Antibacterial Therapy in Cystic Fibrosis

many prospective applications bothin microbiologic research and in clinical microbiologg and it will certainly find its way into the routine clinical microbiology laboratory However, the extent to which this will occur and the pace of development are difficult to predict, although some areas in which hybridization technology will prove to be a useful adjunct to established methods are already well defined. The introduction of nucleic acid hybridization into these areas of diagnostic microbiology will probably depend upon the time needed to realize certain technical improvements.

Antibacterial Therapy In Cystic Fibrosis A Review of the Literature Published

Between 1980 and February 1987

B.C. Michel, M.D.·

T

he use of antibiotics in patients with cystic fibrosis (CF) is a controversial subject. No consensus has been reached on the indications for antibiotic therapy the antibi*De~ent of InternaI

hage, The Netherlands.

Medicine, Red Cross Hospital, s-Craven-

otics to be used, or the dosage schedules. Trials are complicated by the large number of parameters available to monitor the effect of treatment Has a patient improved when he feels better, when the pulmonary function improves, or when the sputum culture becomes negative? Should the patient be treated with antibiotics every 3 months, continuously or should only infectious exacerbations be treated? This presentation reviews the literature on clinical trials published between 1980 and February 1987. A few publications from April 1987 concerning ciprofloxacin are also included. The purpose of the survey is to document and compare current views on antibiotic treatment in patients with CF, or, perhaps even more important, to document little-known aspects of this subject Even though some trials were obviously more elaborate than others, all the data are presented and no preselection on the basis of possible validity has been made. How is an infectious exacerbation in CF defined? Even though the term "exacerbation" is often used, its defining characteristics are not always clear from the literature. In Table 1 the characteristics of patients who entered a trial because of an exacerbation are compared with those of patients who were treated on a regular basis, ie, every 3 months. No obvious differences can be seen. Four bacterial species play an important role as infectious agents in CF patients: Staphylococcus auf'WS, Hemophilus injluenzae, Pseudomonas aeruginosa, and Pseudomonas cepacta. Antimicrobial treatment of each is discussed below

Table I-Laboratory Tel'" ShwachmtJn Score, and PulmontJry Function in Patients With

and Without an lnfectioua Emcerbation*

Shwachman Score

WBCs

Neutrophils

(loefL)

(loefL)

ESR (mmlh)

FVC

FEV 1

PEFR

Exacerbation Prince and Neu, 198()1 Hyatt et aI, 19811 Levy et aI, 19823 Hoogkamp-Korstanje et al, 1983· McLaughlin et aI, 19835 Padoan et aI, 19838 Penketh et al, 19837 Cerny et aI, 19848 Penketh et ai, 19848 Conway et al, 198&° Gold et al, 198511 Jewett et aI, 198511 Krilov et al, 198513

13.2

34

47.4 40 60% 62%

62 45 1.78

44%

1.88

242 250

1.16

12.8

27

13.8

34.5

50% 54% 2.26

54.3 50.5

33%

10.3

66 46.6

Schaad et al, 198614 Smith et ai, 198f>l5 Bosso et al, 19871' Goldfarb et al, 198717

222

0.97 56%

70

12.7 11

40% 1.33

62% 56%

Hodson et aI, 198718 Horrevorts et al, 19871')

55%

40%

2.16

296 40%

1.26

256

42%

Heilesen et al, 198310 Permin et al, 198311 Pedersen et al, 198&1 Shalit et al, 198713

60

15.4 9.9 9.6 9.2

No Exacerbation 9.0 6.3

49% 72% 43%

23

60%

30% 52% 36% 41%

67% 97% 56%

*WBCs =average No, ERS =average erythrocyte sedimentation rate, FVC =forced vital capacity of the lungs in liters and in percentage of predicted values for age, FEV1 forced expiratory volume in 1 s in liters and in percentage of predicted values for age, PEFR =peak expiratory flow rate in Umin and in percentage of predicted vaIues for age.

=

CHEST I 94 I 2 I AUGUST; 1988 I Supplement

1298

Table I-Anti-Pseudomonas Antibiotic Dwltment U. in CliraictJl1HtJll BettDeen 1980 and 1987·

Antibiotic'Studyt

CarbeuiciDiD H-. et ai, 19&'J11 AzIociUin MfcbaIsen etal,198138 Huaug etal, 198:J1S MastelIa etal, 1983'7 McLaugbItn et aI, 19835 PiperaciIIin PriDce etal, If8)1 Hoogbmp-Ionbmje

No. of 1i'eatment Courses

Supplementary

Duration of Amino

Other Antibiotics

(mWkW24h~

(mWkW24h)

%ofPts With Clinical Improvement

%ofPts with

Pulmonary

Therapy (Days)

FJCI

14

9-16

E

500(5)

14 12

12-15 11-14 10-15 10

C E E E

300-600 (3) 250(5) 400 (3)

+

+

~(6)

+

+

11 7

7-14 14

E E

350-500 (6) ~(4)

82 57

22

10-15

E

400 (3)

46

11aerapy*

~

16

A

Pen (mWkW24h)

Cef (mWkW24h)

64 92 30

Improvement 18 20

29

etal,l9834

MIIteIJa etaI, l~ 'DJInmydn

Wientzen et II, lQ803C PermJn et aI, lQ8311

~

M,uer et al, 198238 MastelIa et a1, lQ8331 Caplan et al,198.-

Ceftaidime Cordts et at, 1982«» Cullen etal,lQ83f1 David etII, IfJ83'1 Dodge et at, lQ830 Pacbn et II, 19838 PermJn et II, 1983'l MastelIa etal, 19&')31 lercsmar et al, 1983" Strandvik et al, 1~ BTSRC, 1985Cold et al, 19&;11 CeiJpenmoe Mutella et al, 198:F Jewett et ai, lQ8511 CarbeuiciDiD +gentamicin Beaudry et a1, 198(p3 Martin et ai, 1980" Hodson et ai, 198141 Hodson et aI, 1983Penketh et ai, 198:J7 Penketh et al, 1984' BTSBC,I~

CarbeuiciDiD +tobnmycin

Y.

