Safety of Ceftriaxone Sodium at Extremes of Age

Review

10.1517/14740330802299238 © 2008 Informa UK Ltd ISSN 1474-0338 515All rights reserved: reproduction in whole or in part not permitted

Safety of ceftriaxone sodium at extremes of age Scott V Monte † , William Allan Prescott Jr , Kristin K Johnson , Lori Kuhman & Joseph A Paladino †Diabetes and Cardiovascular Research, CPL Associates, LLC, 3980 Sheridan Drive, Amherst, NY 14226, USA

Background : Isolated reports of neonatal and infant deaths associated with ceftriaxone–calcium precipitation in the lungs and kidneys have prompted a recommendation from the US FDA in June 2007 advising that in patients of all ages, calcium-containing solutions should not be administered simultaneously or within 48 h of the last ceftriaxone dose. Objective : To provide a comprehensive review of the literature surrounding the safety of ceftriaxone in the neonatal ( ≤ 28 days) and geriatric populations ( ≥ 65 years). Methods : Multi-database literature search for original research articles, review articles and case reports pertaining to safety of ceftriaxone in the neonatal and geriatric populations. Results/conclusions : Ceftriaxone should be avoided or significantly minimized in neonates (especially those treated concomitantly with intravenous calcium solutions and those with hyperbilirubinemia), and potentially restricted in the geriatric population treated concomitantly with intravenous calcium.

Keywords: ceftriaxone , geriatrics , neonates , pediatrics , safety

Expert Opin. Drug Saf. (2008) 7(5):515-523

1. Introduction

First marketed in the US in 1984, ceftriaxone is indicated for a wide variety of infections. These include infections of the lower respiratory and urinary tracts, bacterial septicemia, skin and skin structure infections, bone and joint infections, pelvic inflammatory disease, uncomplicated gonorrhea, intra-abdominal infections, acute bacterial otitis media, meningitis, as well as surgical prophylaxis [1] . Broad spectrum activity, extended half-life, ease of administration and a favorable safety profile have made ceftriaxone a mainstay for empiric antimicrobial use in emergent and in-patient care [2] .

In June 2007, a ‘Dear Healthcare Professional’ letter from Roche Pharmaceuticals, distributed at the direction of the FDA, highlighted changes to the package insert concerning administration of ceftriaxone to neonates (especially prematures) in the setting of hyperbilirubinemia or calcium-containing solutions [1,3,4] . In the letter, attention was drawn to in vitro studies demonstrating ceftriaxone’s ability to displace bilirubin from its serum albumin binding sites, thereby increasing the risk of encephalopathy. There was also mention of isolated neonatal deaths attributed to intravenous calcium co-administration that produced renal and pulmonary precipitates. In the wake of iatrogenic neonatal mortality, recommendations against the use of concomitant calcium and ceftriaxone therapy were expanded to include the general population [5-7] . We are not aware of a comprehensive review of the literature accompanying these recommendations. Limiting the utilization of an efficacious and seemingly safe medication may have far-reaching clinical and economic ramifications. Our objective is to systematically review the literature for the safety of ceftriaxone use in the neonatal and geriatric populations.

1. Introduction

2. Ceftriaxone in neonates

(age ≤ 28 days)

3. Ceftriaxone in geriatrics

(age ≥ 65 years)

4. Conclusion

5. Expert opinion

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Safety of ceftriaxone sodium at extremes of age

516 Expert Opin. Drug Saf. (2008) 7(5)

A comprehensive, multi-database literature search was performed for both the neonatal (age ≤ 28 days) and geriatric (age ≥ 65 years) populations. Cumulative Index to Nursing and Allied Health Literature, Evidence Based Medicine (Cochrane Central Register of Controlled Trials and Cochrane Central Register Systematic Reviews), Ovid Healthstar, Ovid Journals and Medline databases were queried for titles including ceftriaxone and safety/adverse event related search terms. The search strategy included original research articles, review articles and case reports pertaining to safety of ceftriaxone; applicable literature was utilized to identify further in-reference publications satisfying the aforementioned neonatal and geriatric specifications. MedWatch reports were requested through the FDA Freedom of Information Act to identify postmarketing surveillance reports.

