Pediatric Pulmonology

State of the Art

Optimization of Anti-pseudomonal Antibiotics forCystic Fibrosis Pulmonary Exacerbations:

I. Aztreonam and Carbapenems

Jeffery T. Zobell, PharmD,1,2* David C. Young, PharmD,3,4 C. Dustin Waters, PharmD, BCPS,4,5

Chris Stockmann, MSc,6,7 Krow Ampofo, MD,6 Catherine M.T. Sherwin, PhD,7 andMichael G. Spigarelli, MD, PhD

7

Summary. Acute pulmonary exacerbations (APE) in cystic fibrosis (CF) are associated with loss

of lung function that may require aggressive management with intravenous antibiotics. The aim

of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic

(PK/PD), tolerability, and efficacy studies utilizing aztreonam and anti-pseudomonal carbape-

nems (i.e., doripenem, imipenem–cilastatin, and meropenem) in the treatment of an APE, and

to identify areas where further study is warranted. The current dosing recommendations in the

United States and Europe for aztreonam are lower than the literature supported dosing range

of 200–300 mg/kg/day divided every 6 hr, maximum 8–12 g/day. In vitro, PK/PD, and tolerability

studies show the potential of doripenem 90 mg/kg/day divided every 8 hr, infused over 4 hr,

maximum 6 g/day in the treatment of APE. Imipenem-cilastatin 100 mg/kg/day divided every

6 hr, maximum 4 g/day and meropenem 120 mg/kg/day divided every 8 hr, maximum 6 g/day

have been shown to be tolerable and effective in the treatment of APE. With availability issues

of new anti-pseudomonal agents and a large percentage of CF patients will not regain their

lung function following an APE, we suggest the need to determine optimization of aztreonam

and meropenem dosing in CF, as well as to determine the clinical efficacy of doripenem in the

treatment of APE. The usefulness of imipenem-cilastatin may be limited due to the rapid devel-

opment of resistance. Pediatr Pulmonol. � 2012 Wiley Periodicals, Inc.

Key words: beta-lactams; Pseudomonas aeruginosa; pharmacokinetics; pharmaco-

dynamics.

Funding source: none reported.

1Pharmacy, Intermountain Primary Children’s Medical Center, Salt Lake

City, Utah.

2Intermountain Cystic Fibrosis Pediatric Center, Salt Lake City, Utah.

3University of Utah College of Pharmacy, Salt Lake City, Utah.

4Intermountain Cystic Fibrosis Adult Center, Salt Lake City, Utah.

5Pharmacy, Intermountain McKay-Dee Hospital Center, Ogden, Utah.

6Division of Pediatric Infectious Disease, University of Utah, Salt Lake

City, Utah.

7Division of Clinical Pharmacology and Clinical Trials Office, Depart-

ment of Pediatrics, University of Utah School of Medicine, Salt Lake

City, Utah.

Conflict of interest: None

A systematic review was conducted using Medline. MeSH and free text

terms included: ‘‘Cystic fibrosis,’’ ‘‘antibiotics,’’ ‘‘pharmacokinetics,’’

‘‘pharmacodynamics,’’ ‘‘aztreonam,’’ ‘‘doripenem,’’ ‘‘imipenem-cilasta-

tin,’’ ‘‘meropenem’’. Search results were restricted to the English

language without an age limit. Also, reference lists and conference

proceedings were reviewed.

*Correspondence to: Jeffery T. Zobell, PharmD, Department of Pharma-

cy, Intermountain Primary Children’s Medical Center, 100 North Mario

Capecchi Drive, Salt Lake City, UT 84113.

E-mail: jeffery.zobell@imail.org

Received 15 April 2012; Accepted 17 May 2012.

DOI 10.1002/ppul.22655

Published online in Wiley Online Library

(wileyonlinelibrary.com).

� 2012 Wiley Periodicals, Inc.

INTRODUCTION

Cystic fibrosis (CF) is a common autosomal recessivedisorder affecting over 30,000 individuals in the UnitedStates.1,2 It is caused by mutations in a single gene onthe long arm of chromosome 7, which encodes thecystic fibrosis transmembrane conductance regulator(CFTR).1,2 CFTR is an active chloride transport channelthat helps maintain fluid balance across epithelialcells.1,2 Defective CFTR channels affect multiple organsystems in individuals with CF, including the gastroin-testinal, reproductive, endocrine, and pulmonarysystems.1,2

The pulmonary effects of CF typically have the larg-est impact on morbidity and mortality, and account for>90% of fatalities due to the disease.1–3 Detrimentaleffects of thick, dehydrated secretions, bacterial infec-tions, and inflammation result in bronchiectasis, andprogressive obstructive airway disease.1–3 Chronic ther-apies such as dornase alpha, hypertonic saline, andchest physiotherapy work to thin and mobilize mucussecretions.3–7 Aerosolized antibiotics (i.e., inhaledtobramycin or aztreonam) and oral azithromycin areused as chronic suppressive therapies and anti-inflam-matory agents, respectively.3,8–11 Acute pulmonaryexacerbations (APE) are managed with either oral oraerosolized antibiotics (mild exacerbations) or with in-travenous antibiotics (moderate to severe exacerbations)which can be administered in the hospital and/or athome.1–3

In 2009, the Cystic Fibrosis Foundation (CFF) re-leased guidelines for the treatment of APE.12 Theseguidelines recommend that APE be treated with twointravenous anti-pseudomonal antibiotics, each with adifferent mechanism of action in an effort to enhanceantibacterial activity and reduce resistance.12 The mostcommon antibiotic classes used in combination forAPE are anti-pseudomonal beta-lactams (98%) andaminoglycosides (61%) according to surveys of CFF-accredited care centers.12–14

Beta-lactam antibiotics share a common chemicalstructure (beta-lactam ring) and mechanism of action(inhibition of bacterial cell wall synthesis via bindingto penicillin binding proteins; Fig. 1).15 Various sidechains and derivatives of the beta-lactam ring charac-terize the different types of beta-lactam antibioticsincluding the penicillin (piperacillin–tazobactam andticarcillin–clavulanate), cephalosporin (ceftazidime andcefepime), carbapenem (doripenem, imipenem–cilastatin,and meropemen), and monobactam (aztreonam)agents.15 Beta-lactam antibiotics exhibit concentration-independent and time-dependent, (time above the mini-mum inhibitory concentration, T > MIC) bactericidalactivity against susceptible bacteria (Fig. 2).15,16 Theseagents achieve maximal microbiological efficacy when

a considerable portion of the penicillin binding proteinsare occupied which can occur at low multiples ofthe minimum inhibitory concentration (MIC) for therelevant pathogen (i.e., 3–4 times MIC) and when thebeta-lactam concentrations remain above the MIC for�20–70% of the dosing interval, depending on the

Fig. 1. Cellular targets for anti-pseudomonal drugs. Cell wall

synthesis is inhibited by beta-lactam agents. The fluoroquino-

lone agents interrupt DNA replication by trapping DNA bound

to the enzyme DNA gyrase. Protein synthesis at the ribosomal

level is targeted by the aminoglycoside agents. The polymixin

agents (i.e., colistimethate sodium) increase the permeability

of the cell membrane through electrostatic interactions.

Fig. 2. Pharmacodynamic parameters of efficacy for anti-

pseudomonal antibiotics. Drug concentration versus time

curve. T > MIC—the duration of time in which serum concen-

trations exceed the MIC (this parameter best predicts microbi-

ologic efficacy for the beta-lactams). Cmax : MIC—the ratio of

the maximum serum drug concentration to the minimum inhib-

itory concentration (MIC) of P. aeruginosa (this parameter best

predicts microbiologic efficacy for the aminoglycosides). AUC:

MIC—the ratio of the area under the serum concentration

versus time curve to the MIC (this parameter best predicts

microbiologic efficacy for fluoroquinolones and colistimethate

sodium).