Martin et II, 18)'1 Hodson et a1, 198141 et aI, 1981M,uer et al, 1982Hodson etal, 198348 PermJn et al, 1983'l
TicarciIIin +gentamicin Penketh etaI, 1983" Tarcillin +tobnmydn McLaugbIin et ai, 19835 OJoway et II, 19851° Gold et ai, 198511 Horrevorts et a1, 198718

6 (3) 10 (3)

13

A

14

E C

8 22 14

P

14 10-15 5-24

C E E

100-150 (3) 200 (3) 100 (1)

3-14 7-31 9-17

E E E E

40-115 100-240 (3) 137 (3) 94 (2-4) ISO (3) ISO (3) 200 (3) [6] (3) 150 (3) 151 (3) 200 (4)

12

15 8 28 17 11 28

A A A

27

15 10

50

~13

14 14 10-15 14-35

E C

E E

E

17

7-17 10-14

E E

fD 12

10-15 5-15

E

11 10 14 9 8 10 32

A

E

E E E E E

E E E

57 ~

+

96 100 91

78 100 100 96 94

35

EK)O (6) 800 (4) [20] (4) [20] (4) [20] (4) [I)] (4) 450 (4)

5 (3) 9 (3) SL S [0.24] (3) SL (3) S (3) S 6.3 (3) SL 9 (3) SL S 10 (3) 10(3) [0.24] (3) SL 10 (3)

+

100 100 100 78

C

A

14

E

390 (6)

(6) S

80

10

E

[I)] (4)

(3) S

100

10 8-21 10-14 19-26

E E E E

~(6)

9 15 15 8

A

E

586 (3) D) (4) EK)O (4)

6 (3) SL 9.2 (3) SL 10 (3) SL 10(3) SL

+ +

+

A

P P

66-83

+

+

C C

9 9

[~]

+

+

800 (4) (4) 500 (3) 500 (3) [20] (4) 500 (3)

A

96

100

13-14 10 14 14 8-10 14

10 9

17 15 13 16

10 11-14 10 8-10 10 10 1-18

66

+

88 55

200 (3) 100 (2)

E

92

100

+ + 85

+

+

100 78-88 14-78

(Continued)

1308

Pulmonary Infection and AntIbiotic 1l'eatment In CystIc Fibrosis

TarciDin +tobramycin + metbiciDin Jewett et al, lQ851J TIC8I'CiIIin +netilmicin Conway et al, lQ851° Schaad et ai, 198&4 Azlocillin +gentamicin Malmborg et ai, 198151 Hodsonetal, 198148 Penketh et ai, 19848 Hodson et ai, 198718 Azlocillin +tOOramycin MfJner etat, 198150 M,Der etal, 198P McLaughlin et a1, 1983' Rubio et al, 198&3 Bosso et a1, 198718 Rubio et a1, 198'7!B Azlocillin +netiImicin Schaad etal, 198&4 Piperacillin +tOOramycin M;Der et sl, 198150 M;Der etai, 198251 Hoogkamp-Korstanje etal,l9834 Ce&uIodin +tOOramydn M,IIer etal, lQ8231 M'" et at, 19825' Ceftazidime +tobnmycin Heilesen et a1, 1~ Strmdvik etal, 198345 ImipenemlciIastItin IriIov et a1, lQ8513 Pedersen et a1, 19&91

Table 2, cor&flnued 13 15 21

A

10 5 10 20 18 18 18 9 10 11

P P

A

8-16

E

200+200 (4)

5-7.5 (3) SL

100

+

8-21 10-17

E E

468 (3) 500 (4)

10 (3) SL 11 (3) SL

+ 100

100 +

10-12 10 10 10

E

IX) (3) [16] (4) [15] (3) [15] (3)

5-8 (2)

E E E

100 100 W

14 14-4.2

C C E E E E

300 300 350 300 350

14 14 10

D)

S (3) S [0.24] (3) SL

(3) (3) (6) (4) (4) (3-4)

10 (3) 10 (3) 6 (3) SL 9 (3) SL S 9 (3-4)

+ 100

100

21

A

12-17

E

500 (4)

11 (3) SL

rr

p P

14 14 14

C C E

300 (3) 300 (3) 300 (4)

10 (3) 10 (3) 7 (3)

P

14 14

C C

14

C

27 7 15

m 11 6

A

E 6-10 14

19 10

100-150 (3) l00-ISO (3) 100 (3) 150 (3)

E C

~

+

+ +

100

+ +

100

+ 43-57

10 10 (3)

100

10 (3) 15 (3)

100 100

75-100

58

+

51

~W(4)

45

Aztreooam

Scully et al, 19fW6 Cipro8oucin Rubio et a1, 198653 Smith etal, 198&5 Bosso et at, 198718 GoIdfIrb et al, 198711 Hodson et at, 19fJ718 Rubio etal, 198'71Jl5 Scully et al, IfB7S7 Sbalit eta1, 19fr713

26 19 10 10 30

20 26 39 14 15

Sbalit etat, 1987S' Placebo

Wientzen etal, 1~

E

A

14-4.2 10 14 21 10 14-4.2 16 14 14

12

E E E E E E E C

C E

85 [1.5] [l.5] [1.5] [2.3] [1.5] [1.5] [1.8] [1.5] [2.0]

(2) (3) (2) (3) (3) (2) (2)

(2)

W 71

78

100 95 92 82

}56 58

0

·Pen =penicillins, Cef=cephalosporins, Amino =aminoglycosides. Unless otherwise noted, parentheses in table enclose number of daily doses. Brackets [] denote dosages in r/day (different from dosages stated in column heads) t+ =and. *P =probenecid, A =supplementary antibiotics. IAntibiotics were prescribed only during exacerbations (E) or in 3-month courses. fS =Aminoglycoside dosage depended on serum level; SL =dosage adjusted according to serum level; (SL) = rate of dosage depended on serum level.

STAPHYLOCOCCUS AUREUS

Littlewood" found that 30 percent of CF patients in the surroundings of Leeds had a staphylococcal infection that was untreated or inadequately treated. According to Friend25 a staphylococcal infection can be treated (1) prophylactically Ie, with continuous administration of antibiotics; (2) with antibiotics as soon as staphylococci are found in the sputum, independent of the clinical condition of the patient; and (3)

only in the case of clinical exacerbations. Schlesinger et al- found fewer S aumu-positive throat cultures, an increase in weight, a decrease in erythrocyte sedimentation rate (ESR1 and a decrease in serum 'Y-globulin levels after 12 months ofcontinuous prophylaxis. Prophylaxis consisted of successive courses of cotrimoxazole, cefadroxin, and dicloxacillin for a period of 3 months. Knightl"' found an improvement in pulmonary function during continuous therapy with flucloxacillin and amoxicillin in 4 patients. CHEST I 84 I 2 I AUGus-r, 1988 I Supplement

1318

Mastellaet aI, 198337 Strandvik et al, 198345 BTSRC, 198&8 Gold et aI, 1985 11 Cefoperazone Mastellaet al, 198337 Jewett et al, 198&1 Imipenemlcilastatin Krilovet aI, 198513 Pedersen et aI, lQ8511 Scully et aI, 198757 Aztreonam Scully et aI, 198&7 Ciprofloxacin Bossoet aI, 198718 Goldfarb et al, 198711 Rubio, 198755

Table 3, continued 6

>32 >16

23.8 0

o o o

>32 >4

21.7 7

>8

9

27

CPACC Cefta ± tobra

20

CPACC

6t 3

16.6 17 37

100 Ciproflox

10

3

>50

>2

7

3

o

100

3

45

o

Shalit et al, 198113

0

100 Ciprofloxl tobra + azlo 37

*Criterion for resistance: the breakpoint of the MIC used by the authors to indicate resistanceof a P,eudornoraa& strain. An MIC in parentheses is one introduced by us. fIDe % resistance figures were based on data supplied by the investigators. "Follow-up" indicates 2 weeks to 3 months after termination of treatment merapy is only mentioned when the antibiotic used in treatment was not the same antibiotic against which susceptibility was tested. Azlo== azlocillin, carb == carbenicillin, cefta == ceftazidime, cefs = cefsulodin, ciproBox = ciproBoxacin, genta = gentamicin, amika = amikacin, meth == methicillin, netil == netilmicin, tobra == tobramycin, ± = with or without, / = or, + = with, CPACC = ceftazidime, piperacillin, azlocillin, cefsulodin, or cefoperazone. tThe strains isolated before and after treatment were not the same.