2. Ceftriaxone in neonates (age £ 28 days)

Ceftriaxone has been safely utilized in pediatric patients for more than 20 years, with the overall adverse event rate being similar to that of adults. The most commonly cited adverse events in pediatrics are diarrhea (5.6%) and hypersensitivity (3.4%), whereas other adverse events typically occur at a rate of less than 1% [8] . Although data supporting the use of ceftriax-one in neonates are limited, clinical experience has suggested it to be well tolerated [9-17] . However, in recent years the use of ceftriaxone in neonates has been mitigated by the emergence of significant toxicity concerns, and the availability of comparative and presumably safer antibiotic agents [18] .

2.1 Hyperbilirubinemia Ceftriaxone possesses the ability to displace bilirubin from serum albumin binding sites, potentially increasing the risk of bilirubin encephalopathy, or kernicterus (chronic and permanent clinical sequelae of bilirubin toxicity to the basal ganglia and brainstem nuclei, resulting in gross yellow staining of the brain and clinical neuromotor and neuroauditory impairment), in hyperbilirubinemic patients [19-25] . Published reports of a similar phenomenon date back to 1956 when sulfisoxazole administration was associated with increased mortality in jaundiced newborns [26] . In 1959, the increased mortality in this population was attributed to displacement of bilirubin from its binding site on serum albumin [27] .

As is the case with sulfisoxazole, ceftriaxone is highly protein bound, ranging from 85 to 95% [28] . The maximal displacement factor, a predictor of the effect that therapeutic levels of a highly protein bound drug has on bilirubin–albumin binding, has been reported to be 2.0 for ceftriaxone. As clini-cally significant displacement of bilirubin is thought to occur at a factor greater than 1.2, ceftriaxone may increase the risk of bilirubin encephalopathy in jaundiced neonates [20] .

Unfortunately, there are conflicting data and no consensus as to the exact bilirubin level below which the use of ceftriaxone in the neonatal population is safe. However, it is known that neonates produce bilirubin at approximately twice the rate

of adults until 10 – 14 days after birth, when it typically declines to adult levels [29] . This may suggest that if exposed to ceftriaxone after 14 days of life, it is less likely the neonate will develop kernicterus, provided the serum bilirubin level is within normal limits.

In most kernicterus cases, total bilirubin levels are > 20 mg/dl [30] . Risk factors for hyperbilirubinemia, maternal–fetal blood type incompatibilities, gestational diabetes, pre-maturity, male gender, glucose-6-phosphate dehydrogenase deficiency, breastfeeding and infection may predispose a neo-nate to developing kernicterus [31] . It is also plausible that ear-lier hospital discharge after birth may delay the diagnosis of hyperbilirubinemia and thus increase the risk of kernicterus. Irrespective of the cause, kernicterus is estimated to be associated with at least 10% mortality and 70% long-term morbidity [32] .

2.2 Cholestasis and pseudolithiasis High concentrations of ceftriaxone in the biliary system can result in ceftriaxone–calcium complex concentrations that exceed solubility limits, thereby yielding precipitation and concerns of cholestasis and pseudolithiasis [33,34] . Cholestasis and pseudolithiasis have been reported to occur commonly in a wide range of pediatric patients, are relatively benign and typically resolve on ceftriaxone discontinuation [35-60] . The occurrence in the neonatal literature is limited to a single case report in which a 17-day-old full-term neonate was treated with ceftriaxone 100 mg/kg/day for suspected sepsis. Following 7 days of treatment, the patient was observed to be icteric, with marked total and direct bilirubin elevations and evidence of biliary sludging on abdominal ultrasound. Following ceftriaxone discontinuation, all laboratory parameters returned to normal within 3 days, and follow-up ultrasound of the gallbladder 7 days later was negative [61] .

2.3 Renal and pulmonary ceftriaxone–calcium precipitates The co-administration of intravenous ceftriaxone and calcium-containing solutions has been reported to result in ceftriaxone–calcium complexation with renal and pulmonary precipitates in the neonatal and infantile populations. This interaction between ceftriaxone and calcium has only been identified when each are administered intravenously. Evidence of an interaction between intravenous ceftriaxone and oral calcium, or between intramuscular ceftriaxone and intravenous or oral calcium is lacking.