2 Zobell et al.

Pediatric Pulmonology

agent.16–19 Beta-lactams may be combined with otheranti-pseudomonal antibiotics (i.e., aminoglycosides,fluoroquinolones, and colistimethate sodium) whichexhibit different mechanisms of action and concentra-tion-dependent bactericidal activity, such as peak con-centration above the MIC (Cmax:MIC) or the ratio ofthe area under the serum concentration curve to theMIC (AUC:MIC).20–22

In the anti-pseudomonal beta-lactam utilization sur-vey, 93% of the respondents reported utilizing intermit-tent beta-lactam dosing (i.e., infused over 30 min),however, a majority of those (58%) chose dosing regi-mens lower than those recommended by the CFF andEuropean guidelines.13,23,24 The findings of this surveysuggest that recommended doses and dosing regimensare not used by a substantial number of CF centersdespite CFF, European, UK CF Trust Working Grouprecommendations, review articles, and literature con-firming the efficacy and safety of higher than Food andDrug Administration (FDA)-approved doses for anti-pseudomonal beta-lactam agents.1,23–32 Possible expla-nations may include concern for dose-related adverseeffects incurred from higher doses, lack of familiaritywith dosing guidelines among CF practitioners, lackof understanding of fundamental pharmacokinetic/pharmacodynamics (PK/PD) principles, and the use ofpublished dosing references which do not containCF-specific dosing recommendations.

This review serves as the first article in a comprehen-sive State of the Art series focusing on summarizing thePK/PD, efficacy, and tolerability studies utilizing anti-pseudomonal antibiotics in the treatment of APE. Thepurpose of this review is to provide a summary ofefficacious and tolerable dosing strategies based on theavailable literature for aztreonam and anti-pseudomonalcarbapenems which have been utilized in the treatmentof APE, and to identify areas where further study iswarranted.

Description of Beta-Lactam Agents

Monobactam

Aztreonam (Azactam1, Princeton, NJ), derived froma fungus, Chromobacterium violceum, contains a mono-cyclic beta-lactam nucleus with a wide-array of activityagainst aerobic gram negative bacteria, includingP. aeruginosa that is available as both an intravenousand aerosolized formulation. 15,33–36 Aztreonam achievesmaximal microbiological efficacy when the penicillinbinding proteins are occupied which can occur at lowmultiples of the MIC for the relevant pathogen (i.e.,3–4 times MIC) and when the beta-lactam concentra-tions remain above the MIC for �50–60% of the dosinginterval.16,17,19 The antimicrobial activity of aztreonamis different from other beta-lactam antibiotics but

similar to aminoglycosides, in that gram positive andanaerobic bacteria are intrinsically resistant to aztreo-nam.15 The most common toxicities related to aztreo-nam are phlebitis, diarrhea, nausea, vomiting, andrash.35 Due to the limited cross-reactivity of aztreonamwith other beta-lactam antibiotics, aztreonam may bewell tolerated by patients with hypersensitivity reac-tions to other beta-lactams.15

Carbapenems

Carbapenems have a wide range of antimicrobial ac-tivity against anaerobic, aerobic gram positive andgram negative bacteria, including activity againstP. aeruginosa. These agents achieve maximal microbio-logical efficacy when the penicillin binding proteins areoccupied which can occur at low multiples of the MICfor the relevant pathogen (i.e., 3–4 times MIC) andwhen the beta-lactam concentrations remain above theMIC for �20–40% of the dosing interval.16,17,19

Carbapenems were derived from thienamycin, a com-pound produced by Streptomyces cattleya.15 The mostcommon toxicities related to carbapenems are nausea,vomiting, seizures, and hypersensitivity in beta-lactamallergic patients.15 Anti-pseudomonal carbapenems in-clude doripenem (Doribax1, Raritan, NJ), imipenem–cilastatin (Primaxin1, Whitehouse Station, NJ), andmeropenem (Merrem1, Wilmington, DE). Ertapenem(Invanz1, Whitehouse Station, NJ) is another carbape-nem agent, but does not display any activity againstP. aeruginosa.37

Pharmacokinetics/Pharmacodynamics

Aztreonam

A PK analysis was performed in pediatric CFpatients who received a single 30 mg/kg intravenousdose of aztreonam. Based on the PK data, it was deter-mined that an aztreonam dose of 50 mg/kg/dose every6 hr would be required to maintain serum aztreonamconcentrations over pseudomonal isolates with higherMICs based on current MIC breakpoints from theEuropean Committee on Antimicrobial SusceptibilityTesting (EUCAST) and Clinical and Laboratory Stand-ards Institute (CLSI): S: �1 mg/L; R: >16 mg/L(EUCAST)38; S: �8 mg/L; R: >32 mg/L (CLSI)(Table 1).39,40

A population PK/PD analysis by Vinks et al.,41

showed that the maximum serum concentration (Cmax),half-life (t1/2), and steady-state volume of distribution(Vss) were not significantly different between patientswith CF and healthy controls. However, CF patientshad significantly increased mean total body clearance(CLs) values (41%; P < 0.01) as well as significantlylower mean area under the curve (AUC) values (23%)

Aztreonam and Carbapenems in CF 3

Pediatric Pulmonology

as compared to healthy controls (P < 0.01). Fornear-maximal bactericidal activity, the PK-PD MICbreakpoint for P. aeruginosa for aztreonam 1 g admin-istered every 8 hr was 2 mg/L. For aztreonam 2 gadministered every 8 hr, the PK-PD MIC breakpoint forP. aeruginosa was 4 mg/L. The authors concluded thatdue to significantly higher CLs in CF versus healthycontrols, aztreonam doses of 2 g every 8 hr may beneeded to achieve bactericidal effects among pseudo-monal isolates with MICs �4 mg/L, and are unlikely tobe effective against higher MIC isolates (Tables 1and 2).41

Doripenem

A single-dose of doripenem 1 and 2 g infused over4 hr was given to 34 adult patients (10 with CF, 24healthy volunteers) to define the PK/PD of doripenemin CF patients.42,43 All PK parameters in patients withCF were comparable to healthy controls. The predictedpercentage of time during which doripenem serum con-centrations remained over an minimum inhibitory con-centration (%T > MIC) of 4 mg/L for P. aeruginosawas shown to be 67% and 83% of the dosing intervalfor doripenem 1 and 2 g, respectively: S: �1 mg/L;R: >4 mg/L (EUCAST); S: �2 mg/L; R: NR (CLSI;Tables 1 and 4).38,39 Additionally, the PD of doripenem1 and 2 g doses infused over 4 hr given every 8 hr wereanalyzed. The PK/PD MIC breakpoint for doripenem1 g infused over 4 hr administered every 8 hr was8 mg/L versus 16 mg/L for doripenem 2 g infused over4 hr administered every 8 hr (Table 2). The authorsconcluded that doripenem 1 g infused over 4 hr admin-istered every 8 hr may be effective in the treatment ofAPEs caused by pseudomonal isolates with MICs�8 mg/L, whereas doripenem 2 g infused over 4 hradministered every 8 hr may be effective in the treat-ment of APEs caused by P. aeruginosa with MICs�16 mg/L.42,43

A PK study was performed with doripenem in 20pediatric CF patients receiving 30 mg/kg/dose, maxi-mum 1 g infused over 4 hr (Table 1). CLs was shownto increase with age, and the Vss was similar betweenthe CF and non-CF pediatric participants. The %T >MIC of 4 mg/L for P. aeruginosa was shown to be 63%of the dosing interval (Tables 1 and 4).43,44

Imipenem–Cilastatin

Four PK studies analyzing imipenem–cilastatin in 77CF patients (age range 8–33 years) have been per-formed utilizing doses ranging from 45–100 mg/kg/daydivided every 6 hr.45–48 The study by Reed et al.45 con-cluded that imipenem–cilastatin administered at a doseof 90–100 mg/kg/day divided every 6 hr would beadequate to maintain serum imipenem concentrations

above the MIC of the majority of P. aeruginosaisolates: S: �4 mg/L; R: >8 mg/L (EUCAST); S:�4 mg/L; R: >16 mg/L (CLSI; Tables 1 and 4).38,39,45

However, based on the short t½ of imipenem–cilastatinin patients with CF, the Pedersen et al.46 study conclud-ed that imipenem–cilastatin 100 mg/kg/day dividedevery 6 hr could not be recommended for the treatmentof P. aeruginosa in APE.46

Meropenem

A single-dose of meropenem 15 mg/kg was given in-travenously to CF patients and healthy controls with theintent to define the PK of meropenem in CF patients instable clinical condition. The AUC, Vss, and CLs, werenot different between CF patients and healthy controls.However, the authors found that CF patients haveshorter mean t½ (0.72 hr vs. 0.99 hr), mean residencetimes (1.09 hr vs. 1.39 hr, P < 0.007), and drug con-centrations above the MIC90 of P. aeruginosa <3.3 hrafter infusion: S: �2 mg/L; R: >8 mg/L (EUCAST);S: �4 mg/L; R: > 16 mg/L (CLSI) (Table 1).38,39