Nolan et aI28 found no supplementary effect when cephaloridin aerosol was concurrently administered with oral cloxacillin in continuous treatment Some 23 percent of the patients continued to harbor S aumu whether treated with cephaloridin or not

The second form of treatment, prescribing antibiotics as soon as S aurew is found in the sputum, is used in Denmark. 28,3O Treatment consists of oxacillin(50 mglkg/24 h) or dicloxacillin (25 mglkg/24 h), combined with fusidic acid

Table 4-1mprovement in Weight and in ShtDGclatrlGn and Beaudry ScoreaDuring treatment

Antibiotic/Study*

Dosage (mg/kgl24 h)

Weight (% Increase)

Shwachman Score (% Increase)

Beaudry Score (% Increase)

Azlocillin

McLaughlin et al, 19835 Ceftazidime Cullen et aI, 198341 Padoan et aI, 19838 Gold et al, 198511

Carbenicillin + gentamicin

Beaudry et aI, 198()33 TIcarcillin + tobramycin McLaughlin et aI, 19835 Conway et al, 198&° Gold et aI 198511 ncarcillin + netilmicin Conway et al, 198510 Schaadet al, 198&4 Azlocillin + tobramycin McLaughlin et aI, 19835 Azlocillin + netilmicin Schaad et aI, 198314 Imipenemlcilastatin Krilov et aI, 198&3 Pedersen et al, lQ8511 t

*+

300 100-240

13 7

150

200

54

1.8

600/5

50

30016 586/9.2 300/10

3.1 3.1

468110 500111

3.2 3.5

13

30016

500/11 30-90 45

13

2.3 8 25

=and CHEST I 94 I 2 I AUGUST; 1988 I Supplement

1338

(50 mg/kg/24 h) and probenecid (10 to 15 mg/kg/24 h) for 14 days. If Staphylococcus is not eradicated from the sputum after 2 to 3 treatment courses, a prolonged course of isoxazolylpenicillin is given. Patients on anti-Pseudomonas therapy are treated with fusidic acid only if they are also infected with staphylococci. Only 9 percent of the patients in the Danish studies harbored a chronic S aureus infection. The number of precipitins against S aureus increased only very slightly and remained low compared to that in other Scandinavian centers. No multiply resistant strains were fOund. Schlesinger et aile found no advantage to the third form of treatment-treating only acute exacerbations-compared to continuous prophylaxis. In 36 percent of the patients, the S aumu Infectionpersisted. Shapera et al31 treated patients with infectious exacerbations for 10 to 35 days with clindamycin (20 mglkw'24 h). In 35 percent the clinical condition improved and in 41 percent S aureus disappeared from the sputum. HEMOPHILUS INFLUENZAE

In general, H influenzae is not cultured for more than a fewmonths from sputum of patients with CF.30 In 75 percent of the patients the sputum is free of H jnftuenzae after treatment. Amoxicillin (25 to 50 mg/kg/24 h given orally) is considered the drug of first choice by most authors. 30 •32 Unfortunately resistance to amoxicillin has become increasingly prevalent in the last years. Cotrimoxazole (30 to 60 mglkg/24 h), erythromycin (30 to 50 mglkg/24 h), tetracycline, and cephalosporins are good alternatives, ifnecessary in combination with rifampicin (15 mg/kg/24 h). Chloramphenicol can be used in seriously ill patients. Knight" warns against using a low dose of amoxicilIin. In his opinion the dosage should be at least 3 g twice daily for several weeks. If Staphylococcus and Hemophilus are cultured from the sputum at the same time, flucloxacilIin, 100 mg/kg/24 h, and amoxicillin, 100 mglkw'24 h should be given together. ~Lactamase-positive Hemophilus is treated with amoxicilIin plus clavulanic acid (Augmentin). PSEUDOMONAS AERUGINOSA ~ICIs anti-Pseudomonas therapy warranted in acute respiratory exacerbations in children with cystic fibrosisP" Under this title Beaudry et al33 in 1980 published a much-eited study comparing the effects of carbenicillin plus gentamicin versus cloxacillin. They found no difference between these regimens in their effects on clinical parameters, pulmonary function, chest radiologic findings, and sputum culture for Pseudomonas. Hyatt et all (sisomicin or carbenicillin plus oxacillin versus monotherapy with oxacillin) and Wientzen et al:M (tobramycin versus placebo) did find an effect of antiPseudomonas therapy on clinical condition, pulmonary function, and Pseudomonas in sputum. Unfortunately the placebo-treated group in the study of Wientzen et al34 included significantly more seriously ill patients (in spite of random ization), making that study less useful. Therefore, the effectiveness of anti-Pseudomonas therapy in acute infectious exacerbations with P aeroginosa has not yet been established. Beaudry et al33 claim that patients benefit more from oxygen,

1348

Table 5-Peceratage ofPatientB with Sputum Cultures Negativefor Pseudomonas aeruginosa After 1i'8atment, Compared with Percentage ofPatienta with Clinical Improvement During 7reatment

Antibiotic/Study"

N

Neg Sputum Cultures (If> ofPts)

Clinical Improvement (% ofPts)

14

7

64

14 12 20 16

29 0 0 0

92 30

11 7

33

82 57

22

5

46

24 12

13 0

92

Carbenicillin

Huang et al, 1985'5 Azlocillin Michalsen et aI, 198136 Huang et ai, lQ8335 Mastella et al, 198337 McLaughlin et ai, 19835 Piperacillin Prince et al, 198()1 Hoogkamp- Korstanje et aI, 19834 Mastella et al, 198337 Tobramycin Wientzen et ai, 1980W Permin et al, lQ8321 Cefsulodin M_ller et aI, 198238 Mastella et ai, 198337 Caplan et al, 198438