Case reports detailing the specific circumstances have not been published but postmarketing surveillance has shown the sudden deaths of five neonates (one full-term, three premature and one of unknown gestational age) related to the concomi-tant use of intravenous ceftriaxone and calcium-containing solutions ( Table 1 ) [4,6] . In four of these five cases, ceftriaxone and the calcium-containing solution seem to have been administered via the same infusion line, whereas in the fifth case they were administered via different sites and at different times. In at least two neonates, autopsy confirmed crystalline

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Monte, Prescott Jr, Johnson, Kuhman & Paladino

Expert Opin. Drug Saf. (2008) 7(5) 517

Tab

le 1

. Po

stm

arke

tin

g s

urv

eilla

nce

rep

ort

s o

f ce

ftri

axo

ne–

calc

ium

inte

ract

ion

.

Cas

e #

(rep

ort

dat

e)

Ag

e Se

x Pr

emat

ure

/fu

ll te

rm (

WG

A)

Cef

tria

xon

e ro

ute

C

a p

rod

uct

ro

ute

In

fusi

on

sit

e O

utc

om

e A

uto

psy

fi n

din

gs

1 (D

ecem

ber

1992

)12

day

sFe

mal

eN

R (N

R)IV

Ca-

cont

aini

ng

solu

tion

IVSa

me

line

(Y-s

ite)

Dea

th: u

nkno

wn

caus

eA

utop

sy r

efus

ed

2 (J

uly

1994

)1

day

NR

Prem

atur

e (N

R)IV

Ca-

gluc

onat

e IV

Sam

e lin

eD

eath

: pul

mon

ary

embo

lism

–

neon

ate

died

imm

edia

tely

fo

llow

ing

inje

ctio

n of

a w

hite

pr

ecip

itate

at

end

of t

ubul

ure

Pulm

onar

y em

bolis

m

3 (N

ovem

ber

1995

)2.

5 m

onth

sN

RN

R (N

R)IV

Ca-

gluc

onat

e IV

NR

Dea

th: c

ardi

omyo

path

y (p

re-e

xist

ing)

Pres

ence

of

crys

tals

in lu

ngs

4 (M

ay 1

996)

3 w

eeks

Mal

eFu

ll te

rm

(37

WG

A)

IVC

a-gl

ucon

ate

IVSa

me

line

Dea

th: c

ardi

opul

mon

ary

arre

st –

ne

onat

e sc

ream

ed w

ith p

ain

and

died

sud

denl

y w

ithin

90

min

fo

llow

ing

ceft

riaxo

ne d

ose

Cry

stal

line

embo

li in

lung

s an

d ki

dney

s

5 (S

epte

mbe

r 19

97)

2 da

ysM

ale

Prem

atur

e (3

1 W

GA

)IV

Ca-

gluc

onat

e IV

Sam

e lin

eD

eath

: car

diac

arr

est

Cry

stal

line

thro

mbi

in

lung

, cor

onar

y,

hepa

tic c

ircul

atio

n

6 (O

ctob

er 1

997)

NR

NR

Prem

atur

e (N

R)IV

Ca-

gluc

onat

e IV

NR

Dea

th: p

ulm

onar

y em

bolis

mN

R

7 (O

ctob

er 2

002)

1 da

yM

ale

Prem

atur

e (3

6 W

GA

)IV

Ca-

gluc

onat

e IV

Diff

eren

t lin

eD

eath

: unk

now

n ca

use

– ne

onat

e ex

perie

nced

acu

te c

ircul

ator

y ar

rest

a

few

min

utes

fol

low

ing

ceft

riaxo

ne

dose

Neg

ativ

e

8 (F

ebru

ary

2004

)1

year

Mal

eFu

ll te

rm

(38

WG

A)

IVC

a-gl

ucon

ate

IVN

RD

eath

: car

diac

arr

est

NR

9 (F

ebru

ary

2007

)50

day

sM

ale

Prem

atur

e (3

0 W

GA

)In

ject

ion

TPN

IVN

RPr

olon

ged

hosp

italiz

atio

n: in

fant

de

velo

ped

shoc

k w

ith b

rady

card

ia,

pallo

r an

d ap

nea

imm

edia

tely

fo

llow

ing

dose

s #1

and

#2

of c

eftr

iaxo

ne

Not

app

licab

le

Ca:

Cal

cium

; IV

: Int

rave

nous

; NR:

Not

rep

orte

d; T

PN: T

otal

par

ente

ral n

utrit

ion;

WG

A: W

eeks

ges

tatio

nal a

ge.