These variables show that meropenem concentrationsrapidly decline in some CF patients; therefore, shorterdosing intervals may be needed in order to maintainadequate meropenem serum concentration levels abovethe MIC90 of P. aeruginosa.49

A small PK study of meropenem 2 g (approximately33 mg/kg/dose) given intravenously every 8 hr was per-formed in six clinically stable CF patients to determineif the recommended maximum doses could sustainadequate serum concentrations above the MIC ofP. aeruginosa (Table 1). The meropenem plasma con-centrations remained above 4 mg/L for at least 50% ofthe dosing interval. The authors concluded that theutilization of high-dose meropenem (33 mg/kg/dose,maximum 2 g IV every 8 hr) optimizes the pharmaco-dynamics of meropenem and maximizes the chance ofachieving a positive clinical response.50

Efficacy/Tolerability

Aztreonam

Aztreonam is not a widely utilized anti-pseudomonalbeta-lactam (2/167 reported dosing regimens, 1%) forthe treatment of APE in CF patients.13 Half of the inter-mittent aztreonam regimens (1/2, 50%) were lower thanthe CFF (150 mg/kg/day div every 6–8 hr)24 and Euro-pean Consensus committee (150 mg/kg/day div every6 hr, maximum 8 g/day) doses for the treatment ofAPE in CF patients.13,23

Several efficacy and tolerability studies have beenperformed utilizing aztreonam (Tables 3 and 4).27,28,51–53

In a study by Scully et al.51 a dose of 2 g of aztreonamevery 8 hr was used. Improvement in clinical status

4 Zobell et al.

Pediatric Pulmonology

TABLE

1—

Summary

ofPharm

acokineticStudiesWithAztreonam

andAnti-PseudomonalCarbapenemsin

CysticFibrosis

Ph

arm

aco

kin

etic

stu

die

s

An

tib

ioti

cR

efer

ence

Stu

dy

po

pu

lati

on

Ag

e(y

rs)

Do

se(m

g/k

g)

Mea

n(�

SD

)t 1

/2

(ho

urs

)

Mea

n(�

SD

)

Vd

(L/k

g)

Mea

n(�

SD

)C

Ls

(ml/

min

/1.7

3m

2)

Mea

n(�

SD

)

AU

C

(mg

hr/

L)

Mea

n(�

SD

)

Cm

ax

(mg

/L)

Mea

n(�

SD

)

Cm

in(m

g/L

)

Azt

reo

nam

Ree

det

al.4

0C

F1

0–

18

30

1.3

�0

.20

.25�

0.0

51

27

.2�

31

.4N

R1

41

–2

28

(ran

ge)

0.4

–2

.8

(ran

ge)

Vin

ks

etal

.41

CF

29

.8�

3.2

(26

–3

5)

2,0

00

1.5

4�

0.1

70

.20�

0.0

21

.84�

0.3

3

ml/

min

/kg

33

6.7

�5

4.7

22

8�

49

NR

Hea

lth

y

con

tro

ls

26

.6�

4.0

(22

–3

5)

2,0

00

1.8

1�

0.3

30

.18�

0.0

41

.31�

0.1

3

ml/

min

/kg

41

4.1

�4

0.8

24

2�

38

NR

Do

rip

enem

Cir

illo

etal

.42

,43

CF

23�

8.7

1,0

00

infu

sed

over

4h

r1

.0�

0.3

12

.6�

3.3

13

.5�

3.8

80

.3�

24

.92

0.0

�5

.6N

R

2,0

00

infu

sed

over

4h

r1

.1�

0.1

12

.4�

2.7

12

.6�

3.6

17

1�

49

.34

3.2

�1

3.9

Hea

lth

y

con

tro

ls

35�

95

00

infu

sed

over

4h

r1

.2�

0.2

18

.0�

4.0

14

.6�

3.2

35

.6�

6.9

8.7

�1

.7N

R

1,0

00

infu

sed

over

4h

r1

.5�

1.6

18

.0�

5.4

13

.8�

2.9

75

.4�

16

.01

8.8

�4

.9

Vac

caro

etal

.43

,44

CF

6–

17

30

infu

sed

over

4h

r

(max

1,0

00

)

NR

Sim

ilar

to

con

tro

ls

Sim

ilar

to

con

tro

ls

96

.1(6

to<

12

yr)

NR

NR

73

(12

to<

18

yr)

Hea

lth

y

con

tro

ls

6–

17

15

infu

sed

over

1h

r

(max

50

0)

NR

Sim

ilar

toC

FS

imil

arto

CF

44

.8(6

to<

12

yr)

NR

NR

31

(12

to<

18

yr)

Imip

enem

-

cila

stat

in

Ree

det

al.4

5C

F1

9�

6

(15

–3

2)

30

div

ever

y6

hr

0.8

�0

.11

0.3

4�

0.1

51

26

4.0

�1

04

.51

25

.4�

9.4

11

90

.5

0.9

�0

.22

0.3

2�

0.0

92

23

9.5

�5

5.2

22

5.5

�8

.22

CF

22�

8

(14

–3

6

60

div

ever

y6

hr

1.0

�0

.21

0.2

5�

0.0

61

18

1.0

�3

8.1

17

6.1

�1

5.1

16

50

.5

1.0

�0

.22

0.2

9�

0.0

52

22

1.0

�5

6.5

26

4.5

�1

9.6

2

CF

16�

3

(12

–2

0)

90

div

ever

y6

hr

0.8

�0

.11

0.2

7�

0.0

41

22

0.0

�5

2.7

18

1.5

�2

1.2

17

80

.9

1.0

�0

.12

0.3

0�

0.1

72

21

8.4

�9

3.4

29

1.8

�3

5.3

2

Ped

erse

n

etal

.46

CF

15

(8–

33

)1

00

div

ever

y6

hr

0.9

80

.50

NR

70

.95

4.6

NR

Str

and

vik

etal

.47

CF

16

(8–

33

)4

5d

ivev

ery

6h

r3

2.4

�6

.81

31

.5�

6.7

2

CF

16

(8–

33

)6

0d

ivev

ery

6h

r4

2.2

�5

.71

33

.7�

4.9

2

Ber

gan

etal

.48

CF

16�

61

11

.2�

0.4

12

7.9

�1

1.3

1L

16

.3�

3.7

1L

/hr

30

.4�

6.8

1

1.1

�0

.12

27

.1�

10

.12

L1

7.1

�4

.12

L/h

r2

9.1

�7

.12

15

0.9

71

NR

NR

32

.81

35

0.4

0.9

02

29

.72

Mer

op

enem

Ch

rist

enss

on

etal

.49

CF

24�

4

(19

–3

1)

1,0

49�

11

6m

g0

.74

11

.0�

2.6

22

4�

58

.38

2.1

�1

8.4

79

.4�

19

.7N

R

Hea

lth

y

con

tro

ls

25�

5

(20

–3

4)

1,0

15�

72

.3m

g0

.99

12

.9�

2.3

18

5�

50

.29

2.7

�2

2.1

74

.7�

14

.7N

R

Bu

iet

al.5

0C

F2

4(1

8–

31

)2

,00

0(3

3)

ever

y8

hr

0.8

6�

0.1

19

.6�

2.2

15

.9�

1.9

12

7�

16

11

3�

13

NR

yrs

,y

ears

;m

g/k

g,

mil

lig

ram

sp

erk

ilo

gra

m;

t 1/2

,h

alf-

life

;V

d,

vo

lum

eo

fd

istr

ibu

tio

n;

L/k

g,

lite

rsp

erk

ilo

gra

m;

CL

s,to

tal

bo

dy

clea

ran

ce;

ml/

min

/1.7

3m

2,

mil

lite

rsp

erm

inu

tep

er1

.73

squ

ared

met

ers;

AU

C,

area

un

der

the

curv

e;m

g�h

r/L

,m

illi

gra

ms

tim

esh

ou

rsp

erli

ters

;C

max,

max

imu

mco

nce

ntr

atio

n;

mg

/L,

mil

lig

ram

sp

erli

ter;

Cm

in,

min

imu

mco

nce

ntr

atio

n;

CF,

cyst

ic

fib

rosi

s;N

R,

no

tre

po

rted

;m

l/m

in/k

g,

mil

lili

ters

per

min

ute

per

kil

og

ram

;L

,li

ters

;L

/hr,

lite

rsp

erh

ou

r;m

g,

mil

lig

ram

s.1F

irst

-do

se.