0

8

25

88

22 14

23 0

55 57

15 8 28 27 11 28 50 17

13 38

80

46

96 78 91

20 12

10 0

Ceftazidime

Cordts et ai, 198240 Cullen et ai, 198341 David et aI, 198342 Mastella et ai, 198337 Padoan et ai, 19836 Permin et ai, lQ8321 BTSRC, 198546 Gold et ai, 198511 Cefoperazone Mastella et aI, 198337 Jewett et aI, 1985lJ Carbenicillin + gentamicin Beaudry et aI, 198()13 Martin et ai, 1980'7 Penketh et aI, 19837 Penketb et aI, 19849 BTSRC, 198546 Carbenicillin + tobramycin Martin et al, 198()C7 Mf611er et ai, 198252 Mf611er et al, 198150 Permin et ai, lQ8321 Carbenicillin + sisomicin Hyatt et al, 19811 TIcarcillin + gentamicin Penketh et aI, 19837 Tlearcillin + tobramycin McLaughlin et al, 19835 Conway et al, 198510 Gold et aI, 198511 TIcarcillin + tobramycin + methicillin Jewett et ai, 198512 TIcarcillin + netilmicin

11 10 8 10

22 9 0 18

96 94

35 100

27

80 0 10

100 100

32

26

78

10 9 9 15

70 78 78 0

15

40

80

8

0

100

17 15 13

40

13

15

0 85

100

(Continued) Pulmonary Infection and AntibioticTreatment in Cystic Fibrosis

Table 5, continued Conway et aI, 198&° Schaad et aI, 198&4 Azlocillin + gentamicin Malmborg et al, 198151 Penketh et al, 19848 Hodson et aI, 198718

Azlocillin + tobramycin M"ller et aI, 198251 M"ller et aI, 198150 McLaughlin et aI, 19835 Rubio, 198755 Azlocillin + netilmicin Schaad et al, 198114 Piperacillin + tobramycin M"ller et al, 198251 M"ller et ai, 198150 Hoogkamp-Korstanje et aI, 19834 Cefsulodin + tobramycin M"ller et al, 198238 M"ller et aI, 198254 Ceftazidime + tobramycin Heilesen et aI, 198310 Imipenemlcilastatin Krilov et aI, 198&3 Pedersen et aI, 198511 Aztreonam ± aminoglycoside Scully et al, 198&8 Ciprofloxacin (orally) Smith et aI, 198&5 Goldfarb et aI, 198711 Hodson et aI, 1987-» Rubio, 1981S15 Scully et aI, 198P'7 ShaIit et aI, 198'713 Placebo Wientzen et al, 198()'W

15 21

33 24

100

10 10 20

30 20 15

100 90 90

18 18 18 11

28 28 7 0

100

21

33

100

27 27

33 33

7

18

100

15 60

20 24

100

11

9

100

19 10

0

58

26

0

85

10 30 20 26 39 29

0 10 0 3

71 100 95 92 82 56

12

0

58

.+ :=and

Table 6-Average PercenttJge ofDecretJN ira &cteritJl Counll o/Pseudomonas ira Sputum

Antibiotic/Study· Azlocillin Mastella et aI, lQ8331 Piperacillin Mastella et aI, lQ8331 Cefsulodin Mastella et aI, lQ8331 Ceftazidime Padoan et aI, 19838 Mastella et al, 198337 Cullen et al, 1983'" Cefoperazone Mastella et aI, lQ8331 TIcarcillin + tobramycin Conway et al, 19851° TIcarcillin + netilmicin Conway et ai, 198510 Imipenem/cilastatin Krilov et aI, 198&3 Ciprofloxacin Shalit et aI, 198713

Dosage (mg/kg/24 h)

Decrease in BacteriaI Counts (%)

400

44.5

400

59

200

64

150 200 100-240

73 77.6 94

200

55

58619.2

61

468/10

73

30-90

60

1,500-2,000

87

.+ :=and of a penicillin and an aminoglycoside, or ceftazidime, seems to be superior to penicillin or tobramycin monotherapy in improving chest radiographic findings (Table 9). Treatment with a combination of ceftazidime and tobramycin results in a higher percentage of patients with pulmonary function Improvements' than does monotherapy or treatment with other antibiotic combinations (Tables 10 and 11). Improve-

Table 7-Average Percentage ofChange ira LabortJtory Valua During 7reatment

bronchodilators, mueolytics, and physical therapy

% Changet

WHICH ANTIBIOTICS SHOULD BE GIVEN, AND IN WHAT DOSES?

Table 2 reviews antibiotic treatment regimens published between 1980 and 1987. A combination of a penicillin and an aminoglycoside is generally used. Due to increasing resistance to penicillin, new antibiotic regimens have been studied. In the past 6 years resistance to carbenicillin varied between 0 percent" and 68 percent," resistance to azlocillin between 0 percentM,SI and 27 percent," and resistance to ticarcillin between 0 percent" and 62 percent'S (Table 3). Resistance to cephalosporins is currently appreciably lower than that to penicillins (ceftazidime, 0 percent ll ,20,42,43,4S,46 to 6 percent," and cefsulodin, 0 percent" to 15.2 percent"), There is no obvious increase in the prevalence of drug resistance in recent years, probably because of the frequent changes of treatment schedules applied. The percentage of drug-resistant microorganisms after therapy varies widely as can be seen from Table 3. Little difference exists between antibiotics or their combinations in effects on clinical condition (Tables 4 and 51 bacterial counts in sputum (Table 6), leukocytes (Table 7), and chest radiographic findings (Table 8). The combination

Antibiotic/Study" Tobramycin Permin et aI, lQ8321 Ceftazidime Permin et al, lQ8321 Gold et aI, 198&1 Carbenicillin + tobramycin Permin et aI, lQ8321 TIcarcillin + netilmicin Schaad et al, 198&4 TIcarcillin + tobramycin Gold et aI, 198511 Azlocillin + netilmicin Schaad et aI, 198&" Ceftazidime + tobramycin Heilesen et al, lQ83iO Imipenemlcilastatin Pedersen et aI, 198511

Dosage ESR WBC Neutr. (mg/kg/24 h) (mmlh) (IODIL) (IOD/L) 10 150 200

-33

-54

-34

-55

-41.6 -30.3

500110

-35

SOOl11

-23

300/10

-31.1 -37.2

SOO/11

-13

-59

-31

-39

100110

-44

45

-33

-69

.+ :=and tESR:= erythrocyte sedimentation rate, WBC:= white blood cell count, Neutr. :=number of neutrophils. CHEST I 94 I 2 I AUGUst 1988 I SUpplement

1358

Table 8-Averclge PerCBfll4ge ofChtJnge in ChriBpin and Nonnan Scorefor X-rtJflFilma ofCllat During treatment

Antibiotic/Study·

Dosage (mglkg/24 h)

% Change C&N Scoret

400

14 (NS)

300 400

13 15

200

12 (NS)

150 200

12 16

200

19 (NS)

