Antimicrobial Therapy Against Staphylococcus aureus, Pseudomonas aeruginosa, and Pseudomonas cepacia

Antimicrobial Therapy Against Staphylococcus aureus, Pseudomonas aeruginosa, and Pseudomonas cepacia

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

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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-

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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

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,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

cations for treatment, the best drugs to use, the ideal dosage and duration of therapy and the best measures of outcome.P It is not even clear whether antibiotics should be used at all," at least in mild or moderate exacerbations, and there is no consensual definition of the precise aims of treatment. This article therefore attempts to define the aims of antimicrobial therapy in CF and to assess how far todays drugs fulfill them. AIMS OF ANTIMICROBIAL THERAPY

Conventionally the treatment of any acute infection is intended to eradicate the organisms and to abolish the local and systemic reactions to the infection. In CF the organism is seldom eradicated, and local and sometimes systemic signs of infection persist The aims of treatment are therefore more subtle and difficult to define. Candidate clinical aims in the short term include reducing the volume and purulence of sputum, reducing fever and malaise, promoting lung function, and increasing the patients appetite and weight. Long-term aims are to reduce the number of exacerbations and hospital admissions, and to maintain the patients physical well-being, weight, and lung function. The medical thrust of both short- and long-term goals is to reduce the numbers of bacteria and bacterial products without inducing drug resistance. ANTIMICROBIAL THERAPY AVAILABLE

A large number of antimicrobial drugs are currently available for treating CF, (Table 1), and more are being developed. Those used in CF chest infections have conven-

tionally been chosenbecause oftheir activity versus adverse

effects profile, together with considerations of cost and ease of administration. The "activity" has been based on in vitro minimum inhibitory concentration (MIC) estimation rather than in vivo clinical efficac~ and in CF this simple approach may well be misleading. Factors that suggest that in vitro activities may not be reflected in vivo are listed in Table 2. Hypersensitivity reactions to all these drugs occasionally occur, but other adverse effects are relatively uncommon, considering the number of courses of treatment given. The aminoglycosides may in theory produce cumulative renal toxicity and ototoxicity but this has not been a clinical problem to date. Piperacillin has been reported to cause febrile reactions unacceptably often in CF. 6 Of much greater clinical concern has been the development of bacterial resistance to multiple antibiotics. 7 This has not occurred often with S aureus, but is frequent with P aeroginosa, especially in patients who are deteriorating and who have many infective exacerbations requiring frequent treatment. Presumably antibiotics select out preexisting mutant organisms, or mutation occurs during therapy However; multiple-drug resistance has occurred much more often in some centers than in others, even when the same antibiotic policies are followed. Some of this difference may be due to different laboratory methods. Fortunately clinical improvement often follows antibiotic therapy even when the organisms show in vitro resistance, so the relevance of multiple-drug resistance remains unclear. The emergence of P cepacia8 in CF is in many respects similar to multipledrug resistance in P aeroginosa. Severe CF, frequent ami-

Table I-Antibiotic TlterGPII AtNJilable in CF AgGirut Staphylococcus aureus, Pseudomonas aeruginosa, and Pseudomonas Cepacia*

MIC. Staphylococcus aumut

(mg/L)

Commonly used drugs: Cloxacillinlflucloxacillin Tetracycline Fusidate Erythromycin Cefuroxime Chloramphenicol Ciprofloxacin mmethoprim-sulfamethoxazole Other drugs available:

0.25 0.12 0.06 0.12 1.0 4 0.12 Variable

Clindamycin

0.1

Vancomycin Gentamicin Ceftazidime

1.6 0.06 4

tMost strains are now resistant to benzylpenicillin.