2S

tead

y-s

tate

.

Aztreonam and Carbapenems in CF 5

Pediatric Pulmonology

from baseline was observed; however, eradication ofP. aeruginosa was not achieved, and serum concentra-tions only exceeded the mean MIC for P. aeruginosaisolates for 3.5 hr after the start of infusion (Table 4).51

Based on the PK/PD study mentioned previously, thisdosing strategy may not be effective against pseudomo-nal isolates with higher MICs (Table 2).41 Larger andmore frequent aztreonam dosing strategies of 200–300 mg/kg/day divided every 6 hr, maximum 8–12 g/day utilized in four other studies showed clinical andmicrobiological efficacy in the treatment of APE due toP. aeruginosa, and were well-tolerated with no reportsof major adverse events (Tables 3 and 4).27,28,52,53 Theefficacy and tolerability of aerosolized aztreonam in thetreatment of APE is currently unknown, therefore fur-ther studies are warranted.

Doripenem

According to the utilization survey of anti-pseudomo-nal beta-lactams, no CFF-accredited centers reportedthe use of doripenem in the treatment of APE.13 It wasrecently approved by the FDA in 2007.54 The FDA-approved dose is 500 mg every 8 hr.54 No efficacy dataexists in CF and pediatric patients. There are also nodosing recommendations from the CFF, the EuropeanConsensus Committee, and the UK CF Trust. However,in vitro microbiological studies by Chen et al.,55 andTraczewski and Brown56 in CF patients show the poten-tial clinical efficacy of doripenem against P. aeruginosa(Table 4).55,56 The tolerability of doripenem in bothpediatric and adult CF patients was evaluated by Cirilloet al.42 and Vaccaro et al.44 both of which reported nomajor adverse events (Table 4).

Imipenem–Cilastatin

No CFF-accredited care center reported the use ofimipenem–cilastatin as their first-line anti-pseudomonalbeta-lactam in the treatment of APE in the beta-lactam

utilization survey.13 The FDA-approved dose for imipe-nem–cilastatin is very similar to the CFF dosing recom-mendations, the European Consensus Committeerecommendations, the UK CF Trust recommendations,and dosing recommendations from review articles forimipenem–cilastatin in CF patients.1,2,23–25,57 Multipleclinical efficacy and tolerability studies with imipenem–cilastatin in CF support these dosing recommendations(Tables 3 and 4).46,47,58,59

The imipenem–cilastatin dosing regimens utilized inthe four efficacy and tolerability studies ranged from30 to 100 mg/kg/day divided every 6 hr (Tables 3and 4).46,47,58,59 Although imipenem–cilastatin wasshown to be tolerable and efficacious in the treatmentof APE, resistance to P. aeruginosa developed rapidly,and the authors could not recommend imipenem–cilastatin for routine use for the treatment of APE.46,58,59

Meropenem

Meropenem is the only anti-pseudomonal carbape-nem that was reported to be utilized in a recent survey(21/167 reported dosing regimens, 13%) for the treat-ment of APE in CF patients.13 Approximately, half ofintermittent meropenem regimens (9/20, 45%) werelower than the FDA-approved meningitis (120 mg/kg/day div every 8 hr, maximum 6 g/day)60 and EuropeanConsensus guideline (60–120 mg/kg/day div every 8 hr,maximum 6 g/day)23 doses for the treatment of APE inCF patients.13 Three studies analyzing the tolerabilityand efficacy of meropenem in APE have been per-formed in 136 CF patients (age range 4–64 years)utilizing doses ranging from 75–120 mg/kg/day, up to3.75–6 g/day.30,32,61 These multicenter randomizedcomparative studies analyzed the clinical efficacy andtolerability of meropenem versus ceftazidime. Merope-nem was shown to be a well-tolerated and effectivealternative to ceftazidime alone and in combinationwith tobramycin in the treatment of APE secondary toP. aeruginosa, with recommendations that monitoring

TABLE 2—Summary of Pharmacodynamic Studies With Aztreonam and Anti-Pseudomonal Carbapenems in CysticFibrosis

Pharmacodynamic Studies

Antibiotic Study Dose (mg) Significant findings

Aztreonam Vinks et al.41 2,000 Higher CLs in CF vs. controls

Lower AUC in CF vs. controls

PK-PD MIC breakpoint (1 g every 8 hr) � 2 mg/L

PK-PD MIC breakpoint (2 g every 8 hr) � 4 mg/L

Doripenem Cirillo et al.42 1,000 every 8 hr, infused over 4 hr 1,000 mg ¼ PK/PD MIC breakpoint �8 mg/L

2,000 every 8 hr, infused over 4 hr 2,000 mg ¼ PK/PD MIC breakpoint �16 mg/L

CLs, total body clearance; CF, cystic fibrosis; AUC, area under the curve; mg, milligrams; PK-PD MIC breakpoint, pharmacokinetic/

pharmacodynamic minimum inhibitory concentration breakpoint (i.e., highest MIC with a PTA � 90%); mg/L, millgrams per liter.

6 Zobell et al.

Pediatric Pulmonology

TABLE

3—

Summary

ofEfficacyStudiesofAztreonam

andAnti-PseudomonalCarbapenemsin

CysticFibrosis

An

tib

ioti

cS

tud

yM

ean

(�S

D)

age

(yrs

)D

ose

(mg

/kg

/day

)O

utc

om

es

Azt

reo

nam

Scu

lly

etal

.51

19

(12

–3

2)

2,0

00

mg

ever

y8

hr

wit

h

amin

og

lyco

sid

es

"cl

inic

alst

atu

s(8

5%

of

epis

od

es);

Mea

nin

terv

alo

f

imp

rovem

ent¼

7d

ays

Bo

sso

etal

.52

14

(6–

32

)2

00

div

ever

y6

hr

"cl

inic

alan

dp

ulm

on

ary

sco

res

&W

BC

(P<

0.0

5);

Mea

nin

terv

alo

f

imp

rovem

ent¼

12

.5d

ays

Bo

sso

etal

.53

14

20

0d

ivev

ery

6h

rþ

tob

ram

yci

no

r

azlo

cill

inþ

tob

ram

yci

n

"cl

inic

al&

pu

lmo

nar

ysc

ore

s,W

BC

,P

FT

s,X

-ray

s

Azt

reo

nam

(A)þ

Cef

tazi

dim

e(C

)

Sal

het

al.2

81

6–

32

(bo

thg

rou

ps)

2,0

00

mg

ever

y6

hr

(8g

/day

;b

oth

gro

up

s)

A:"

FE

V1%

pre

dic

ted

(P<

0.0

1);#s

pu

tum

wei

gh

t(P

<0

.05

);"

pat

ien

tw

ell-

bei

ng

(P<

0.0

01

)

Slo

wer

#in

FE

V1%

pre

dic

ted

inaz

treo

nam

vs.

ceft

azid

ime

atd

ay4

2

(P<

0.0

5)

Sch

aad

etal

.27

15

.4�

6.0

(2.3

–2

5.4

)

(bo

thg

rou

ps)

30

0d

ivev

ery

6h

r(m

ax1

2g

/day

)þ

amik

acin

(bo

thg

rou

ps)

A:#s

pu

tum

wei

gh

t(P

<0

.00

5),

WB

C,b

and

neu

tro

ph

ils

(P<

0.0

01

),

ES

R(P

<0

.05

)

"cli

nic

al/r

adio

gra

ph

ic&

rad

iolo

gic

sco

res,

FE

V1%

pre

dic

ted

,th

ora

cic

gas

vo

lum

e(P

<0

.05

),F

VC

%p

red

icte

d(P

<0

.01

),&

ox

yg

en

satu

rati

on

s(P

<0

.00

5)

Do

rip

enem

Cir

illo

etal

.42

23�

8.7

—D

ori

pen

em1

,00

0–

2,0

00

ever

y8

hr

infu

sed

over

4h

r

NR

35�

9—

Hea

lth

yco

ntr

ols

Vac

caro

etal

.44

6–

17

yea

rs9

0ev

ery

8h

r,in

fuse

dover

4h

r

(max

1,0

00

mg

/do

se)