Azlocillin Mastella et al, 198337 Piperacillin Hoogkamp-Korstanje et al, 19834 Mastella et ai, 198337 Cefsulodin Mastella et ai, 198337 Ceftazidime Padoan et ai, 19838 Mastella et ai, 198337 CefOperazone Mastella et ai, 198337 Carbenicillin + gentamicin Martin et ai, 198()47 Carbenicillin + tobramycin Martin et aI, 198()C7 T1C8J"cillin + netilmicin Conway et ai, 198&0 Schaad et al, 198&4 TIcarcillin + tobramycin Conway et ai, 198510 Azlocillin + netilmicin Schaad et al, 198614 Piperacillin + tobramycin Hoogkamp-Korstanje et al, 19834

800/9

15

800/9

30

468110

12

500/11

11

586/9.2

21

BOO/II

11

300/7

17

*+ =and tC&:N = Chrispin and Norman score. NS = not Significant ment in the ESR was better after treatment with ceftazidime or a combination of tobramycin and ticarcillin than after other treatment regimens (see Table 7). The combination of tobramycin and carbenicillin resulted in the highest percentage of patients free of Pseudomonas in sputum (see Table 5). No correlation exists, however, between clinical improvement and eradication of Pseudomonas from the sputum after treatment (Table 5). Currently used combinations of penicillins and aminoglycosides are azlocillin (300 to 600 mglkg/24 h), carbenicillin (450 to 800 mglkgl24 h), or ticarcillin (300 to 600 mg/kgl24 h) with gentamicin (5 to 9 mg/kgl24 h), tobramycin (6 to 15 mg/kgl24 h), netilmicin (10 to 11 mglkg/24 h), or sisomicin (280 mg/m t/24 h). It was recently shown that an adjustment in dose interval based on the serum tobramycin level has a significant effect on pulmonary function. 19 The effectiveness of the various penicillins seems to be similar. McLaughlin et als and Schaad et al14 compared ticarcillin with azlocillin; Mf611er et al,38.52 Hodson et aI,49 Penketh et aI,9 and Huang et alMcompared carbenicillin and azlocillin (the first three groups combined the penicillins with an aminoglycoside; Huang et alM used penicillin monotherapy). Penlceth et al' compared ticarcillin with carbenicillin (both combined with gentamicin). Mf611er et al38.51 found a better effect on Pseudomonas with carbenicillin than with azlocillin (78 percent versus 28 percent of the patients were free of Pseudomonas). However, Huang

1388

et alM found more patients clinically improved after treatment with azlocillin than with carbenicillin. Other authors found no differences between penicillins in effects on clinical condition, pulmonary function, or Pseudomonas in sputum. After the use of piperacillin, a serum-sickness-like symptom was described in 24 to 72 percentsS·59 of the patients. In comparing gentamicin with tobramycinv-" and tobramycin with netilmicin, 10 we found no differences in effects on clinical condition, pulmonary function, or Pseudomonas in sputum. Since 1983 ceftazidime (40 to 240 mglkg/24 h) and cefsulodin (100 to 200 mglkg/24 h) have been increasingly used, sometimes combined with tobramycin. The effect of both antibiotics is similar." Compared with the combination of a penicillin and an aminoglycoside, ceftazidime may lead to a greater improvement in pulmonary function" and clinical condition.« Less initial drug resistance has also been reported.v-" Twenty-two of 26 patients treated with aztreonam showed clinical improvement, but Pseudomonas remained present in sputum cultures of all patients." The percentage of resistant strains increased from 3 to 7 percent. No double-blind trials comparing this narrow-spectrum penicillin to other antibiotics have been published. As a result of the search for a useful oral treatment against Pseudomonas, ciprofloxacin was introduced in 1985, in a dosage of 1,000 to 1,500 mg/day for 10 days. In 0 to 22 percent of the patients Pseudomonas disappeared from the sputum.IS.18.81 A comparison of ciprofloxacin with azlocillin (15 g/24 h) and gentamicin (0.24 g/24 h) showed that ciprofloxacin resulted in more improvement in pulmonary function. This effect was still evident 6 weeks after treatment with ciprofloxacin was discontinued, in contrast to azlocillin and gentamicin. Resistant Pseudomonas strains were found in 10 percent of patients after treatment with ciprofloxacin and in 15 percent after treatment with azlocillin plus gentamicin.

Indicationsfor Antibiotic Treatment Most investigators give antibiotics directed against

P aeroginosa only in the case of infectious exacerbations.

However, the Danish group" favors treatment every 3 months of patients harboring Pseudomonas for more than 6 months or who have more than two serum precipitins against Pseudomonas persisting for 14 days or more. They reported an increase in 5-year survival rate from 54 percent in 1975 (when only exacerbations were treated) to 82 percent in 1980 (after they had used the 3-month treatment regimen for 5 years). Because the number of resistant strains and adverse reactions increase when antibiotics are given more often, 30 the long-term usefulness of this schedule of treatment should be established.

Aerosol Therapy A disadvantage of aminoglycosides is the necessity of parenteral administration. They can, however, also be given by aerosol. Several indications for aerosol-treatment are given in the literature: (1) for infectious exacerbations in children up to 1 year of age;81 (2) to maintain antibiotic efficacy after intravenous therapy." (3) to prevent frequent hospital admissions for periods of weeks to months;J4,61.&2 (4) to retard the deterioration in pulmonary function by daily administration;32.62 and (5) to prevent colonization of the Pulmonary Infection and Antibiotic 1reatment In Cystic Rbrosis

Table 9-PercenlagB ojftJtienta tDitla Changa on eMIt BtJdiogrtJpIaa

AntibioticJStudy·

N

Carbenicillin Huang et aI, 198335

No Change

Improvement

(% ofPts)

Method of Describing

(II ofPts)

Radiographst

11

9

Authors

10

30

Authors

7

57

C~N

11

Authors

Azlocillin

Huang et al, lQ8335 Piperacillin Hoogkamp-Korstanje et al, 19834 Tobramycin Wientzen et al, 1~ Cefsulodin Caplan et al, 1984Ceftazidime Padoan et al, l~e Cefoperazone Jewett et al, lQ8511 TIcarcillin + tobramycin Conway et al, 198&°

9

78

14

+

11

18

12

92

Authors 73

Brasfield

93

15

ncarcillin + tobramycin + methicillin Jewett et al, 198511 Netilmicin + ticarcillin Conway et al, 1985 10 Piperacillin + tobramycin Hcogkamp-Korstanje et al, 19834 Imipenemlcilastatin Pedersen et al, lQ8511

13

92

12

25

10

+

9

56

Placebo

C~N

Bras6eld

7

Wientzen et al, 1~

C&N

75

C~N

71

C~N

Authors

33

Authors

*+ = and tRadiographs are described by the method ofChrispin and Norman (C~N~ the method of Bras6eld, or a method developed by the authors.

