CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 2, AUGUST 1992

CLINICAL EFFICACY OF CIPROFLOXACIN IN LONG-TERM THERAPY FOR CHRONIC RESPIRATORY TRACT INFECTIONS

M. YOSHIDA, 1 K. WATANABE, 1 N. TAMARU, 1 T. ISHIBASHI, 2 M. TAKAMOTO, 2 H. YAMADA, 3 M. ANDO, 4 M. KIDO, 5 Y. ICHIKAWA, 6 Y. MATSUZAKI, 7 AND

E. KINUWAKI 8

12nd Department of lnternal Medicine, School of Medicine, Fukuoka University, Fukuoka, 2Department of Internal Medicine, National Ohmuta Hospital, Ohmuta, 3Department of Internal Medicine, Saga Medical School, Saga, 41st Department of Internal Medicine,

Kumamoto University, Kumamoto, 5Pulmonary Division, University of Occupational and Environmental Health, Kitakyusyu, elst Department of lnternal Medicine, Kurume University, Kurume, 7Department of Internal Medicine, National Fukuoka-Higashi

Hospital, Fukuoka, and Spulmonary Division, Kumamoto Central Hospital, Kumamoto, Japan

ABSTRACT

The clinical e f f i c a c y o f ciprofloxacin was evaluated in 83 patients w i t h chronic respiratory tract infection. Each patient received ciprofloxa- cin 200 mg TID for 2 or 4 weeks . A f t e r 2 w e e k s o f treatment for acute exacerbation of chronic respiratory tract infection, 21 (52.5%) o f 40 evaluable patients were considered "improved." A f t e r 4 w e e k s o f treat- ment, 24 (75%) of 32 evaluable patients were judged "improved." An additional 2 weeks of treatment increased the rate of improvement. On t h e other hand, only 6 (23.1%) a n d 7 (26.9%) o f 26 evaluable patients w e r e considered "improved" after 2 and 4 w e e k s o f t r e a t m e n t , respec- tively, for chronic inflammation. Ciprofloxacin was also administered to 6 patients for more than 60 days to examine its prophylactic e f f ec t against acute exacerbation. No patient had an acute exacerbation within 60 days of treatment. Ciprofloxacin is a useful oral antibacte- rial agent for the treatment and prophylaxis of acute exacerbation of chronic respiratory tract infection.

INTRODUCTION

Ciprofloxacin, one of the new quinolones, has broad antibacterial activity against both gram-positive cocci and gram-negative' bacilli. Compared with other new quinolones, ciprofloxacin is characterized by its superior antibacterial activity against major pathogenic organisms in chronic re- spiratory tract infections, such as Moraxella catarrhalis, Haemophilis in- fluenzae, and Pseudomonas aeruginosa. 1

We administered oral ciprofloxacin to patients with chronic respira- tory tract infections to study the therapeutic effect on acute exacerbation

Address correspondence to: Prof. Minoru Yoshida, 2nd Department of Internal Medicine, School of Medi- cine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku. Fukuoka, Japan. Received for publication on May 15, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted.

296 0011-393XJ92/$3.50

M. YOSHIDA ET AL.

and chronic inflammation, the prophylactic effects of long-term treatment against acute exacerbation, and the safety of long-term therapy.

P A T I E N T S AND M E T H O D S

Eighty-three patients with chronic respiratory tract infections treated in our hospitals between September 1988 and March 1990 were enrolled in this multicenter open trial. All patients provided informed consent to par- ticipation in the study.

Ciprofloxacin 200 mg/day TID was administered orally for 2 weeks to 10 patients and for at least 4 weeks to 58 patients. After 2 and 4 weeks of treatment, therapeutic effects were evaluated by a comprehensive analysis of both subjective findings, such as fever, cough, and sputum, and objective findings, such as chest roentgenogram, bacteria isolated from sputum, and other laboratory data, including white blood cell count, C-reactive protein, and erythrocyte sedimentation rate. Clinical responses were classified as "improved," "slightly improved," or "unchanged or exacerbated."