Exp

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material in, but not limited to, the pulmonary and renal vasculature. In a third neonate, autopsy identified a pulmonary embolism, believed to have occurred secondary to the injection of a white precipitate that had formed at the end of the intra-venous tubing. In addition to these five postmarketing reports, the FDA has received four additional reports of an interaction between intravenously administered ceftriaxone and calcium-containing solutions (calcium gluconate and total parenteral nutrition) in patients ≤ 1 year of age ( Table 1 ) [6] . Three of these cases resulted in death, one of whose autopsy showed evidence of crystalline precipitates in the lungs.

The FDA has recommended that ceftriaxone should not be reconstituted, mixed or administered simultaneously to any patient, especially neonates, regardless of the site of infusion, with calcium-containing solutions for intravenous administration (Ringer’s solution, Ringer’s lactate solution, Hartmann’s solution or parenteral nutrition), nor should calcium-containing solutions be given within 48 h of ceftriax-one administration. The interval recommendation was derived from the theoretical possibility that a patient may be at risk for this interaction until ceftriaxone clearance is nearly complete. The elimination half-life of ceftriaxone is 4.3 – 4.6 h in pediatric patients, 5.8 – 8.7 h in healthy adults and 8.9 h in elderly subjects [1] . Therefore, the recommended interval of 48 h exceeds five ceftriaxone half-lifes and would be expected to adequately cover most age groups. However, ceftriaxone clearance is highly variable in neonates, with the slowest clearance observed during the first week of life [62] . The half-life of ceftriaxone in neonates ranges from 5.2 to 18.6 h, and has been observed to be as long as 34 h in indi-vidual patients. Thus, if ceftriaxone is used in the neonatal population, a longer time interval between ceftriaxone discontinuation and the use of intravenous calcium-containing solutions may be warranted [10,11,62,63] .

Although the reported cases suggest an interaction between intravenous ceftriaxone and calcium-containing solutions, critical analysis of the reports suggest that the presence of confounding factors such as severe underlying medical conditions, hypersensitivity to ceftriaxone and potential dosing errors with other medications must be considered. In addition, several studies evaluating the pharmacokinetics and safety of ceftriaxone in neonates have not identified a risk of ceftriaxone–calcium precipitation in the lungs or kidneys [9-17] , despite one such study including the use of total parenteral nutrition [12] . Unfortunately, these studies are not robust, with small patient populations and inconsistent medication, fluid and nutrition documentation being primary limitations.

3. Ceftriaxone in geriatrics (age ≥ 65 years)

Ceftriaxone is a frequently prescribed antibiotic in the geriatric population owing to its broad spectrum of action and ability to treat a variety of infections, such as urinary tract infection and pneumonia, commonly seen in older populations.

From a dosing and tolerability perspective, it is an ideal compound for the geriatric population owing to the absence of renal or hepatic adjustment requirements and infrequent adverse events. In the general population, eosinophilia (6%), thrombocytosis (5.1%), elevated liver function tests (3.1 – 3.3%) and diarrhea (2.7%) are encountered with ceftriaxone treatment. In rare cases, more serious adverse events such as hyperbili-rubinemia and pseudolithiasis are known to occur [1] . Few publications focus on adverse events of ceftriaxone in the geri-atric population. Reviewing the available literature for the spectrum of ceftriaxone adverse events, the most robust data were identified through case reporting. Table 2 presents a sum-mary of the case report literature for ceftriaxone-associated adverse events in the geriatric population.

3.1 Hyperbilirubinemia The most common case reports of ceftriaxone-associated events in the geriatric population describe hyperbilirubinemia, notably an increase in indirect bilirubin. These cases are associated with a ceftriaxone-induced immune hemolytic anemia [64-67] . Iatrogenic immune hemolytic anemia occurs secondary to antibody production that leads to the destruction of red blood cells and thereby to an increase in the breakdown of hemoglobin, an increase in lactate dehydrogenase and a subsequent increase in indirect bilirubin [68] . Therefore, the mechanism of hyperbilirubinemia observed in this population is correlated with hemolysis and not with the displacement of bilirubin from albumin binding sites. In most ceftriaxone-induced hemolytic anemia cases, resolution has been swift with ceftriaxone discontinuance or medical intervention [64-67] . In only one case was death a reported outcome [67] .