Table lo-PercenttJge ofPattentI with lmprooement in PulrnonsrrI Function ~

ofPts. with Improved Lung Function:* to:

AntibioticJStudy* Piperacillin Hoogkamp-Korstanje et al, 19834 Ceftazidime Gold et al, 198511 Carbenicillin + gentamicin Beaudry et ai, lQ8013 ncarcillin + tobramycin Conway et al, 198&° Gold et al, lQ8511 Horrevorts et al, 198718 llcarcillin + netilmicin Conway et al, 198&° Piperacillin + tobramycin Hoogkamp-ICorstanje et al, 19834 Cefsulodin + tobramycin Mfjller et al, 1982M

Ceftazidime

+ tobramycin

Heilesen et al, 1983Ciprofloxacin Shalit et al, 198'7J3

N 7

Criterion >10

FVC

FEV1

29

29

83

17 (>10%)

15 13 16

(>10%)

12

(>10%)

7

>10%

43

60

>20%

51

30

88

66

80

78

14-78

~20%

83

88 >20%

PEFR

36

11

8

FEF..7I

57 51 100

75

17

27

*+ =and tCriterion =the minimum percent improvement a patient should show to be classified as "improved." If the criterion is mentioned in parentheses it has been set by us at a level of 1~. *FVC = forcedvital capacity of the lungs, FEV1 = forced expiratory volume in 1 second, FEF18-71 = maximum midexpiratory ft~ PEFR peak expiratory flaw rate.

=

CHEST I 94 I 2 I AUGUST, 1888 I SUpplement

1378

Table ll-~e Percenllmprovement in Pulmonary Function During therapy % Improvement in Pulmonary Functiont

AntibioticJStudy*

Azlocillin

McLaughlin et ai, 19835

Piperacl1lin

Hooglcamp-ICbrstanje et ai, 19834 Ceftazidime Gold et ai, 198511 Carbenicillin + gentamicin Beaudry et ai, 1980'3 Penketh et ai, 1983"'

Penketh et al, 19841 11carcl1lin + gentaiDicin Penketh et al, 1983"

ncareillin +

tobi'amycln

McLaughlin et ai, 19835 Conway et al, 198510 Gold et ai, 198311 11carcl1lin + netilmicin Conway et ai, lQ8510 SChaad et al, 198614 AzIoci1lin + gentamicin Penketh et al, 1983' Hodson et al, 198718

+ tobramycin McLaughlin et ai, lQ83S Azlocillin + netilmicin Schaad et al, 198614 Piperacillin + tobramycin Hoogkamp..Korstanje et sl, 19834 Ceftazidime + tobramycin Heflesen et ai, 1~ lmipenemlcilastatin Azlocillin

Krilov et ai, 198513

Pedersen et ai, I98&' Ciprolloucin (orally) Smith et ai, lQ8615 Goldfarb et al, 198711 Hodson et al, 198718 Shalit et al, 198113

Dosaget (mglkg/24 h)

FVC

FEV1

300

15

28

300

9

10 13.1

200

60015 20 v/dayand serum level 20 V/day and serum level

FEFI&-15

PEFR 21

25.6 88

41.2

36.9

43

45.1

41.1

20 v/day and serum level

34.5

40.1

46.2

30016 586/9.2

6

12.5

13.0 21

30016

468110 500111

33.3

28.7

54.7 47

24

41.7

45.9

41.4

26

29

22

300/6

11

18

14

500111

30

3CYJn

19

45

100/10

45

73

30-90 45

9 35

22

500 2x dailyi 750 3x daily 5OO3xdaily 750-1,()()() 2x daily

30 18 43 12

15 v/dayand serum level 15 V/day and serum level

51

8 24

22

50

28

12

47 19

*+ =and tSerum level a: dosage according to serum level. daily: dosage in mglkg twice dail)t IFVC = forced vital capacity oflungs, FEV1 = forced expiratory volume, FEF1&-15 = maximum midexpiratory fl~ PEFR = peak expiratory flow rate.

*2x

lungs with P aeroginosa.14· 83 After several months of treatment with ceftazidime and carbenicillin by aerosol, Hodson et al showed that pulmonary

function improved and that fewer exacerbations were seen, compared with results of placebo therapy Resistant strains occurred in 10 percent of the patients so treated.· Other atithorsao·e. state that aerosol therapy should not be used on a routine basis until more data about the origin and incidence of resistance and side effects are available and until dosages and indications for use have been established.

1888

PSEUDOMONAS CEPACIA

An increase in colonization with P cepacia from9.6 percent in 1970 to 18.1 percent in 1981 has been observed.- Nolan et ailS foundthat more than 40 percent of CF patients under their care had a P cepacia-Positive sputum culture. Hardy et alee found an unchanged prevalence of 20 percent between 1978 and 1985. P cepacia is hot sensitive to aminoglycosides (94 to 100 percent resistance), amoxicillin (97 percent resistance), ticarcillin (98 percent resistance), or sulfamethoxazole (90 percent resistance). Ceftazidime is the only Pulmonary Infectionand AntibioticTreatment in CystIc Fibrosis