R E S U L T S

The study population consisted of 45 men and 38 women ages 23 to 91 years (mean age, 63 years). Fifteen patients were excluded from the eval- uation of drug efficacy for the following reasons: 9 patients received other antibiotics, 4 patients had side effects or abnormal laboratory findings, and 2 patients had acute bronchitis, a disease not included in the protocol. Drug efficacy was evaluated in the remaining 68 patients, including 28 with bronchiectasis, 17 with chronic bronchitis, 10 with diffuse panbron- chiolitis, and 13 with secondary infections from other lung diseases, such as old pulmonary tuberculosis, pulmonary emphysema, and pneumoconi- osis. Underlying diseases of the lung were observed in 44 (64.7%) patients. Forty-one patients had acute exacerbations and 27 had chronic inflamma- tion. The prophylactic effects against acute exacerbation of long-term treatment with ciprofloxacin were evaluated in 6 patients.

Fifty-six pathogenic organisms were isolated from 45 (66.2%) patients. The isolated pathogens consisted of 21 strains of P aeruginosa, 13 strains of H influenzae, 7 strains of Streptococcus pneumoniae, 5 strains of M catarrhalis, and 10 other strains (Table I).

After 2 weeks of treatment for acute exacerbation, 21 (52.5%) of 40 evaluable patients were judged "improved," 17 were "slightly improved," and 2 were "unchanged or exacerbated." After 4 weeks of treatment, 24 (75%) of 32 evaluable patients were found to be "improved," 5 were "slightly improved," and 3 were "unchanged or exacerbated." The rates of clinical efficacy after 2 and 4 weeks of treatment, respectively, were 53.8%

297

CLINICAL EFFICACY OF CIPROFLOXACIN

Table I. Organisms isolated from pat ients wi th chronic respiratory t ract infection before adminis t ra t ion of ciprofloxacin.

Total

Diagnosis

Secondary Infection Diffuse Chronic with Chronic

Bronchiectasis Panbronchiolitis Bronchitis Pulmonary Disease

No. of patients With isolates 45 (66.2%) 23 (82.1%) Without isolates 23 (33.8%) 5 (17.9%)

No. of strains Pseudomonas aeruginosa 21 12 Haemophilus influenzae 13 5 Streptococcus pneumoniae 7 1 Moraxella catarrhalis 5 3 Achromobacter xylosoxydans 2 Staphylococcus aureus 1 Haemophilus parainfluenzae 1 Klebsiella pneumoniae 1 1 Pseudomonas sp 1 Beta-streptococcus 1 1 Acinetobacter anitratus 1 1 Enterobacter agglomerans 1 NFGNR 1 1

(90.0%) 10 (58.8%) 5 (38.5%) (10.0%) 7 (41.2%) o (61.5%)

2 6 1 2 3 3 3 1 2 1 1 2

1 1

NFGNR = nonfermenting gram-negative rods.

and 65.2% for bronchiectasis, 50% and 100% for DPB, 70% and 77.8% for chronic bronchitis, and 33.3% and 62.5% for secondary infection with chronic pulmonary diseases (Table II).

After 2 weeks of t rea tment for chronic inflammation, 6 (23.1%) of 26 evaluable pat ients were considered "improved," 14 were "slightly im- proved," and 6 were "unchanged or exacerbated." Seven (26.9%) patients were found to be "improved" after 4 weeks of t reatment, while 14 were "slightly improved" and 5 were "unchanged or exacerbated." The rates of efficacy after 2 and 4 weeks of treatment, respectively, were 15.4% and 30.8% for bronchiectasis, 0% each for DPB, 28.6% and 14.3% for chronic bronchitis, and 50% each for secondary infections with chronic pulmonary diseases (Table III).