MlCeo Pseudomonas aerogit108tJf Aminoglycosides: Gentamicin, tobramycin, amikacin netilmicin

(mglL)

1-4

~-lactam

Carbenicillin Azlocillin, mezlocillin, ticarcillin Piperacillin Aztreonam Cephalosporins Ceftazidime Cefsulodin Cefoperazone Imipenem Quinolones Ciprofloxacin Ofloxacinlnorfloxacin Enoxacin

64-128

32

16 16-32

2 8 16

0.5 2

4

MIC50 Pseudomonas cepacia

(mg/L)

16

Aminoglycosides

Blactain

128

~-lactams

Cephalosporins Ceftazidime Cefotaxime Aztreonam

'Irimethoprtm

2

8 16 "Highly susceptible" but variable

• Antibiotic therapy against other organisms found in CF (eg, Hemophilus injluenzae) is outside the scope of this article.

noglycoside use, and a sibling with CF were all initially associated with the acquisition of P cepacia. However, subsequent studies" have not confirmed these findings, and the organism may be less important than was first thought. P cepacia is relatively resistant to most drugs other than third-generation cephalosporins and trimethoprim, and further antibiotic resistance may develop with more treatment. CHEST I 94 I 2 I AUGUSl: 1988 I Supplement

141 S

Table !-Why in vitro S ~ May Not Predict in vivollaulta 1. Mixed bacterial populations containing resistant and sensitive strains

2. Improvement due to multiple causes: physiotherapy bed rest, improved compliance, resolution of viral inflammation, antibiotics 3. Drug activity in relevant compartment usually not known: blood, airwa~ sputum 4. Drug activity aItered by sputum: ions, cells, proteins 5. Antibacterial action multifactorial: killing, growth inhibition, altered products, altered metabolism

In common with resistant P aeroginosa, the in vitro resistance of P cepaCia does not always predict in vivo treatment results.

Table 3-ControUed '1HtJla ofAntibiotica in CF Study Placebo or inactive control Beaudry et al, 198()1° Weintzen et aI, 198()11 Gold, 19873 One or more antibiotics Parry et aI, 197712 Kraunse et aI, 197913 Hyatt et aI, 198114 Gordts et aI, 198215

TREATMENT TRIALS IN

CF

There are many phase 2 studies that assess the responses to single antibiotics. These studies almost invariably show clinical benefit, with some improvement in lung function. The predominant organism in the sputum usually persists, and if eradicated returns within a few weeks. Recent reports have assessed bacterial load as numbers of colony-forming units; although this measure is highly variable, a drop of 2 to 4 loglocounts is often seen. Drug resistance may develop during a single course of treatment and may revert to a drugsensitive pattern equally quickly Controlled trials of antibiotics in acute pulmonary exacerbations were rare until a few years ago. Some are summarized in Table 3. Five main conclusions may be drawn from these studies: 1. Placebo-controlled studies show little if any antibiotic benefit for acute exacerbations. The one study in which the placebo-treated patients seemed to do poorly" is difficult to interpret as the randomization did not stratify for severity of eF, and the worst patients received placebo. Nevertheless, most clinicians have a very strong impression that antibiotics help. The conflict suggests that many factors in addition to antibiotics contribute to improvement, including physicthera~ bed rest, improved compliance, and time to marshal host defenses. Much larger studies may need to be performed to demonstrate the magnitude of any antibiotic benefit 2. One drug is as good as 2. No study has shown any clinical benefit from 2 or more drugs. This is hardly surprising in view of the multifactorial nature of the improvement Similarlj; drug resistance has seldom been a greater problem with monotherapy It is therefore difficult to justify the use of 2 drugs on the evidence of clinical trials alone. There are, however, good theoretical and in vitro reasons for using more than 1 drug, and fears of eventual drug resistance after repeated treatments may persuade many clinicians to continue with the current 2-drug regimens. 3. Short courses of antibiotics tend to reduce bacterial numbers transiently but eradication is uncommon. The bacterial flora returns to pretreatment levels within a few weeks. 4. Antibiotic resistance may develop during a short course of treatment in a minority of patients, but drug-sensitive organisms often return over subsequent weeks. However, frequent antibiotic courses may contribute to the develop1428