antibiotic that is sometimes effective.65 •67 Gold et al67 treated 18 exacerbations in 14 patients with ceftazidime monotherapy or ceftazidime in combination with piperacillin, tobramycin, or cotrimoxazole. Six patients showed clinical improvement; four patients died. No effect was demonstrated on white blood cell count, ESR, or patient weight. REFERENCES 1 Prince AS, Neu HC. Use of piperacillin, a semisynthetic penicillin in the therapy of acute exacerbations of pulmonary disease in patients with cystic fibrosis. J Pediatr 1980; 97:148-51 2 Hyatt AC, Chipps BE, Kumor KM, Mellits ED, Lietman PS~ Rosenstein BJ. A double blind controlled trial of anti-Pseudomonas chemotherapy of acute respiratory exacerbations in patients with cystic fibrosis. J Pediatr 1981; 99:307-11 3 Levy J, Baran 0, Klastersky J. Anti-Pseudomonas activity of azlocillin during pulmonary infection in patients with cystic fibrosis. J Antimicrob Chemother 1982; 10:235-38 4 Hoogkamp- Korstanje jAA, van der Laag J. Piperacillin and tobramycin in the treatment of Pseudomonas lung infections in cystic fibrosis. J Antimicrob Chemother 1983; 12:175-83 5 McLaughlin FJ, Matthews WJ, Strieder OJ, Sullivan B, Taneja A, M urphy ~ et al. Clinical and bacteriological responses to three antibiotic regimens for acute exacerbations of cystic fibrosis: ticarcillin-tobramycin, azlocillin-tobramycin and azlocillin-placebo. J Infect Dis 1983; 147:559-67 6 Padoan R, Brienza A, Crossignani RM, Lodi G, Giunta A, Assael BM, et ale Ceftazidime in treatment of acute pulmonary exacerbations in patients with cystic fibrosis. J Pediatr 1983; 103:320-24 7 Penketh ARL, Hodson ME, Batten JC. TIcarcillin compared with carbenicillin in the treatment of exacerbations of bronchopulmonary infection in cystic fibrosis. Br J Dis Chest 1983; 79:179-84 8 Cerny FJ, Cropp GJA, Bye MR. Hospital therapy improves exercise tolerance and lung function in cystic fibrosis. Am J Dis Child 1984; 138:261-65 9 Penketh ARL, Hodson ME, Gaya H, Batten JC. Azlocillin compared with carbenicillin in the treatment of bronchopulmonary infection due to Pseudomonas aeruginosa in cystic fibrosis. Thorax 1984; 39:299-304 10 Conway S~ Miller MG, Ramsden C, Littlewood JM. Intensive treatment of Pseudomonas chest infection in cystic fibrosis: a comparison of tobramycin and ticarcillin and netilmicin and ticarcillin. Acta Paedriatr Scand 1985; 74:107-13 11 Gold R, Overmeyer A, Knie B, Fleming PC, Levison H. Controlled trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of acute respiratory exacerbations in patients with cystic fibrosis. Pediatr Infect Dis 1985; 4:172-77 12 Jewett cv Ledbetter J, Lyrene RK, Brasfield OM, TIller RE. Comparison of cefoperazone sodium vs. methicillin, ticarcillin and tobramycin in treatment of pulmonary exacerbations in patients with cystic fibrosis. J Pediatr 1985; 106:669-72 13 Krilov LR, Blumer JL, Stern RC, Hartstein AI, Iglewski BN, Goldmann DA. ImipenemlCilastatin in acute pulmonary exacerbations of cystic fibrosis. Rev Infect Dis 1985; 7(supp13):S48289 14 Schaad UB, Desgrandchamps 0, Kraemer R. Antimicrobial therapy of PsetU1omonas pulmonary exacerbations in cystic fibrosis: a prospective evaluation of netilmicin plus azlomicin vs. netilmicin plus ticarcillin. Acta Paediatr Scand 1986; 75:128-38 15 Smith MJ, Hodson ME, Batten JC. Ciprofloxacin in cystic fibrosis. Lancet 1986; 1:1103 16 Bosso JA, Black PG, Matsen JM. Ciprofloxacin versus tobramycin plus azlocillin in pulmonary exacerbations in adult patients with cystic fibrosis. Am J Med 1987; 82(suppl A):I80-84

17 Goldfarb J, Stern RC, Reed MD, Yamashita TS, Myers CM, Blumer JL. Ciprofloxacin monotherapy for acute pulmonary exacerbations of cystic fibrosis. Am J Moo 1987; 82(suppl A):17479 18 Hodson ME, Roberts CM, Butland RJA, Smith MJ, Batten JC. Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeroginosa infection in adults with cystic fibrosis. Lancet 1987; 1:235-37 19 Horrevorts AM, de Witte J, Degener JE, et ale Tobramycin in patients with cystic fibrosis: adjustment in dosing interval for effective treatment Chest 1987; 92:844-48 20 Heilesen AM, Permin H, Koch C, H.,iby N. Ueatment of chronic Pseudomonas aenJginosa infection in cystic fibrosis patients with ceftazidime and tobramycin. Scand J Infect Dis 1983; 15:271-76 21 Permin H, Koch C, Heiby N, Christensen H, M.,ller A, M.,ller S. Ceftazidime treatment of chronic Pseudomonas aeroginosa respiratory tract infection in cystic fibrosis. J Antimicrob Chemother 1983; 12(suppl A):313-23 22 Pedersen SS, Pressler 'I: Heiby N, Bentzon M, Koch C. Imipenemlcilastatin treatment of multiresistant PsetU1omonas aeroginosa lung infection in cystic fibrosis. J Antimicrob Chemother 1985; 16:629-35 23 ShaIit I, Stutman HR, Marks MI, Chartrand SA, Hilman BC. Randomized study of two dosage regimens of ciprofloxacin for treating chronic bronchopulmonary infection in patients with cystic fibrosis. Am J Med 1987; 82(suppl A):189-95 24 Littlewood JM. An overview of the management of cystic fibrosis. J R Soc Med 1986; 79(SI2):55-63 25 Friend PA. Pulmonary infections in cystic fibrosis. J Infect 1986; 13:55-72 26 Schlesinger E, Miller ~ van der Hardt H, Schirg E, Rieger CHL. Effect of longterm continuous anti-staphylococcal antibiotic treatment in young children with cystic fibrosis (poster 414~ In: Lawson D, ed. Cystic fibrosis: horizons. New York: John Wiley & Sons, Inc, 1984:280 27 Knight RK. Antibiotic doses for the bronchiectasis of cystic fibrosis. Lancet 1983; 2:970-71 28 Nolan G, McIvor £ Levison H, Fleming PC, Corey M, Gold R. Antibiotic prophylaxis in cystic fibrosis: inhaled cephaloridine as an adjunct to oral cloxacillin. J Pediatr 1982; 101:626-30 29 SzaffM, Heiby N. Antibiotic treatment of Staphylococcus aurew infection in cystic fibrosis. Acta Paediatr Scand 1982; 71:821-26 30 Heiby N, Friis B, Jensen K, Koch C, M_ller NE, St_vring S, Szaff M. Antimicrobial chemotherapy in cystic fibrosis patients. Act Paediatr Scand 1982; 301(suppl):75-100 31 Shapera RM, Warwick WJ, Matsen JM. Clindamycin therapy of staphylococcal pulmonary infections in patients with cystic fibrosis. J Pediatr 1981; 99:647-50 32 Hodson ME. Cystic fibrosis. Postgrad Med J 1984; 60:225-33 33 Beaudry PH, Marks MI, McDougall D, Desmond K, Rangel R. Is anti-Pseudomonas therapy warranted in acute respiratory exacerbations in children with cystic fibrosis? J Pediatr 1980; 97:144-47 34 Wientzen R, Prestidge CB, Kramer RI, McCracken GH, Nelson JD. Acute pulmonary exacerbations in cystic fibrosis: a double blind trial of tobramycin and placebo therapy Am J Dis Child 1980; 134:1134-38 35 Huang NN, Palmer J, Keith H, Schidlow 0, Braverman S, Goldberg M. Comparative efficacy and tolerance study of azlocillin and carbenicillin in patients with cystic fibrosis: a double blind study J Antimicrob Chemother 1983; II(suppl B):205-14 36 Michalsen H, Bergan 1: Azlocillin with and without an aminoglycoside against respiratory tract infections in children with cystic fibrosis. Scand J Infect Dis 1981; 29(suppl):92-97 37 Mastella G, Agostini M, Barlocco G, Buonomi U, Borgo G, CHEST I 94 I 2 I AUGUst 1988 I Supplement

1398

Bozzino L, et al. Alternative antibiotics for the treatment of Pseudomonas infections in cystic fibrosis. J Antimicrob Chemotber 1983; 12(suppl A):297-311