NR

Imip

enem

-cil

asta

tin

Ped

erse

net

al.5

81

8(1

1–

30

)4

5d

ivev

ery

6h

r"

Sh

wac

hm

ansc

ore

s,ch

est

ausc

ula

tory

sco

res,

FV

C%

&F

EV

1%

pre

dic

ted

(P<

0.0

1)

#sp

utu

mp

rod

uct

ion

(P<

0.0

1),

WB

C(P

<0

.02

)&

rest

ing

pu

lse

rate

(P<

0.0

5)

Ped

erse

net

al.4

61

5(8

–3

3)

10

0d

ivev

ery

6h

rþ

tob

ram

yci

n"

FV

C%

&F

EV

1%

pre

dic

ted

;#

WB

C

Str

and

vik

etal

.47

16

(8–

33

)4

5–

60

div

ever

y6

hr

"S

hw

ach

man

sco

res,

FV

C%

&F

EV

1%

pre

dic

ted

,(P

<0

.00

1),

bo

dy

wei

gh

t(P

<0

.01

),b

loo

do

xy

gen

(P<

0.0

5);#

resp

irat

ory

&p

uls

e

rate

,W

BC

(P<

0.0

1),

spu

tum

pro

du

ctio

n

Kri

lov

etal

.59

12

–3

63

0–

90

div

ever

y6

hr

"S

hw

ach

man

,cl

inic

alsc

ore

s(P

<0

.00

1),

FV

C%

pre

dic

ted

(P<

0.0

1)

Mer

op

enem

þC

efta

zid

ime

By

rne

etal

.61

16

(6–

33

)—C

efta

zid

ime

(C)

(C)

15

0d

ivev

ery

8h

r(m

ax7

.5g

/day

)M

:9

8%

clin

ical

resp

on

sera

te;"F

EV

1%

&F

VC

%p

red

icte

d;#s

pu

tum

pro

du

ctio

n(P

<0

.05

)1

5(4

–2

8)—

Mer

op

enem

(M)

(M)

75

div

ever

y8

hr

(max

3.7

5g

/day

)

Blu

mer

etal

.32

5–

64

bo

thg

rou

ps

(C)

15

0d

ivev

ery

8h

r(m

ax6

g/d

ay)þ

tob

ram

yci

n

M:"

FE

V1%

pre

dic

ted

(P¼

0.0

00

2);#

AC

Ssc

ore

s(P

<0

.00

1);

96

%

clin

ical

resp

on

der

s;L

arg

erre

lati

ve

chan

ge

inF

EV

1%

pre

dic

ted

at

day

7v

s.ce

ftaz

idim

eg

rou

p(P

¼0

.07

)w

ith

maj

ori

tyo

f"

occ

urr

ing

in1

st7

day

s;L

arg

er"

FE

V1%

pre

dic

ted

vs.

ceft

azid

ime

(P<

0.0

01

);"

trea

tmen

tre

spo

nd

ers

atd

ay7

vs.

ceft

azid

ime

(P¼

0.0

4);

Sh

ort

erti

me

for

50

%cl

inic

alre

spo

nse

rate

(4d

ays

vs.

6

day

s)v

s.ce

ftaz

idim

e;ti

me

ton

ext

exac

erb

atio

n¼

17

6d

ays

(M)

12

0d

ivev

ery

8h

r(m

ax6

g/d

ay)þ

tob

ram

yci

n

Lat

zin

etal

.30

16

.9�

7.7

—ce

ftaz

idim

e(C

)2

00

–4

00

div

ever

y

8–

12

hrþ

tob

ram

yci

n

M:"

FE

V1%

,F

VC

%&

ME

F2

5%

pre

dic

ted

(P<

0.0

5);#

WB

C,C

RP

(P<

0.0

5)

17�

9—

mer

op

enem

(M)

12

0d

ivev

ery

8h

r

(max

6g

/day

)þ

tob

ram

yci

n

yrs

,y

ears

;m

g/k

g/d

ay,

mil

lig

ram

sp

erk

ilo

gra

mp

erd

ay;

mg

,m

illi

gra

ms;",

incr

ease

d;

WB

C,

wh

ite

blo

od

cou

nt;

PF

Ts,

pu

lmo

nar

yfu

nct

ion

test

s;F

EV

1%

pre

dic

ted

,fo

rced

exp

irat

ory

vo

lum

e

in1

sec

per

cen

tp

red

icte

d;#,

dec

reas

ed;

ES

R,

ery

thro

cyte

sed

imen

tati

on

rate

;F

VC

%p

red

icte

d,

forc

edv

ital

cap

acit

yp

erce

nt

pre

dic

ted

;N

R,

no

tre

po

rted

;A

CS

,ac

ute

clin

ical

sco

re;

ME

F2

5%

pre

dic

ted

,m

ean

exp

irat

ory

flow

of

25

%p

red

icte

d;

CR

P,C

-rea

ctiv

ep

rote

in.

Aztreonam and Carbapenems in CF 7

Pediatric Pulmonology

TABLE

4—

Summary

ofMicrobiologicalandAdverseEffects

From

StudiesofAztreonam

andAnti-PseudomonalCarbapenemsin

CysticFibrosis

An

tib

ioti

cS

tud

yM

icro

bio

log

ical

resu

lts

Ad

ver

seef

fect

s

Azt

reo

nam

Scu

lly

etal

.51

No

erad

icat

ion

of

PA

;se

rum

con

cen

trat

ion

s>

mea

nPA

MIC

for

3.5

hr

afte

rst

art

of

infu

sio

n

Tra

nsi

ent"

of

alk

alin

ep

ho

sph

atas

e

(46

%o

fp

atie

nts

)

Bo

sso

etal

.52

�3

log

10

red

uct

ion

insp

utu

mPA

in6

0%

of

pat

ien

ts;

No

chan

ge

inm

ean

PA

MIC

;E

rad

icat

ion

of

PA

in1

1p

atie

nts

Tra

nsi

ent"

of

AS

T,

AL

T(6

4%

of

pat

ien

s)

Bo

sso

etal

.53

Su

scep

tib

ilit

yo

fPA

toaz

treo

nam

þto

bra

my

cin

dec

reas

edT

ran

sien

t"

inL

FT

s

Azt

reo

nam

(A)þ

Cef

tazi

dim

e(C

)

Sal

het

al.2

8A

:E

rad

icat

ion

of

PA

(1);"i

nPA

MIC

to>

16

mg

/L(3

)&"f

rom

8to

16

mg

/L(2

);N

od

iffe

ren

cein

dru

gre

sist

ance

or

sen

siti

vit

ies

bet

wee

ng

rou

ps

No

chan

ges

inla

bo

rato

ry

par

amet

ers

wer

eo

bse

rved

Sch

aad

etal

.27

A:

No

chan

ges

inPA

susc

epti

bil

ity

toaz

treo

nam

or

amik

acin

Era

dic

atio

nac

hie

ved

in6

1%

of

pat

ien

tsin

aztr

eon

am/a

mik

acin

gro

up

(P<

0.0

1);#

GN

Bin

spu

tum

(P<

0.0

05

)

A:

Mil

dth

rom

bo

cyto

pen

ia(1

1%

),

Tra

nsi

ent"

inA

ST

,A

LT

(14

%)

Do

rip

enem

Ch

enet

al.5

5L

ow

est

MIC

50

(8m

g/L

)&

MIC

90

(32

mg

/L)

for

mu

coid

PA

,&

B.cepacia

com

ple

x&

no

n-m

uco

idPA

(64

mg

/L)

NR

Tra

czew

ski

and

Bro

wn

56

Low

est

MIC

50

(0.2

5m

g/L

)&

MIC

90

(2m

g/L

)fo

rPA

;E

qu

al

MIC

90

(8m

g/L

)to

levo

flo

xac

info

rB.cepacia

;G

oo

dac

tiv

ity

agai

nst

mo

rere

sist

ant

imip

enem

PA

iso

late

s

NR

Cir

illo

etal

.42

T>

MIC

(4m

g/L

)o

fPA

wer

e6

7%

&8

3%

of

do

sin

gin

terv

al

for

1&

2g

do

ses,

resp

ecti

vel

y

Tra

nsi

ent

mil

dco

ug

h,

nau

sea,

hy

per

ten

sio

n

Vac

caro

etal

.44

T>

MIC

(4m

g/L

)o

fPA

wer

e6

3%

of

do

sin

gin

terv

alN

ose

rio

us

adver

seef

fect

sre

po

rted

Imip

enem

-cil

asta

tin

Ped

erse

net

al.5

81

0�

"M

ICs

afte

r1

wee

ko

ftr

eatm

ent

(P<

0.0

1);