McLaughlin et aI, 198316

Hoogkamp-Korstanje et al, 1983 17 BTSRC, 198518

Jewett et aI, 198519 Smith et aI, 198f)1WJ Rubio et aI, 198&1 Hodson et aI, 198722

Long-term therapy Loening-Baucke et aI, 197923 Hodson et aI, 198114

Jensen et al, 1987lP:5

Drugs

Cloxacillin vs carbenicillin + tobramycin Placebo vs tobramycin Placebo vs ceftazidime

TIcarcillin vs gentamicin vs both Netilmicin vs netilmicin + carbenicillin Oxacillinvs oxacillin + sisomicin + carbenicillin Ceftazidime vs ticarcillin + tobramycin Azlocillin vs azlocillin + tobramycin vs ticarcillin + tobramycin Piperacillin vs piperacillin + tobramycin Ceftazidime vs carbenicillin + gentamicin Cefoperazone vs methicillin + ticarcillin + tobramycin Azlocillin vs azlocillin + tobramycin Ciprolloxacin vs azlocillin + tobramycin Ciprofloxacin vs azlocillin + gentamicin

Placebo vs cephalexin Placebo vs carbenicillin + gentamicin (nebulized) Placebo vs colistin

ment of durable multiple-antibiotic resistance in Pseudo-

monas infection.

5. New drugs tend to be preferred to their predecessors.

This can be attributed partly to the ease of administration of the newer agents (eg, ceftazidime and ciproHoxacin) and partly to investigator enthusiasm, but it may also represent a real benefit of exposing the bacteria to a new and potent agent However, it is most unlikely that any improvement in antibacterial action will last. Resistance to ceftazidime has become a problem in some centers, and despite the impressively low MICs of some new agents, the organisms are seldom eradicated. Whereas all of the controlled studies have assessed acute clinical response, changes in bacterial numbers and products and long-term outcome have been monitored less consistently Similarly long-term clinical benefits (eg, time to next infection, rate of decline of lung function) are rarely reported, and any advantages have been modest. There are few controlled studies of long-term antibiotic therapy Many clinicians recommend continuous antistaphyPulmonary Infection and Antibiotic Treatment in Cystic Fibrosis

lococcal prophylaxis, and the improved survival of CF patients over the past 30 years may well be due in part to this policy One controlled bial13 assessed the value of cephalexin as prophylaxis in 17 patients with CF and showed a benefit in terms of fewer infections and fewer hospital admissions, as well as better weight Not surprisingly the benefit was confined to those with S tJUreus and H influenme infections; it did not extend to those with P aerogino86 infections. Controlled bials of nebulized annpseudomonal antibiotics have shown clinical benefit without the development of important antibiotic resistance. On balance, these few studies suggest a genuine albeit small benefit from prophylactic antibiotics in selected groups of patients. but the results cannot be extended to all patients with CF. OTHER ANTIBACTERIAL AGENTS

The fact that antibiotics may result in improvement without altering bacterial numbers suggests that there is much more to the treatment of CF infections than simple bacterial killing; other agents that affect bacterial growth or metabolism may well be worth exploring. The mucolytic agent mesna inhibits the growth of P aeroginosa and reduces the MIC of azlocillin by as much as 32 times. Similarl~ Nacetylcysteine potentiates the antipseudomonal activity of carbenicillin. Another approach has been to change the ionic environment with EDTA, which chelates divalent anions. This agent has marked antipseudomonal activity and enhances the effect of a number of antibiotics. .Amiloride, a pyraziDe antibiotic, inhibits bacterial growth but interferes with the activity of some antibiotics. Although there are no controlled trials showing benefit of these drugs, the in vitro activity suggests that further evaluation would be worthwhile. CONCLUSION