A bacteriologic response to ciprofloxacin was observed in 59.3% and 57.1% of patients with acute exacerbation after 2 and 4 weeks of treat- ment, respectively (Table IV). However, ciprofloxacin was effective in only 9.1% and 14.3% of the patients with chronic inflammation after 2 and 4 weeks of t reatment , respectively (Table V).

The rates of bacterial eradication after 2 and 4 weeks of t reatment, respectively, were 21.1% and 17.6% for P aeruginosa, 72.7% each for H influenzae, 66.7% and 50% for S pneumoniae, and 100% and 75.5% for M catarrhalis (Table VI). The overall eradication rates after 2 and 4 weeks of t rea tment were 46.3% and 50%, respectively.

The prophylactic effects of long-term t rea tment with ciprofloxacin in 6 patients with acute exacerbation are summarized in Table VII. No patient

298

Tab

le I

I. C

lini

cal

resp

onse

to

cipr

oflo

xaci

n in

pat

ien

ts w

ith

acu

te e

xace

rbat

ion.

Diag

nosi

s

Resp

onse

at 2

Wee

ks

Resp

onse

at 4

Wee

ks

Impr

oved

Sl

ight

ly Im

prov

ed

Unch

ange

d Ef

ficac

y Rat

e Un

judg

ed

Impr

oved

Sl

ight

ly Im

prov

ed

Unch

ange

d Ef

ficac

y Rat

e

Bonc

hiec

tasi

s 7

Diff

use

panb

ronc

hiol

itis

4 C

hron

ic b

ronc

hitis

7

Sec

onda

ry in

fect

ion

3 O

PT

1 P

ulm

onar

y fib

rosi

s 1

Pul

mon

ary

emph

ysem

a 1

PC

PC +

O

PT

PC +

br

onch

iect

asis

To

tal

21

5 1

53.8

%

1 5

1 2

62.5

%

4 5O

. O%

7

100%

3

70.0

%

7 2

77.8

%

5 1

33.3

%

5 2

1 62

.5%

3

25.0

%

3 1

75.0

%

100%

1

100%

10

0%

1 0%

1

0%

1 0%

1

100%

1

O%

1

O%

17

2

52.5

%

1 24

5

3 75

.0%

OPT

=

old

pulm

onar

y tu

berc

ulos

is;

PC =

pn

eum

ocon

osis

.

Tab

le I

II.

Cli

nica

l re

spo

nse

to

cipr

oflo

xaci

n in

pat

ien

ts w

ith

chr

onic

in

flam

mat

ion

.

Resp

onse

at 2

Wee

ks

Diag

nosi

s Im

prov

ed

Slig

htly

lmpr

oved

Un

chan

ged

Effic

acy R

ate

Unju

dged

Im

prov

ed

0

Bonc

hiec

tasi

s 2

6 5

15.4

%

1 4

Diff

use

panb

ronc

hiol

itis

2 0%

C

hron

ic b

ronc

hitis

2

5 28

.6%

1

Sec

onda

ry in

fect

ion

2 1

1 50

.0%

2

Pul

mon

ary e

mph

ysem

a 2

100%

2

PC

1 0%

P

ulm

onar

y em

phys

ema

+ PC

1

0%

Tota

l 6

14

6 23

.1%

1

7

(3 r~

(3

Resp

onse

at 4

Wee

ks

>

Slig

htly

Impr

oved

Un

chan

ged

Effic

acy R

ate

5 4

30.8

%

,~

2 0%

o

6 14

.3%

~

1 1

50.0

%

1oo%

~=

1 0%

1

0%

o 14

5

26.9

%

(3

PC =

pn

eum

ocon

osis

.

Tab

le I

V.

Bac

teri

olog

ic r

espo

nse

to c

ipro

flox

acin

in

pati

ents

wit

h ac

ute

exac

erba

tion

.