Res

ista

nt

stra

ins

emer

ged

inal

lp

atie

nts

Eo

sin

op

hil

ia,"

AL

T(9

0%

),M

ild

nau

sea,

Glo

ssit

is

Ped

erse

net

al.4

6N

oer

adic

atio

no

fPA

;"

MIC

saf

ter

14

&4

5d

ays

(P<

0.0

1);

Res

ista

nt

stra

ins

emer

ged

inal

lp

atie

nts

Eo

sin

op

hil

ia(3

0%

),n

ause

a&

vo

mit

ing

(70

%),

mac

uo

pap

ula

rra

sh,

pal

pit

atio

ns,

hea

dac

he

Str

and

vik

etal

.47

No

erad

icat

ion

of

PA

;"

MIC

s;Is

ola

tes

rem

ain

edsu

scep

tib

le"

AL

T,

AS

T

Kri

lov

etal

.59

37

%o

fPA

iso

late

sw

ere

resi

stan

tat

end

of

stu

dy

;"M

ICs

du

rin

g

stu

dy

(8to

>1

6m

g/L

);O

ther

resi

stan

tb

acte

ria

emer

ged

;

Em

erg

ence

of

resi

stan

ceo

ccu

rred

inal

ld

osi

ng

reg

imen

s

Nau

sea,

rash

Mer

op

enem

(M)þ

Cef

tazi

dim

e

By

rne

etal

.61

M:

73

%#

tota

lb

acte

rial

cou

nt;#

bac

teri

alco

lony

cou

nts

in6

0%

of

iso

late

s;8

mg

/L-i

nh

ibit

89

%o

fPA

iso

late

s;

0.5

mg

/L-i

nh

ibit

49

%o

fPA

iso

late

s

M:"

AL

T,

AS

T

Blu

mer

etal

.32

M:#l

og

10

PA

load

insp

utu

m(P

<0

.00

01

);7

6%

had

#�2

log

10

inb

acte

rial

load

;N

ore

sist

ant

iso

late

sat

end

of

stu

dy

M:"

AS

T,

AL

T,

alk

alin

ep

ho

sph

atas

e

Lat

zin

etal

.30

M:#

PA

iso

late

s,PA

CF

Us

(P<

0.0

5)

M:

nau

sea,

dia

rrh

ea,

hea

dac

he,

alle

rgic

reac

tio

ns,

no

se-b

leed

ing

,fa

tig

ue,

acu

tep

ancr

eati

tis,

IV-s

ite

pro

ble

ms;"

alk

alin

ep

ho

sph

atas

e(P

<0

.05

)

PA

,Pseudomonasaeruginosa

;",

incr

ease

d;

MIC

,m

inim

um

inh

ibit

ory

con

cen

trat

ion

;A

ST

,as

par

tate

tran

sam

inas

e;A

LT

,al

anin

etr

ansa

min

ase;

LF

Ts,

liver

fun

ctio

nte

sts;

mg

/L,

mil

lig

ram

s

per

lite

r;G

NB

,g

ram

neg

ativ

eb

acil

li;

MIC

50,

min

imu

min

hib

ito

ryco

nce

ntr

atio

nfo

r5

0%

of

iso

late

s;M

IC9

0,

min

imu

min

hib

ito

ryco

nce

ntr

atio

nfo

r9

0%

of

iso

late

s;N

R,

no

tre

po

rted

;

T>

MIC

,p

erce

nta

ge

of

tim

ed

rug

con

cen

trat

ion

rem

ain

above

the

min

imu

min

hib

ito

ryco

nce

ntr

atio

n;

CF

Us,

colo

ny

form

ing

un

its;

IV,

intr

aven

ou

s;#,

dec

reas

ed.

8 Zobell et al.

Pediatric Pulmonology

of hepatic function may be warranted (Tables 3and 4).30,32,61

Evidenced-Based Summary of Anti-PseudomonalBeta-Lactams

Aztreonam

The literature does not support the CFF and Europe-an Consensus Committee dosing recommendations ofaztreonam 150 mg/kg/day divided every 6–8 hr, maxi-mum 8 g/day.23,24 The UK CF Trust Working Grouprecommendation is 90–200 mg/kg/day divided 6–8 hr,maximum 8 g/day.25 An intravenous aztreonam dosingregimen of 200–300 mg/kg/day divided every 6 hr,maximum 8–12 g/day, was shown to be a well-toleratedand effective dosing regimen for the treatment ofP. aeruginosa in APE in 133 patients (Tables 3 and 4),although this exceeds the current FDA labeling recom-mendation (Tables 3–5).35 Further study is needed todefine the maximum dose, and optimal PK/PD param-eters of aztreonam in CF for the treatment of APE.

Doripenem

As doripenem was recently approved (2007) for usein the US, limited literature evidence exists describingthe use of doripenem in CF. However, the literature inCF does not support the FDA-approved54 dosing recom-mendation of intravenous doripenem 500 mg every8 hr. The literature supports a dosing recommendationof intravenous doripenem 90 mg/kg/day divided every8 hr, infused over 4 hr, maximum 6 g/day, as a tolera-ble and potentially optimal dosing regimen for the treat-ment of P. aeruginosa in APE (Tables 1, 2, 4,and 5).42,44 Future study is needed to determine theclinical efficacy of this dosing regimen in APE.

Imipenem–Cilastatin

The literature supports the FDA-approved, CFF,European Consensus Committee, and UK CF TrustWorking Group dosing recommendations of intravenous

imipenem–cilastatin 100 mg/kg/day divided every 6 hr,maximum 4 g/day, as a tolerable and effective dosingregimen for the treatment of P. aeruginosa in APE,though the development of resistance may be an issue(Tables 3–5).23,24,46,57–59 In addition to the developmentof resistance, imipenem–cilastatin use is limited by itsrisk of lowering the seizure threshold and the presenceof strict hospital/institutional formularies limitingaccess to this antibiotic.57,62–64 Although there are gapsin the literature, the development of resistance has lim-ited the usefulness of this medication for the treatmentAPE secondary to P. aeruginosa in CF patients.46,58,59

Meropenem

The literature supports the FDA-approved meningitis,European Consensus Committee, and UK CF TrustWorking Group dosing recommendations of intravenousmeropenem 120 mg/kg/day divided every 8 hr, maxi-mum 6 g/day, as a tolerable and effective dosing regi-men for the treatment of P. aeruginosa in APE(Tables 1, 3–5).23,25,30,32,50,60 CFF guideline recommen-dations do not exist for meropenem, as this agent wasnot marketed when the CFF guidelines were ap-proved.24 No PD modeling studies exist for pediatricand adult CF populations making determination of opti-mal dosing recommendations difficult.

CONCLUSIONS

This review has provided an overview of the PK/PD,tolerability, and efficacy studies utilizing intravenousaztreonam and anti-pseudomonal carbapenems ap-proved in the US in the treatment of APE. Studies haveshown that approximately 25% of CF patients will notregain their lung function following a pulmonaryexacerbation despite aggressive treatment with two ormore anti-pseudomonal antibiotics.65,66 It is possiblethat currently available anti-pseudomonal antibiotics,including beta-lactams are being used sub-optimally byCF clinicians, which has been suggested by recent sur-veys.13,14 Multiple explanations may exist ranging from

TABLE 5—Evidence-Based Dosing Summary of Intravenous Anti-Pseudomonal Beta-Lactams for Pediatric and Adult CFPatients

Antibiotic Dose (mg/kg/day) Maximum dose (grams/day)

Monobactam

Aztreonam25,27,28,40,52,53 200–300 div every 6 hr 8–12

Carbapenems

Doripenem42,44 90 div every 8 hr, infused over 4 hr 6

Imipenem–cilastatin23,24,45,46 100 div every 6 hr1 4

Meropenem23,25,30,32,50 120 div every 8 hr 6

mg/kg/day, milligrams per kilogram per day; div, divided.1Limited usefulness due to development of resistance.