3.2 Cholestasis and pseudolithiasis Ceftriaxone-associated cholestasis and pseudolithiasis have been documented in the pediatric and adult literature but only isolated case reports have been described in the geriatric population [69,70] . In one patient, discontinuance of ceftriaxone did not ameliorate symptoms and cholecystectomy was required [69] , whereas in the latter case, discontinuance led to complete resolution [70] .

To explain the influence of ceftriaxone on the incidence of gallbladder lithiasis, 74 patients were evaluated after receiving at least 7 days of ceftriaxone (n = 40) or amoxicillin/clavulanate (n = 34) [71] . Biliary ultrasound was performed at baseline and repeated at 6 and 12 months. Gallbladder lithiasis was seen in 5 patients in each treatment group. In the ceftriaxone group, it was reported that 1 patient had a pre-existing stone, 2 were probable for pre-existing stones (control sonography was not performed until days 2 through 6 of antibiotic therapy) and 2 had new biliary precipitates. The amoxicillin/clavulanate arm showed similar results with 2 patients having pre-existing biliary stones, 2 having probable pre-existing stones and 1 developing a new stone. This analysis concluded that ceftriaxone did not

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Tab

le 2

. Cas

e re

po

rts

of

ceft

riax

on

e-as

soci

ated

ad

vers

e ev

ents

in t

he

ger

iatr

ic p

op

ula

tio

n.

Ref

. A

ge/

sex

Prim

ary

dia

gn

osi

s D

ays

on

ce

ftri

axo

ne

(rea

ctio

n o

nse

t)

Do

se

Clin

ical

fea

ture

s A

dve

rse

even

t In

terv

enti

on

O

utc

om

e

Fale

zza

et a

l. [6

4]

79/F

Div

ertic

uliti

s7

(day

7)

2 g

daily

Pain

, fat

igue

, pal

lor,

jaun

dice

, an

emia

, sig

ns o

f in

trav

ascu

lar

hem

olys

is, i

ncre

ased

indi

rect

bili

rubi

n,

elev

ated

LD

H a

nd h

emog

lobi

nem

ia

IHA

Dis

cont

inua

nce

Reso

lutio

n

Lo [6

5]

67/F

Sept

ic a

rthr

itis

34 (d

ay 3

4)U

nkno

wn

Ane

mia

, ele

vate

d to

tal b

iliru

bin,

LD

H

and

hem

oglo

binu

riaIH

AD

isco

ntin

uanc

e C

ortic

oste

roid

sRe

solu

tion

Long

o et

al.

[66]

80

/MBr

onch

opne

umon

ia13

(day

16)

2 g

daily

Pain

less

, afe

brile

, cho

lest

atic

ja

undi

ce, l

etha

rgy,

ane

mia

, po

sitiv

e C

oom

bs Ig

G t

est,

el

evat

ed A

ST a

nd A

LT, e

leva

ted

tota

l and

con

juga

ted

bilir

ubin

, el

evat

ed ϒ

-glu

tam

yl t

rans

pept

idas

e,

elev

ated

alk

alin

e ph

osph

atas

e

IHA

A

cute

hep

atiti

s Er

ythr

obla

stoc

ytop

enia

Ster

oids

Im

mun

oglo

bulin

s RB

C t

rans

fusi

on

Reso

lutio

n

Selts

am e

t al.

[67]

68

/FM

enin

gora

dicu

litis

10 (d

ay 1

0)U

nkno

wn

Lum

bar

pain

, ane

mia

, hem

oglo

binu

ria,

elev

ated

LD

H, e

leva

ted

tota

l bili

rubi

n an

d re

nal f

ailu

re

IHA

Dia

lysi

sRe

solu

tion

Selts

am e

t al.

[67]

64

/FO

bstr

uctiv

e ja

undi

ce1

(30

min

)2

gLu

mba

r pa

in, s

hock

, ane

mia

, el

evat

ed L

DH

, hem

oglo

binu

riaIH

AU

nspe

cifi e

dD

eath

Fam

ular

o et

al.