Resp

onse

at 2

Wee

ks

Elim

i- Su

per-

Er

adic

a-

Elim

i- Di

agno

sis

nate

d D

ecre

ased

Pe

rsis

ted

infe

ctio

n ti

on R

ate

Unk

now

n ha

ted

Resp

onse

at 4

Wee

ks

Supe

r-

Erad

ica-

De

crea

sed

Pers

iste

d in

fect

ion

tion

Rate

Un

know

n

¢o

Bonc

hiec

tasi

s 4

3 3

1 45

.5%

3

3 D

iffus

e pa

nbro

nchi

oliti

s 1

3 2

50.0

%

2 3

1 C

hron

ic b

ronc

hitis

4

2 66

.7%

3

1 1

Sec

onda

ry in

fect

ion

3 10

0%

6 2

1 O

PT

1 10

0%

3 1

Pul

mon

ary

fibro

sis

1 P

ulm

onar

y em

phys

ema

1 10

0%

PC

1 10

0%

1 PC

+

OPT

1

1 PC

+

bron

chie

ctas

is

1 To

tal

12

3 8

3 57

.7%

14

9

3

3 50

.0%

2

1 2

71.4

%

2 1

40.0

%

4 66

.7%

5

100%

3 1

100%

0%

6 3

57.1

%

1 11

,< o .= >=

>

OPT

=

old

pulm

onar

y tu

berc

ulos

is;

PC =

pn

eum

ocon

osis

.

Tab

le V

. B

acte

riol

ogic

res

pons

e to

cip

rofl

oxac

in i

n pa

tien

ts w

ith

chro

nic

infl

amm

atio

n.

Resp

onse

at 2

Wee

ks

Elim

i- Su

per-

Er

adic

a-

Elim

i- Di

agno

sis

nate

d D

ecre

ased

Per

sist

ed i

nfec

tion

tion

Rat

e U

nkno

wn

nate

d

Resp

onse

at 4

Wee

ks

Supe

r-

Erad

ica-

De

crea

sed

Pers

iste

d in

fect

ion

tion

Rate

Un

know

n

¢.,0

Bonc

hiec

tasi

s 4

4 0%

6

1 D

iffus

e pa

nbro

nchi

oliti

s 2

Chr

onic

bro

nchi

tis

1 2

33.3

%

4 S

econ

dary

infe

ctio

n 4

Pul

mon

ary e

mph

ysem

a 2

PC

1 P

ulm

onar

y em

phys

ema

+ PC

1

Tota

l 1

4 6

9.1%

16

1

4 3

12.5

%

5 1

100%

1

2 2

0%

3 1

0%

3 2 1

0%

1 7

5 1

14.3

%

12

PC =

pn

eum

ocon

osis

.

Tab

le V

I. B

acte

riol

ogic

res

pons

e to

cip

rofl

oxac

in i

n p

atie

nts

wit

h ch

roni

c re

spir

ator

y tr

act

infe

ctio

n.

Org

anis

ms

Resp

onse

at 2

Wee

ks

Resp

onse

at 4

Wee

ks

Appe

aran

ce

Appe

aran

ce

Elim

inat

ed

Dec

reas

ed P

ersi

sted

Unk

now

n af

ter T

reat

men

t El

imin

ated

D

ecre

ased

Per

sist

ed U

nkno

wn

afte

r Tre

atm

ent

Pseu

dom

onas

aeru

gino

sa

4 (2

1.1%

) 5

Hae

mop

hilu

s inf

luen

zae

8 (7

2.7%

) St

rept

ococ

cus p

neum

onia

e 2

(66.

7%)

¢~

Mor

axel

la ca

tarrh

alis

2

(100

%)

Achr

omob

acte

r xyl

osox

ydan

s 1

(50.