Aztreonam and Carbapenems in CF 9

Pediatric Pulmonology

concern for adverse effects due to higher doses to useof published dosing references which do not containCF-specific dosing recommendations. As new anti-pseudomonal agents are scarce, standardization of boththe dosing and dosing regimens of currently availableanti-pseudomonal antibiotics used to treat APE, as wellas additional education, implementation strategies, andrandomized, controlled trials with these standardizeddosing regimens to analyze clinical endpoints may behelpful for CF practitioners in optimizing the treatmentof APE secondary to P aeruginosa (Table 5).

ACKNOWLEDGMENTS

The authors would like to thank Dr. Kevin Epps,Pharm.D., BCPS, from the Pharmacy Department atSt. Vincent’s Medical Center Riverside, Jacksonville,FL, Dr. Jared Cash, Pharm.D., BCPS from the Pharma-cy Department at Intermountain Primary Children’sMedical Center, Salt Lake City, UT, and Dr. BarbaraChatfield, M.D., Director of the Intermountain CysticFibrosis Pediatric Center, Salt Lake City, UT, for theircontributions to the editing and reviewing of this manu-script. The authors would like extend a special thanksto Dr. Lisa Saiman, MD, MPH, Professor of ClinicalPediatrics, Pediatric Infectious Diseases, ColumbiaUniversity Medical Center, New York, NY for the con-ception and design of this manuscript, for the extensivereview and editing, and the overall success of thisseries.

REFERENCES

1. Ramsey BW. Management of pulmonary disease in patients

with cystic fibrosis. N Engl J Med 1996;335:179–188.

2. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and man-

agement of pulmonary infections in cystic fibrosis. Am J Respir

Crit Care Med 2003;168:918–951.

3. Flume PA, O’Sullivan BP, Robinson KA, Goss CH, Mogayzel

PJ, Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L,

et al. Cystic fibrosis pulmonary guidelines: chronic medications

for maintenance of lung health. Am J Respir Crit Care Med

2007;176:957–969.

4. McCool FD, Rosen MJ. Nonpharmacologic airway clearance

therapies: ACCP evidence-based clinical practice guidelines.

Chest 2006;129:250S–259S.

5. Flume PA, Robinson KA, O’Sullivan BP, Finder JD, Vender

RL, Willey-Courand DB, White TB, Marshall BC. Cystic fibro-

sis pulmonary guidelines: Airway clearance therapies. Respir

Care 2009;54:522–537.

6. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash

ML, Ramsey BW, Rosenstein BJ, Smith AL, Wohl ME. Effect

of aerosolized recombinant human DNase on exacerbations of

respiratory symptoms and on pulmonary function in patients

with cystic fibrosis. The Pulmozyme Study Group. N Engl J

Med 1994;331:637–642.

7. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP,

Marks GB, Belousova EG, Xuan W, Bye PTP. A controlled trial

of long-term inhaled hypertonic saline in patients with cystic

fibrosis. N Engl J Med 2006;354:229–240.

8. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery

AB, Williams-Warren J, Vasiljev-K M, Borowitz D, Bowman

CM, Marshall BC, et al. Intermittent administration of inhaled

tobramycin in patients with cystic fibrosis. Cystic Fibrosis

Inhaled Tobramycin Study Group. N Engl J Med 1999;340:

23–30.

9. Retsch-Bogart GZ, Quittner AL, Gibson RL, Oemann CM,

McCoy KS, Montgomery AB, Cooper PJ. Efficacy and safety of

inhaled aztreonam lysine for airway pseudomonas in cystic

fibrosis. Chest 2009;135:1223–1232.

10. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner

AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ,

Campbell PW. Azithromycin in patients with cystic fibrosis

chronically infected with Pseudomonas aeruginosa: A random-

ized controlled trial. JAMA 2003;290:1749–1756.

11. Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster

M, Hocevar-Trnka J, Goss CH, Rose LM, Burns JL, Marshall

BC, et al. Effect of azithromycin on pulmonary function in

patients with cystic fibrosis uninfected with Pseudomonas

aeruginosa: A randomized controlled trial. JAMA 2010;303:

1707–1715.

12. Flume PA, Mogayzel PJ, Robinson KA, Goss CH, Rosenblatt

RL, Kuhn RJ, Marshall BC. Cystic fibrosis pulmonary guide-

lines: Treatment of pulmonary exacerbations. Am J Respir Crit

Care Med 2009;180:802–808.

13. Zobell JT, Young DC, Waters CD, Ampofo K, Cash J, Marshall

BC, Olson J, Chatfield BA. A survey of the utilization of anti-

pseudomonal beta-lactam therapy in cystic fibrosis patients.

Pediatr Pulmonol 2011;46:987–990.

14. Van Meter DJ, Corriveau M, Ahern JW, Lahiri T. A survey of

once-daily dosage tobramycin therapy in patients with cystic

fibrosis. Pediatr Pulmonol 2009;44:325–329.

15. Petri WA. In: Hardman JG, Limbird LE, editors. Chapter 45:

Antimicrobial agents: Penicillins, Cephalosporins, and Other

Beta-Lactam Antibiotics, in Goodman and Gilman’s The

Pharmacological Basis of Therapeutics. New York: McGraw-

Hill; 2001. pp 1189–1218.

16. Burgess DS. Use of pharmacokinetics and pharmacodynamics

to optimize antimicrobial treatment of Pseudomonas aeruginosa

infections. Clin Infect Dis 2005;40:S99–S104.

17. Craig WA. Pharmacokinetic/pharmacodynamic parameters:

rationale for antibacterial dosing of mice and men. Clin Infect

Dis 1998;26:1–10; quiz 11–12.

18. Burgess DS, Hastings RW, Hardin TC. Pharmacokinetics and

pharmacodynamics of cefepime administered by intermittent

and continuous infusion. Clin Ther 2000;22:66–75.

19. Drusano GL. Antimicrobial pharmacodynamics: critical inter-

actions of ‘bug and drug’. Nat Rev Microbiol 2004;2:289–

300.

20. Chambers HF. In: Hardman JG, Limbird LE, editors. Chapter

46: Antimicrobial agents: the Aminoglycosides, in Goodman

and Gilman’s the pharmacological basis of therapeutics. New

York: McGraw-Hill; 2001. pp 1219–1238.

21. Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T,

Forrest A, Drusano GL. Pharmacokinetics-pharmacodynamics

of antimicrobial therapy: it’s not just for mice anymore. Clin

Infect Dis 2007;44:79–86.

22. Colistimethate sodium approved package labeling. 2010. X-Gen

Pharmaceuticals, Big Flats, NY.

23. Doring G, Conway SP, Heijerman HGM, Hodson ME, Hoiby N,

Smyth A, Touw DJ. Antibiotic therapy against Pseudomonas

aeruginosa in cystic fibrosis: a European consensus. Eur

Respir J 2000;16:749–767.

10 Zobell et al.

Pediatric Pulmonology

24. Foundation CF. Microbiology and infectious disease in cystic

fibrosis in Cystic Fibrosis Foundation Consensus Conference.

1994.

25. Trust UCF. Antibiotic treatment for cystic fibrosis in UK Cystic

Fibrosis Trust Antibiotic Working Group. 2009.

26. Zobell JT, Ampofo K, Cash J, Korgenski K, Chatfield BA. High

dose intermittent ticarcillin-clavulanate administration in pediat-

ric cystic fibrosis patients. J Cystic Fibrosis 2010;9:280–283.

27. Schaad UB, Wedgwood-Krucko J, Guenin K, Buehlmann U,

Kraemer R. Antipseudomonal therapy in cystic fibrosis: aztreo-

nam and amikacin versus ceftazidime and amikacin adminis-

tered intravenously followed by oral ciprofloxacin. Eur J Clin

Microbiol Infect Dis 1989;8:858–865.

28. Salh B, Bilton D, Dodd M, Abbot J, Webb K. A comparison of

aztreonam and ceftazidime in the treatment of respiratory infec-

tions in adults with cystic fibrosis. Scand J Infect Dis 1992;

24:215–218.

29. Reed MD, Stern RC, Myers CM, Klinger JD, Yamashita TS,

Blumer JL. Therapeutic evaluation of piperacillin for acute

pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol

1987;3:101–109.

30. Latzin P, Fehling M, Bauernfeind A, Reinhardt D, Kappler M,

Griese M. Efficacy and safety of intravenous meropenem and

tobramycin versus ceftazidime and tobramycin in cystic fibrosis.

J Cystic Fibrosis 2008;7:142–146.