[69]

71

/FTo

oth

absc

ess

10 (d

ay 1

0)2

g da

ilyFe

ver,

leuk

ocyt

osis

, bili

ary

vom

iting

, se

vere

pai

n in

the

epi

gast

rium

, RU

Q

and

periu

mbi

lical

reg

ion

radi

atin

g to

th

e ba

ck, e

leva

ted

seru

m a

myl

ase,

lip

ase,

AST

and

ALT

, alk

alin

e ph

osph

atas

e, t

otal

bili

rubi

n,

ϒ -gl

utam

yl t

rans

pept

idas

e

Bilia

ry s

ludg

e A

cute

cho

lecy

stits

Pa

ncre

atiti

s

Cho

lecy

stec

tom

yRe

solu

tion

Zinb

erg

et a

l. [7

0]

73/F

Intr

aven

ous

site

in

fect

ion

14 (d

ay 1

2)1

g q1

2Po

stpr

andi

al n

ause

a, e

piga

stric

an

d RU

Q p

ain,

ele

vate

d al

kalin

e ph

osph

atas

e, A

ST a

nd A

LT,

elev

ated

am

ylas

e

Bilia

ry o

bstr

uctio

n (p

seud

olith

iasi

s)D

isco

ntin

uanc

eRe

solu

tion

Thom

as e

t al

. [72

] 77

/FU

TI, b

acte

rem

ia,

infe

cted

hip

pro

sthe

sis

26 (d

ay 1

9)2

g da

ilyItc

hy g

ener

aliz

ed r

ash,

eo

sino

phili

a, n

eutr

open

iaN

eutr

open

iaD

isco

ntin

uanc

eRe

solu

tion

Gro

ssjo

han

et a

l. [7

3]

66/U

Borr

elio

sis

10 (d

ay 1

0)2

g da

ilyTh

rom

bocy

tope

nia

Thro

mbo

cyto

peni

aD

isco

ntin

uanc

eRe

solu

tion

Zim

mer

man

[74]

71

/FG

ram

-neg

ativ

e ca

thet

er s

epsi

s4

(day

4)

2 g

daily

Acu

te a

bdom

inal

pai

n, le

ukoc

ytos

is,

jaun

dice

, mar

kedl

y el

evat

ed

amyl

ase

and

lipas

e

Panc

reat

itis

Dis

cont

inua

nce

Reso

lutio

n

ALT

: Ala

nine

am

inot

rans

fera

se; A

ST: A

spar

tate

am

inot

rans

fera

se; F

: Fem

ale;

IHA

: Im

mun

e he

mol

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induce gallstone formation more frequently than an antibiotic that is not eliminated through the bile.

Although the aforementioned analysis was not specific to the geriatric population (mean age: amoxicillin/clavulanate 44 ± 19.4 years, ceftriaxone 51 ± 18.8 years), the infrequent occurrence of cholestasis and pseudolithiasis in the geriatric case report literature concurrent with findings in older individuals that suggest ceftriaxone may not induce gallstone formation more frequently than agents not eliminated through the bile is suggestive that ceftriaxone is a safe therapeutic selection for geriatric patients.

3.3 Blood dyscrasias, hepatitis and pancreatitis Ceftriaxone associated neutropenia [72] , thrombocytopenia [73] , elevations in liver enzymes [66] and pancreatitis [69,74] have been infrequently reported in the geriatric literature. In these adverse event case reports, ceftriaxone discontinuation resulted in symptom resolution and return to baseline status.

3.4 Renal and pulmonary ceftriaxone–calcium precipitates There have been no published reports involving precipitates in the lungs or kidneys of ceftriaxone-treated geriatric patients [5,6] . However, the potential for renal and pulmonary precipitates during concomitant ceftriaxone and calcium therapy is of practical importance owing to common require-ments for parenteral nutrition and other intravenous solutions containing calcium. The absence of documented renal and pulmonary precipitates is noted within the prescribing clarification for ceftriaxone by means of the provisional statement that concerns beyond the neonatal population are theoretical [5] .