Antibacterial drugs have played a central role in the treatment of CF for more than 30 years and are probably a major factor in the improved survival during this period. A large number of drugs are available against each colonizing organism, but their use has developed empirically more often than by controlled trials. A better understanding of why the organisms colonize the lungs in CF, how they cause

lungdamage, and howantibiotics modify bacterial behavior

is required to make treatment more rational. More rational and precise antimicrobial therapy should in turn improve the outlook for patients with CF. REFERENCES 1 Nelson JD. Management of acute pulmonary exacerbations in CF: a critical appraisal. J Pediatr 1985; 106:1030-34 2 Rubio TI Infection in patients with cystic 8brosis. Am J Med 1986; 81(suppllA):73-77 3 Cold It Mild to moderate chest exacerbations: do antibiotics help? Pediatr Pulmonoll987; Suppll:38-39 4 Gould 1M, Wise R. Pseudomonas ~ginosa: Clinical manifestations and management Lancet 1985; 12:1224-26 5 Gregory WJ, Mcnabb PC. Pseudomonas ceJXICia. Infect Control 1986; 7:281-84 6 Stead RJ, Kennedy HG, Hodson ME, et al. Adverse reactions to piperacillin in cystic fibrosis. Lancet 1984; 1:857-58 7 Sheldon CD, Hodson ME. Multiresistant Pseudomonas aeru-

ginosa in patients with CF. Thorax 1987; 42:739 8 Tablan OC, Chorba TL, Schidlow D~ et al. Pseudomonas ceJXICia colonization in patients with CF: risk factors and clinical outcome. J Pediatr 1985; 107:382-92 9 18blan OC. National surveillance of P,eudomonas ceJXICia colonization in CF: a preliminary report. Pediatr Pulmonol 1987; Suppll:l29 10 Beaudry PH, Marks MIt McDougall D, et ale Is antipseudomonal therapy warranted in acute respiratory exacerbations in children with CF? J Pediatr 1980; 97:144-47 11 Weintzen R, Prestidge CB t ~er R, et ale Acute pulmonary exacerbations in CF: a double blind bia1 of tobramycin and placebo therap)t Am J Dis Child 1980; 134:1134-38 12 Parry MIt: Neu HC, Merlino M, et al. 1reatment of pulmonary infections in patients with CF: a comparative study of ticarcillin and gentamicin. J Pediatr 1977; 90:141-48 13 Kraunse PJ, Young LS; Cherry JD, et al. The treatment of exacerbations of pulmonary disease in CF: netilmicin compared with netilmicin and carbenicillin. Curr Ther Res 1979; 2.5:60912 14 Hyatt AC, Chipps BE, Kumor KM, et al. A double-blind controlled trial of anti-pseudomonal chemotherapy of acute respiratory exacerbations in patients with CF. J Pediatr 1981; 99:307-11 15 Cordts B, Dab I, Butzler JE Ceftazidime in CF. Lancet 1982; 1:1355 . 16 McLaughlin FJ, Matthews WJ, Strieder DJ, et ale Clinical and bacteriological responses to three antibiotic regimens for acute exacerbations of CF: ticarcillin-tobramyctn, azlocillin-tobramycin and azlocillin-p1acebo. J Infect Dis 1983; 147:559-64 17 Hoogkamp-Korstanje JAA, van der Laag J. Piperacillin and tobramycin in the treabnent of PIet.Ulotraona lung infection in CF: J Antimicrob Chemother 1983; 12:175-78 18 British Thoracic Society Research Committee. Ceftazidime compared with gentamicin and carbenicillin in patients with CIt: pulmonary Pseudomonas infection, and an exacerbation of respiratory symptoms. Thorax 1985; 40:358-63 19 Jewett C~ Ledbetter J, Lyrene RIC. Comparison of cefoperazone sodium versus methicillin, ticareillin and tobramycin in treatment of pulmonary exacerbation in patients with CF. J Pediatr 1985; 106:669-72 20 Smith AL, Bubio E Doershusk C, et al, Comparison of azlocillin alone versus azlocillin and tobramycin for sudobronchial infection in CF: Cited in: Am J Med 1986; 81(suppllA):73-77 21 Rubio 'I: Shapiro C. Ciproftoxacin in the treatment of pseudomonas infection in CF (abstract), In: Proceedings of the 27th Annual Meeting of the CF Club. Bethesda, MD: CF Foundation 1986:101 22 Hodson ME, Roberts CM, Butland RjA, et al. Oral ciproftoxacin compared with conventional intravenous treatment for P,eudomonas aet1IgiflO8tl infections in adults with CF: Lancet 1987; 1:235-37 23 Loenmg-Baueke VA, Mischler E, Myers MG. A placebo controlled trial of cephalexin therapy in the ambulatory management of patients with CF: J Pediatr 1979; 95:630-33 24 Hodson ME, Penketh ARL, Batten JC. Aerosol carbenicillin ar.d gentamicin treatment of PIet.Ulotraona aeruginoso infections in patients with CF: Lancet 1981; 2:1137-39 25 Jensen 'I: Pedersen SS, Garne S, et al. Colistin inhalation therapy in CF patients with chronic broncho-pulmonary Pseudomonas aeruginostJ infection. Oslo: European \\brking Group for CF, 1987 26 HeafDI: ~bbGJ, MatthewDJ.lnvitroassessmentofcombined antibiotic and mucolytic treatment for PIet.Ulotraona aerogiflOltJ infection in CF: Arch Dis Child 1983; 58:824-36 27 \\bod RE, Klinger jn, Thomassen MJ, et ale The effect ofEDTA and antibiotics on Pseudomonas aet1IgiflO8tl isolated from CF