0%)

Stap

hylo

cocc

us au

reus

H

aem

ophi

lus p

arai

nflu

enza

e (0

%)

Kleb

siel

la pn

eum

onia

e 1

(100

%)

Pseu

dom

onas

sp

Beta

-stre

ptoc

occu

s 1

(100

%)

Acin

etob

acte

r ani

tratu

s (0

%)

Ente

roba

cter

aggl

omer

ans

NFG

NR

Pseu

dom

onas

putid

a Ps

eudo

mon

as flu

ores

cens

To

tal

19 (

46.3

%)

5

10

2 1

3 (1

7.6%

) 2

12

1 1

3 2

8 (7

2.7%

) 1

2 1

1 1

4 3

2 (5

0.0%

) 2

1 3

3 (7

5.5%

) 1

1 1

2 (1

00 %

) 1

(0%

) 1

1 1(

100%

) 1

1 (1

00%

)

1 1

1(10

0°1o

) 1

1 1

1 1

17

15

5 21

(50

.0%

) 3

18

4 5

o

NFG

NR =

no

nfer

men

tin,

gram

-neg

ativ

e ro

ds.

Tab

le V

II.

Cli

nica

l re

sult

s of

long

-ter

m t

reat

men

t w

ith

cipr

oflo

xaci

n in

pat

ient

s w

ith

acut

e ex

acer

bati

on.

Patie

nt

Num

ber

Age/

Sex

Cipr

oflo

xaci

n Cl

inic

al R

espo

nse

Diag

nosi

s an

d Un

derly

ing

Dise

ases

Da

ily D

ose

Dura

tion

2 W

eeks

4

Wee

ks

Resu

lts

>

1 69

/F

Chr

onic

bron

chiti

s 60

0 m

g 69

day

s Im

prov

ed

2 78

/F

Chr

onic

bron

chiti

s; b

ronc

hial

asth

ma

600

mg

85 d

ays

Impr

oved

3

61/F

C

hron

ic br

onch

itis;

imm

unol

ogic

def

icie

ncy

600

mg

136

days

S

light

ly im

prov

ed

4 77

/F

Chr

onic

bron

chiti

s; is

chem

ic h

eart

dise

ase

600

mg

64 d

ays

Slig

htly

impr

oved

5

71/F

In

fect

ion w

ith b

ronc

hiec

tasi

s 60

0 m

g 16

8 da

ys

Slig

htly

impr

oved

6

66/M

In

fect

ion w

ith b

ronc

hiec

tasi

s; hy

perte

nsio

n 60

0 m

g 20

0 da

ys

Unj

udge

d

Impr

oved

Impr

oved

Im

prov

ed

Slig

htly

impr

oved

Im

prov

ed

Impr

oved

Wel

l con

trolle

d fo

r 2

mon

ths

then

sho

wed

acu

te e

xace

rbat

ion

Wel

l con

trolle

d fo

r 85

day

s W

ell c

ontro

lled

for

3 m

onth

s th

en s

how

ed a

cute

exce

rbat

ion

Wel

l con

trolle

d fo

r 64

day

s W

ell c

ontro

lled

for

168

days

W

ell c

ontro

lled

for

200

days

>

£3

©

©

©

>

('3

M. YOSHIDA ET AL.

showed an acute exacerbation within 60 days of treatment. Only I patient had acute exacerbation after 60 days from the start of the t rea tment and only 1 patient had an exacerbation after 90 days. The remaining 4 patients were without acute exacerbation for up to 200 days.

All 83 patients were evaluated for drug safety; of these, 3 (3.61%) patients reported adverse reactions. A 60-year-old man experienced nau- sea and abdominal pain, a 55-year-old woman had numbness of the fingers and nausea, and a 23-year-old woman had diarrhea. None of these side effects were severe, and all symptoms disappeared within 2 days after discontinuation of treatment. Abnormal laboratory findings were observed in 5 patients: 2 patients with eosinophilia, 1 with elevated ALT, 1 with elevated LDH, and 1 with elevated ASAT, ALT, and BUN. All findings were normalized after the t rea tment was discontinued or completed.

D I S C U S S I O N

Ciprofloxacin has excellent antimicrobial activity against common chronic respiratory tract pathogens, including P aeruginosa, H influenzae, K pneu- moniae, and M catarrhalis. Kobayashi and colleagues 2 reported that cip- rofloxacin is more effective than cefaclor in the t rea tment of chronic re- spiratory tract infection.