38 M_ller NE, Koch C, Vesterhauge S, Jensen K. Treatment of pulmonary Pseudomonas aeruginosa infection in cystic fibrosis with cefsulodin. Scand J Infect Dis 1982; 14:207-11 39 Caplan DB, Buchanan C. 'Ireatment of lower respiratory tract infections due to P,eudomonas aeroginosa in patients with cystic fibrosis. Rev Infect Dis 1984; 6(suppI3):S705-10 40 Cordts B, Dab I, Butzler JE Ceftazidime in cystic fibrosis. Lancet 1982; 1:1355 41 Cullen KI; McCrae WM, Govan J, Raeburn }A, Ingram TM. Ceftazidime in cystic fibrosis: clinical, microbiological and immunological studies. J Antimicrob Chemother 1983; 12(suppl A):369-75 42 David TJ, Phillips BM, Connor PJ. Ceftazidime: a significant advance in the treatment of cystic fibrosis. J Antimicrob Chemother 1983; 12(suppl A):337-40 43 Dodge J, Zamiri I, Goodchild M, Ingram E Experience with ceftazidime in cystic fibrosis. J Antimicrob Chemother 1983; 12(suppl A):325-29 44 Kercsmar CM, Stem RC, Reed MD, Myers CM, MurdeD D, Blumer JL. Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response. J Antimicrob Chemother 1983; 12(suppl

A):289-95 45 Strandvik B, Malmborg AS, Alfredson H, Ericsson A. Clinical results and pharmacokinetics of ceftazidime treatment in patients with cystic fibrosis. J Antimicrob Chemother 1983; 12(suppl A):283-87 46 British Thoracic Society Research Committee. Ceftazidime compared with gentamicin and carbenicillin in patients with cystic fibrosis, pulmonary Pseudomonas infection and an exacerbation of respiratory symptoms. Thorax 1985; 40:358-63 47 Martin AJ, Smalley CA, George RH, Healing DE, Anderson CM. Gentamicin and tobramycin compared in the treatment of mucoid Pseudomonas lung infections in cystic fibrosis. Arch Dis Child 1980; 55:604-07 48 Hodson ME, Batten JC. Azlocillin compared with carbenicillin, and tobramycin compared with gentamicin in the treatment of P,euclomonas aeruginosa infection in patients with cystic fibrosis. Monogr Paediatr 1981; 14:124-27 49 Hodson ME, Wingfield HJ, Batten JC. Tobramycin and carbenicillin compared with gentamicin and carbenicillin in the treatment of infection with Pseudomonas aeruginosa in adult patients with cystic fibrosis. Br J Dis Chest 1983; 77:71-7 50 Mfltller NE, Heiby N. Antibiotic treatment of chronic Pseudomonas aenlginosa infection in cystic fibrosis patients. Scand J Infect Dis [suppl] 1981; 24:87-91 51 Malmborg AS, Alfredsson H, Kusoffsky E, Strandvik B. Azlocillin and gentamicin in respiratory tract infections with Pseudomonas aeruginosa in patients with cystic fibrosis. Scand J Infect Dis [suppl] 1981; 29:64-69 52 Mfltller NE, Riewerts Eriksen K, Feddersen C, Flensborg E~ Heiby N, Nom N, et all Chemotherapy against Pseudomonas aenlginosa in cystic fibrosis a study of carbenicillin, azlocillin or piperacillin in combination with tobramycin. Eur J Respir Dis 1982; 63: 130-39 53 Rubio Shapiro C. Ciprofloxacin in the treatment of Pseudomonas infection in cystic fibrosis patients. J Antimicrob Chemother 1986; 18:S147-52 54 Mf/tller NE, Koch C, Heiby N, Jensen K. Treatment ofpulmonary Pseudomonas aeruginosa infection in cystic fibrosis with cefsulodin combined with tobramycin. In: Proceedings of the 12th International Congress of Chemotherapy Curr Chemother Immunother 1982; 1:533-34 55 Rubio TI Ciprofloxacin: comparative data in cystic fibrosis. Am J Med 1987; 82(suppl A):185-88

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

respiratory tract infections due to Pseudomonas aeroginosa in patients with cystic fibrosis. Rev Infect Dis 1985; 7(suppI4):S669-

74

57 Scully BE, Nakatomi M, Ores C, Davidson S, Neu HC. Ciprofloxacin therapy in cystic fibrosis. Am J Med 1987; 82(suppl A):196-201 58 Strandvik B. Adverse reactions to piperacillin in patients with cystic fibrosis. Lancet 1984; 1:1362 59 Stead RJ, Kennedy HG, Hodson ME, Batten JC. Adverse reactions to piperacillin in adults with cystic fibrosis. Thorax 1985; 40:184-86 60 Szaff M, Heiby N, Flensborg EW Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection. Acta Paediatr Scand 1983; 72:65157 61 Mearns MB. Cystic fibrosis. Arch Dis Child 1985; 60:272-77 62 Hodson ME, Penketh ARL, Batten JC. Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeroginosa infections in patients with cystic fibrosis. Lancet 1981; 2:1137-39 63 Littlewood JM, Miller MG, Ghoneim AI: Ramsden CH. Nebulised colomycin for early Pseudomonas colonisation in cystic fibrosis. Lancet 1985; 1:865 64 MacLusky I, Levison H, Gold R, McLaughlin FJ. Inhaled antibiotics in cystic fibrosis: is there a therapeutic effect? J Pediatr 1986; 108:861-65 65 Isles A, Maclusky I, Corey M, Gold R, Prober C, Fleming :P, et all Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104:206-10 66 Hardy KA, McGowan KL, Fisher MC, Schidlow D~ Pseudomonas cepacia in the hospital setting: lack of transmission between cystic fibrosis patients. J Pediatr 1986; 109:51-54 67 Gold R, Jin E, Levison H, Isles A, Fleming PC. Ceftazidime alone and in combination in patients with cystic fibrosis: lack of efficacy in treatment of severe respiratory infections caused by Pseudomonas cepacia. J Antimicrob Chemother 1983; 12(suppl A):331-36

Antimicrobial Therapy Against Staphylococcus aureus, Pseudomonas aeruginosa, and Pseudomonas cepacia Duncan M. Geddes, M.D., F.R.C.R*

The aims of antimicrobial therapy extend beyond shortterm bacterial killing to long-term maintenance of weight and lung function. A review of antimicrobial drug trials shows that empiricism is still ahead of science and more studies are needed both to justify current practice and to make future changes logical.

n

1408

,l ntimicrobial therapy for cystic fibrosis (CF) has developed

.t1

empirically over the past 30 years, and controlled trials have usually followed rather than preceded the development of well-established treatment. As a result, although there are many drugs effective against the organisms commonly associated with CF, much doubt remains concerning indi*Brompton Hospital, London, England. Pulmonary Infectionand AntibioticTreatment in Cystic Fibrosis