<, CHEST I 94 I 2 I AUGUS'T. 1988 I Supplement

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patients: a new chemotherapeutic approach. In: Sturgess M, ed. Penpectives in CIt: Proceedings of the Eighth International Congress on CIt: Toronto: Canadian CF Foundation, 1980:36569

Discussion ChrVtitln Koch, M.D., Ph.D. *

advances over the last years in the prevention of T hepulmonary damage in CF, and the ensuing improve-

ments in life quality and long-term survival, can be almost completely ascribed to better control of the recurrent and chronic infections caused by S aIIt'WS and P aeroginosa. A growing number of effective antimicrobial agents is available, and these can be used in various combinations and routes of administration and applied in different treatment regimens. It is essential that different regimens be comparable from center to center and within centers, and it is necessary to subject new drugs and regimens to formal controlled trials that evaluate both short-term and long-term clinical effects. Any true therapeutic improvement must be reflected in decreased morbidity and improved overall survival rate. This requires strict control of larger groups of patients and comprehensive collection ofdata according to fixed protocols. In our center, which currently treats 213 of 274 Danish patients with CF, all patients are seen at least monthlg and almost all admissions for antipseudomonal treatment are in our department. Details of our current treatment regimens have been given elsewhere.' Routine treatment whenever S aumu is isolated-regardless of the clinical conditionconsists of a 14-day course of oral dicloxacillin in combination with fucidic acid. In case of penicillin allergy rifampicin and fucidic acid are given. This results in an overall eradication frequency of 74%.1 In case of eradication failure, prolonged treatment with these drugs or with clindamycin, and sometimes inhalation therapy with methicillin, is carried out. Less than 10% of patients will harbor S aIIrws for 6 months or more, and less than 1% for any further extended period.s It was further found that 41% of 224 patients had serum levels of specific S tJUf'W8 antibodies within the normal range; levels were stable over many years of observation and did not show any correlation with long-term prognosis," Early work from our department established the relationship of duration of chronic P aeruginosa infection to levels of specific serum antibodies, decreased pulmonary function, and poor prognosis. Extensive laboratory studies subsequently led to the present concept of immune-mediated tissue damage, thus providing a scientific explanation for the clinical observations. 3 As a direct consequence, and prompted by an unacceptably high mortality in 1975-1976 we changed our policy of "on demand" antipseudomonal treatment to a regimen of 14-day courses of antipseudomonal treatment every 3 months for all patients with chronic P aeroginostJ infection.· This was followed by an increase in 5-year survival from onset of chronic P aeroginostJ infection from 54% to 82%,· and our most recent survey showed a cumulative survival rate 10 years after onset of chronic *Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark.