In this study, we administered ciprofloxacin to patients with chronic respiratory tract infection to study the drug's efficacy and safety in acute exacerbation and chronic inflammation and its prophylactic effects against acute exacerbation during long-term treatment. In patients with acute exacerbation, 52.5% were clinically improved and only 5% were "un- changed or exacerbated" after 2 weeks of treatment. Clinical improvement after 4 weeks of t reatment increased to 75%. This result indicates that many of the "slightly improved" patients became "improved" after an ad- ditional 2 weeks of t reatment. From these findings, an additional 2 weeks of t rea tment could be expected to further improve acute exacerbation in patients who are "slightly improved" after an initial 2 weeks of treatment.

In contrast, the rate of clinical efficacy for patients with chronic in- f lammation was low. Since inflammatory findings were not so apparent in the chronic inflammatory stage even before treatment, it was difficult to see clear improvement after treatment. However, ciprofloxacin could also be effective in the chronic inflammatory stage, because no patient showed an exacerbation during the additional 2 weeks of treatment.

The prophylactic t rea tment in 6 patients for more than 60 days re- sulted in no exacerbations within 60 days of t rea tment and in 4 patients with no exacerbations after up to 200 days of treatment. Thus ciprofloxacin appears to be a useful agent for long-term prophylactic treatment.

The rate of bacterial eradication was relatively good against all bac- terial strains except P aeruginosa. The eradication rate against P aeru-

305

CLINICAL EFFICACY OF CIPROFLOXACIN

ginosa was about 20%, approximately the same as that achieved by other new quinolones. 3'4 The bacteriologic effect for patients with acute exacer- bation was fairly good, while eradication of bacteria was poor in patients with chronic respiratory tract infections. Complete eradication of bacteria is extremely difficult in cases of chronic inflammatory bronchiectasis, in which P aeruginosa often increases in number.

Adverse reactions were observed in 3 patients, but all symptoms dis- appeared within 2 days after the treatment was discontinued. Seven ab- normal laboratory findings were seen in 5 patients, but no severe clinical problems occurred. The frequency of adverse reactions and abnormal lab- oratory findings was about the same as that previously reported. 1

Based on these results, we conclude that ciprofloxacin is a useful oral antibacterial agent for the treatment and prophylaxis of acute exacerba- tion of chronic respiratory tract infection. However, because the numbers of ciprofloxacin-resistant bacteria have been increasing, 5'6 patients should be carefully selected for long-term administration of prophylactic cipro- floxacin to avoid increasing the number of resistant bacteria.

Acknowledgments

The authors wish to acknowledge the contribution made by the other phy- sicians who participated in the study. The study was supported by Bayer Yakuhin, Ltd., Osaka, Japan.

References:

1. Sanders CC, Sanders WE, Goering RV. Overview of preclinical studies with ciprofloxacin. Am J Med 1987; 82(4A):2-11.

2. Kobayashi H, Takamura K, Takeda H, et al. Comparative clinical study of ciprofioxacin and cefaclor in the treatment of respiratory tract infections. Chemotherapy 1986; 34: 1011-1037.

3. Maesen FPV, Davies BI, Baur C, Sumajow CA. Clinical, microbiological and pharmaco- kinetic studies on ofloxacin in acute purulent exacerbations of chronic respiratory dis- ease. J Antimicrob Chemother 1986; 18:629-634.

4. Wijnands WJA, van Griethuysen AJA, Vree TB, et al. Enoxacin in lower respiratory tract infections. J Antimicrob Chemother 1986; 18:719-727.

5. Nagatake T, Takahashi A, Yamashita H, et al. Bacterial resistance of four fluoro- quinolone agents in respiratory and urinary tract infections. Chemotherapy 1990; 38: 330-341.

6. Deguchi K. Pyridone carboxylate-resistant strains of bacteria. Med Dent J 1990; 26:489- 494.

306