31. Hubert D, Le Roux E, Lavrut T, Wallaert B, Scheid P, Manach

D, Grenet D, Sermet-Gaudelus I, Ramel S, Cracowski C. et al.

Continuous versus intermittent infusions of ceftazidime for

treating exacerbation of cystic fibrosis. Antimicrob Agents

Chemother 2009;53:3650–3656.

32. Blumer JL, Saiman L, Konstan MW, Melnick D. The efficacy

and safety of meropenem and tobramycin vs ceftazidime and

tobramycin in the treatment of acute pulmonary exacerbations

in patients with cystic fibrosis. Chest 2005;128:2336–2346.

33. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug infor-

mation handbook. 2011. Hudson, OH: Lexi-Comp, Inc.

34. Taketomo CK, Hodding JH, Kraus DM. Pediatric dosage hand-

book. Hudson, OH: Lexi-Comp, Inc; 2011.

35. Azactam1 approved package labeling. Princeton, NJ: Bristol

Meyers Squibb; 2010.

36. Cayston1 approved package labeling. Foster City, CA: Gilead

Sciences, Inc; 2010.

37. Invanz1 approved package labeling. Whitehouse Station, NJ:

Merck & Co., Inc; 2011.

38. Testing ECoAS. Breakpoint tables for interpretation of MICs

and zone diameters. Basel, Switzerland: EUCAST; 2011.

39. Institute CaLS. Performance standards for antimicrobial suscep-

tibility testing: Twenty-first international supplement m 100-

S21. 2011. Wayne, PA: CLSI.

40. Reed MD, Aronoff SC, Stern RC, Yamashita TS, Myers CM,

Friedhoff LT, Blumer JL. Single-dose pharmacokinetics of

aztreonam in children with cystic fibrosis. Pediatr Pulmonol

1986;2:282–286.

41. Vinks AA, van Rossem RN, Mathot RA, Heijerman HG,

Mouton JW. Pharmacokinetics of aztreonam in healthy subjects

and patients with cystic fibrosis and evaluation of dose-exposure

relationships using monte carlo simulation. Antimicrob Agents

Chemother 2007;51:3049–3055.

42. Cirillo I, Vaccaro N, Redman R, Black PL, Kearns GL. Pharma-

cokinetics of single-dose doripenem in adults with cystic fibro-

sis. J Clin Pharmacol 2011; DOI 10.1177/0091270011427564.

43. Cirillo I, Vaccaro N, Turner K, Solanki B, Natarajan J, Redman

R. Pharmacokinetics, safety, and tolerability of doripenem after

0.5-, 1-, and 4-hour infusions in healthy volunteers. J Clin

Pharmacol 2009;49:798–806.

44. Vaccaro NCI, Redman R, Black P, Kearns GL. Pharmacokinet-

ics of doripenem in pediatric patients with cystic fibrosis. Am J

Respir Crit Care Med 2011;183:A5728.

45. Reed MD, Stern RC, O’Brien CA, Yamashita TS, Myers CM,

Blumer JL. Pharmacokinetics of imipenem and cilastatin in

patients with cystic fibrosis. Antimicrob Agents Chemother

1985;27:583–588.

46. Pedersen SS, Pressler T, Jensen T, Rosdahl VT, Bentzon

MW, Hoiby N, Koch C. Combined imipenem/cilastatin and

tobramycin therapy of multiresistant Pseudomonas aeruginosa

in cystic fibrosis. J Antimicrob Chemother 1987;19:101–107.

47. Strandvik B, Malmborg AS, Bergan T, Michalsen H, Storrosten

OT, Wretlind B. Imipenem/cilastatin, an alternative treatment of

pseudomonas infection in cystic fibrosis. J Antimicrob Chemo-

ther 1988;21:471–480.

48. Bergan T, Michalsen H, Malmborg AS, Pedersen SS, Pressler T,

Storrosten OT, Strandvik B. Pharmacokinetic evaluation of

imipenem combined with cilastatin in cystic fibrosis. Chemo-

therapy 1993;39:369–373.

49. Christensson BA, Ljungberg B, Eriksson L, Nilsson-Ehle I.

Pharmacokinetics of meropenem in patients with cystic fibrosis.

Eur J Clin Microbiol Infect Dis 1998;17:873–876.

50. Bui KQ, Ambrose PG, Nicolau DP, Lapin CD, Nightingale

CH, Quintiliani R. Pharmacokinetics of high-dose meropenem

in adult cystic fibrosis patients. Chemotherapy 2001;47:153–

156.

51. Scully BE, Ores CN, Prince AS, Neu HC. Treatment of lower

respiratory tract infections due to Pseudomonas aeruginosa in

patients with cystic fibrosis. Rev Infect Dis 1985;7:S669–S674.

52. Bosso JA, Black PG, Matsen JM. Efficacy of aztreonam in

pulmonary exacerbations of cystic fibrosis. Pediatr Infect Dis J

1987;6:393–397.

53. Bosso JA, Black PG. Controlled trial of aztreonam vs. tobramy-

cin and azlocillin for acute pulmonary exacerbations of cystic

fibrosis. Pediatr Infect Dis J 1988;7:171–176.

54. Doribax1 approved package labeling. Raritan, NJ: Ortho

McNeil Janssen; 2009.

55. Chen Y, Garber E, Zhao Q, Ge Y, Wikler MA, Kaniga K,

Saiman L. In vitro activity of doripenem (S-4661) against multi-

drug-resistant gram-negative bacilli isolated from patients with

cystic fibrosis. Antimicrob Agents Chemother 2005;49:2510–

2511.

56. Traczewski MM, Brown SD. In vitro activity of doripenem

against Pseudomonas aeruginosa and Burkholderia cepacia

isolates from both cystic fibrosis and non-cystic fibrosis patients.

Antimicrob Agents Chemother 2006;50:819–821.

57. Primaxin1 approved package labeling. Whitehouse Station, NJ:

Merck; 2009.

58. Pedersen SS, Pressler T, Hoiby N, Bentzon MW, Koch C.

Imipenem/cilastatin treatment of multiresistant Pseudomonas

aeruginosa lung infection in cystic fibrosis. J Antimicrob

Chemother 1985;16:629–635.

59. Krilov LR, Blumer JL, Stern RC, Hartstein AI, Iglewski BN.

Imipenem/cilastatin in acute pulmonary exacerbations of cystic

fibrosis. Rev Infect Dis 1985;7:S482–S489.

60. Merrem1 approved package labeling. Wilmington, DE: Astra-

Zeneca; 2009.

61. Byrne S, Maddison J, Connor P, Doughty I, Dodd M, Jenney M,

Webb AK, David TJ. Clinical evaluation of meropenem versus

ceftazidime for the treatment of Pseudomonas spp. infections in

cystic fibrosis patients. J Antimicrob Chemother 1995;36:135–

143.

62. Lima AL, Oliveira PR, Paula AP, Dal-Paz K, Almeida JN, Felix

Cda S, Rossi F. Carbapenem stewardship: positive impact on

hospital ecology. Braz J Infect Dis 2011;15:1–5.

Aztreonam and Carbapenems in CF 11

Pediatric Pulmonology

63. Nicolau DP, Carmeli Y, Crank CW, Goff DA, Graber CJ, Lima

AL, Goldstein EJ. Carbapenem stewardship: does ertapenem

affect Pseudomonas susceptibility to other carbapenems? A

review of the evidence. Int J Antimicrob Agents 2012;39:

11–15.

64. Dellit TH, Owens RC, McGowan JE, Gerding DN, Weinstein

RA, Burke JP, Huskins WC, Paterson DL, Fishman NO,

Carpenter CF. et al. Infectious Diseases Society of America

and the Society for Healthcare Epidemiology of America

guidelines for developing an institutional program to en-

hance antimicrobial stewardship. Clin Infect Dis 2007;44:159–

177.

65. Sanders DB, Hoffman LR, Emerson J, Gibson RL, Rosenfeld

M, Redding GJ, Goss CH. Return of FEV1 after pulmonary ex-

acerbation in children with cystic fibrosis. Pediatr Pulmonol

2010;45:127–134.

66. Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding

GJ, Goss CH. Failure to recover to baseline pulmonary function

after cystic fibrosis pulmonary exacerbation. Am J Respir Crit

Care Med 2010;182:627–632.

12 Zobell et al.

Pediatric Pulmonology