4. Conclusion

Despite a lack of robust data, isolated case reports of deaths in neonates treated concomitantly with intravenous ceftriaxone and calcium-containing solutions, the suggested increased risk of kernicterus in hyperbilirubinemic neonates treated with ceftriaxone and the availability of safer alternatives suggest that it is prudent to avoid or significantly minimize the use of this antibiotic in this population. Neonates and young infants, in whom death has also been reported, may be most vulnerable to serious adverse events with ceftriaxone given the anatomic structure of their pulmonary vasculature, low circulating blood volume, immaturity of the blood–brain barrier and the prolonged half-life of the antibiotic [75,76] . In contrast to this population, there is no evidence suggesting a risk for intravascular precipitates in the geriatric population treated with ceftriaxone and calcium-containing solutions. Regardless, the presence of theoretical risk remains, and the current manufacturer’s recommendation is to avoid the mixing or simultaneous administration of ceftriaxone and calcium-containing solutions and to

avoid the administration of calcium-containing solutions within 48 h of the most recent ceftriaxone dose in any patient, including non-neonatal populations.

5. Expert opinion

Ceftriaxone offers excellent cerebrospinal fluid penetration and tissue distribution, a long elimination half-life allowing once daily dosing in most cases and efficacy against many pathogens of bacterial sepsis and meningitis. Although ceftriaxone has been used for more than 20 years, the occurrence of sporadic but serious adverse events have given rise to concerns about safety, especially in neonates treated concomitantly with intravenous calcium-containing solutions. Although analysis of individual reports detailing the interaction between ceftriaxone and intravenous calcium-containing solutions may be incomplete or contain confounding variables, analysis of all cases collectively suggest the interaction to be clinically significant. If used in this population, the recommended 48-h window between the last ceftriaxone dose and the initiation of intravenous calcium may be too narrow, especially among neonates in their first week of life, in whom 96 h may be more appropriate. Regardless, ceftriaxone is traditionally avoided in neonates irrespective of bilirubin level or current hydration fluids (calcium-containing or otherwise), and it seems even more prudent now to continue this practice. In most cases, cefotaxime may serve as an appropriate alternative antimicrobial agent [18] , although in cases where coverage with greater Gram-positive activity is required, an alternative such as cefepime may be considered [77] . It is difficult to make definitive recommendations about the use of ceftriaxone in older pediatric populations at this time. However, owing to the severity of this adverse event, the use of ceftriaxone with intravenous calcium-containing solutions cannot be recom-mended without a greater compilation of safety data, especially in infants in whom adverse consequences have been reported. If ceftriaxone and intravenous calcium-containing solutions are used concomitantly in older children and adolescents, caution is advised.

In the geriatric population, ceftriaxone has been used with an infrequent occurrence of adverse events. Most adverse events are mild and transient as resolution is common with discontinuance or minor medical intervention. Recent renal and pulmonary events noted in the neonatal population have created concern for the geriatric population that has an inherent requirement for exogenous calcium. In a situation where theoretical concern is extrapolated from a distinctly dissimilar population, there will be controversy about the prudent course of action. Intuitively, years of clinical experience would provide grounds to subvert recommendations that stipulate avoidance of concomitant use and a 48-h window after the administration of ceftriaxone before intravenous calcium-containing solutions

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Declaration of interest

The authors declare no conflict of interest and have received no payment in the preparation of this manuscript.

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Affi liation Scott V Monte † 1 PharmD , William Allan Prescott Jr 2 PharmD , Kristin K Johnson 3 PharmD , Lori Kuhman 4 PharmD & Joseph A Paladino 5 PharmD † Author for correspondence 1 Clinical Assistant Professor, University at Buffalo, Director of Diabetes and Cardiovascular Research, CPL Associates, LLC, 3980 Sheridan Drive, Amherst, NY 14226, USA Tel: +1 1 011 716 839 4931 ext. 217 ;Fax: +1 716 713 52423 ; E-mail: [email protected] 2 Clinical Assistant Professor University at Buffalo, 313 Cooke Hall, Amherst, NY 14260, USA 3 Clinical Instructor, University at Buffalo, Clinical Pharmacy Coordinator, The Women and Children’s Hospital of Buffalo, 219 Bryant Street, Buffalo, NY 14222, USA 4 Clinical Pharmacy Coordinator Kaleida Health Gates Circle Hospital, 3 Gates Circle, Buffalo, NY 14209, USA 5 Clinical Professor, University at Buffalo, Director, Outcomes Research, CPL Associates, LLC, 3980 Sheridan Drive, Amherst, NY 14226, USA

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