low milk/serum ratio. Negligible transfer of aztreonam

into milk is also suggested by other data (2).



RELATIVE DOSE IN MILK

The amount of aztreonam which a suckling infant would ingest in a feed is at

maximum 0.2% (1 x 180/1000)* of the weight-adjusted maternal single dose. The

dose to the infant would be less than this estimate if aztreonam is incompletely

absorbed from its gastrointestinal tract.

DATA ON THE INFANT

No data are recorded.

ASSESSMENT AND RECOMMENDATIONS

The risk to the suckling infant of administering aztreonam to its mother is low on

the basis that the quantity of drug that passes into milk is small. Breast feeding may

be regarded as safe.

* An explanation of the calculation(s) appears on pp 71-72.



83



Antimicrobial drugs, pp. 75-203

REFERENCES

1. Ito K, Hirose R, Tamaya T, Yamada Y, Izumi K (1990) Pharmacokinetic and clinical studies on

aztreonam in the perinatal period. Jpn. J. Antibiot., 43, 719-726.

2. Matsuda S, Oh K, Hirayama H, Shimizu T, Sengoku K, Haga H, Inoue H et al. (1990)

Pharmacokinetics and clinical evaluations on aztreonam in perinatal infections in obstetrics and

gynecology. Jpn. J. Antibiot., 43, 736-753.



84



Antimicrobial drugs, pp. 75-203



BENZYLPENICILLIN

GENERAL



Benzylpenicillin is an antibiotic that is acid labile and is not suitable for administration by mouth. Following i.m. injection in the adult, it penetrates effectively

into most tissues. About 50% is bound to plasma proteins and it is rapidly excreted

in the urine. The plasma half-life is 0.5 h.

EVALUATION OF DATA



Passage of penicillin into human milk has been reported as follows:

Treatment conditions

Dose x Frequency x

Duration; Route; No.

of patients; Lactation

stage



Concentration

(mg/1)

Milk



360 mg • 1/d x 1 d;

0.21

i.m.; 2-3; 5-7 d

120-360 mg x 1/d •

0.12

1 d; i.m.; 13; 2-8 d

60 mg x lid x 1 d; i.m.; <0.01--0.02

7; 2 - 5 d

60 mg x 2/h • 6 h;

0.03

i.m.; 3; 2-5 d



Milk/

plasma

ratio

Plasma



Maximum

observed

milk conc.

(mg/1)



Absolute dose

to infant (mg/kg/day)

Ave



Max



Ref.



0.37



0.57



0.37



0.03



0.06



(1)



0.34



0.35



0.58



0.02



0.09



(2)



0.23-1.15



.



0.48



0.06



.



.

-



.



(3)

-



-



(3)



The milk and serum concentration-time profiles were defined over 6 h after dosing in reference (1) and were concurrent. In references (1) and (2) the quoted milk and serum concentrations were average values and the maximum

concentration was the highest value recorded in an individual. In reference (3) only a single pair of milk and serum samples was taken from each mother 1-2 h after the last dose. Both references (2) and (3) give doses and

concentrations in units and units/ml and a conversion of 1 unit = 0.6 Ixg has been used. Passage of certain derivatives of benzylpenicillin into breast milk has also been studied; these include dimethoxyphenylpeniciUin, methylphenylisoxazoylylpenicillin, methylchlorophenylisoxazolylpenicillin and methyldichlorophenylisoxazolylpenicillin (1). The milk concentrations of these substances after a single dose are in general similar to those of

benzylpenicillin.



RELATIVE DOSE IN MILK

The amount of benzylpenicillin that a suckling infant would ingest in a feed is at

maximum 0.2% (0.37 x 180/360)* of the weight-adjusted maternal single dose (1).



* An explanation of the calculation (s) appears on pp. 71-72.



85



Antimicrobial drugs, pp. 75-203



DATA ON THE INFANT

No adverse effects were reported in the infants studied.

ASSESSMENT AND RECOMMENDATIONS

Only single dose data are available, but the risk to the suckling infant of administering benzylpenicillin to its mother is low on the basis that the quantity of drug

that passes into milk is small. Breast feeding may be regarded as safe.

REFERENCES

1. Matsuda S (1984) Transfer of antibiotics into matemal milk. Biol. Res. Pregnancy Perinatol., 5,

57-60.

2. RozanskyR, Brzezinsky A (1949) The excretion of penicillin in human milk. J. Lab. Clin. Med.,

34, 497-500.

3. Greene HJ, Burkhart B, Hobby GL (1946) Excretion of penicillin in human milk following parturition. Am. J. Obstet. Gynecol., 51,732-733.



86



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