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P aeroginoaa infection, of 90%.5 The advent of a series of new antipseudomonal agents that have counterbalanced the emerging problems of hypersensitivity and resistant strains has undoubtedly influenced present outcomes. ~ fonnally tested and subsequently incorporated the following antibiotics in our treatment regimens: azlocillin, piperacillin, cefsulodin, eeftazidfme, thienamycin, ofloxacin, and ciprofloxacin. 1.6-8 ~ are currently conducting clinical trials of aztreonam, and have already reported on the safety of this drug in p-1actaD)-hypersensitive patients.' More than 80% of our patients receive daily inhalations of colimycin, which diminishes reactivation of infection between courses, 10 and selected patients receive ciprofloxacin for varying periods between courses. Prolonged courses and shortened intertreatment intervals are used in very unstable patients. Our most recent survey shows that pulmonary function can now be maintained nearly unaltered over many years of observation."

Whereas S aumus no longer presents a major threat to long-term survival and quality of life in most, if not all, CF patients, P aerogif&08(J still presents the greatest obstacle to the attainment of prolonged well-being. However, developments have greatly improved our knowledge of proper management of this complication and led to major improvements in long-term survival. We are currently investigating the effect of very early eradication of P aeroginosa on subsequent development of chronic infection, since this would be a major step forward. Until the basic defect in CF can be corrected or compensated for, future efforts should be directed toward this goal, as well as toward further improvement in antimicrobial and anti-inflammatory therapy for already infected patients.

REFERENCES

1 H_iby N, Friis B, Jensen K, Koch C, M_ller NE, Stevring S, Szaft" M. Antimicrobial chemotherapy in cystic fibrosis patients. Acta Paediatr Scand [Suppl] 1982;3Ql:75-100 2 SzafI"M, Heiby N. Antibiotic treatment of Staphylococcus aumu infection in cystic fibrosis. Acta Paediatr Scand 1982;71:821-26 3 Heiby N, Schi_tz PO. Immune complex mediated tissue damage in the lungs of cystic fibrosis patients with chronic P,eudomonas aeroginoStJ infection. Acta Paediatr Scand [Suppl] 1982;301:6373

4 SzafI" M, ""iby N, Flensborg EW Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseutlornonas aeroginotltJ infection. Acta Paediatr Scand 1983;72:65157 5 Pedersen SS, Jensen 'I: Heiby N, Koch C, Flensborg EW Management of Pseudomonas aerogif108tJ lung infection in Danish cystic fibrosis patients. Acta PaediatrScand 1987;76:95561 6 Pedersen SS, Pressler 'I: Pedersen M, H"iby N, Friis-M"ller A, Koch C. Immediate and prolonged clinical efficacyof ceftazidime venus ceftazidime plus tobramycin in chronic Pseudomonas aerogiflO8tl infection in cystic fibrosis. Scand J Infect Dis 1986;

18:133-37

7 Pedersen SS, Pressler 'I: H"iby N, ~is Bentzon M, Koch C. Imipenemlcilastatin treatment of multiresistant Pseudornoratu aeruginosa lung infection in cystic fibrosis. J Antimicrob Chemother 1985; 16:629-35 8 Jensen 'I: Pedersen SS, Nielsen CH, Hefby N, Koch C. Comparison of the efficacy and safety of ciprofloxacin and PulmonaryInfectionand Antibiotic Treatment in Cystic Rbrosis