FOURTH CONSENSUS CONFERENCE ON ANTIMICROBIAL THERAPY

R E S P I R A T O R Y T R A C T I N F E C T I O N S October 18, 1991 - Lille, France

organised by the French Language Society of Infectious Diseases (SPILF)

wi th the pa r t i c ipa t ion of : the F r e n c h L a n g u a g e Soc ie ty for P n e u m o l o g y , the F r e n c h L a n g u a g e Soc i e ty for I n t ens ive Care, the F r e n c h Soc ie ty for Mic rob io logy , the F r e n c h Soc ie ty

for E N T Diseases , the In fec t ious and Trop ica l D i s e a s e G r o u p o f the F r e n c h Soc i e ty

for Pedia t r ics , the A ssoc i a t i on for C o n t i n u i n g E d u c a t i o n in P n e u m o l o g y

SUMMARY Management of respiratory tract infections requires knowledge of current etiologic agents, evaluation of host factors, and assessment of available therapeutic tools with minimal ecologic risks and optimal cost-effectiveness. Changes occur in the epidemiology of bacteria responsible for respiratory tract infection. These changes involve the distribution of causative agents and, above all, their susceptibility to antimicrobial drugs. The relative incidence of Legionella in- fections is declining, but interest in the identification of other agents is being overshadowed by concern over mutations among pneumococci. The resistance of pneumococci to macrolides and tetracyclines was already a significant cause for concern in France when evidence that this agent is losing its previously consistent susceptibility to penicillins began to accumulate. The immediate consequences of this multiresistance of pneumococci probably do not warrant radical changes in current strategies for selecting antimicrobial regimens. However, the 1990% may witness further changes in pneumococcal resistance patterns, and the recommendations developed in the 1980% to target Haernophilus influenzae and beta-lactamase-producing agents may become obsolete. In a given patient, few tools are available for achieving immediate specific causative diagnosis. It follows that therapeutic decisions rest primarily on the evaluation of host factors and of features indicating a need for hospitalization. Therapy is dependent on age and on identification of criteria indicating life-threatening or potentially disabling disease. In sum, assessment of the patient's previous heal- th status is given first priority over strlcfly microbiologic criteria. Extensive clinical and microbiological epidemiology studies are desirable.

I - WHICH EPIDEMIOLOGIC, PHARMACOKINETIC, AND CLINICAL CRITERIA ARE USEFUL FOR THE RATIONAL SELECTION OF AN ANTIMICROBIAL REGIMEN FOR THE TREATMENT OF ACUTE OTITIS MEDIA IN PEDIATRIC PATIENT ?

Acute otitis media (AOM) in pediatric patients, although common, is not a benign condition. Rational antimicrobial the- rapy is warranted by the possibility of infrequent but severe complications, including meningitis. Changes in bacterial epidemiology require modifications in antimicrobial strategies to take into account the emergence of new strains of pneumococci with decreased susceptibility to penicillins and of penicillin-resistant H. influenzae strains.

• Epidemiology First-line treatment of AOM is empiric and rests on epidemiologic data. Five bacterial species cause AOM in infants above six months of age: Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalls, Strepto- coccus pyogenes, and Staphylococcus aureus. The proportion of cases in which H. influenzae h recovered does not vary with age in patients between six months and three years of age. S. pneumoniae is recovered with increased fre- quency between 6 and 12 months of age. Pseudomonas aeruglnosa and S. aureus are more common in infants less than six months of age. • H. influenzae produces a beta-lactamase responsible for resistance to aminopenicillins in 20 to 30% of strains recovered from patients with AOM.

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• Twenty-two per cent of pneumococci recovered from middle ear fluid have decreased susceptibility to penicillins. In addition, 25% of strains are resistant to tetracyclines, 40% are resistant to erythromycin, and 30% are resistant to cotrimoxazole.

• Furthermore, 90% of strains of M. catarrhalis and S. aureus produce a beta-lactamase.

• Clinical criteria Although the treatment of AOM is empiric, a number of clinical criteria may affect the choice of the antimicrobial agent, although none are perfectly reliable as predictive criteria:

• concomitant otitis and conjunctivitis suggests H. influenzae infection;

• otalgia with fever above 39°C suggests pneumococcal disease, especially in infants aged six to 12 months.

• Antimicrobial therapy Although infrequent, severe complications (otomastoiditis, meningitis, cellulitis) responsible for permanent sequela~ may occur in AOM. This fact fully justifies routine use of antimicrobial therapy in patients with AOM. The oral route should be preferred in common, uncomplicated AOM.

• Amoxicillin and macrolides should no longer be given as first-line therapy because of the resistance patterns of cur- rent causative agents.

• The empiric treatment of AOM should take two incontrovertible facts into account: - production of beta-lactamases; - emergence of pneumococci with decreased susceptibility to penicillins, on which the activity of beta-lactams is va- riable, i.e., identical with (amoxicillin) or less marked than (cefuroxime-axetil, first-generation cephalosporins, cefixime) that of penicillin.

• The amoxicillin-clavulanic acid combination remains one of the treatments of first choice provided the dosage of amoxicillin is increased (twofold, i.e., to 80 mg/kg/day), since the MIC 90 is 2 mg/l.

• MIC 90 values for second and third-generation cephalosporins against pneumococci with decreased susceptibility to penicillins range from 8 to 64 rag/l: increasing the dosage does not guarantee clinical effectiveness. However these agents are effective on beta4actamase-producing strains of H. influenzae. • The erythromycin-sulfasoxizole combination is active against H. influenzae but each constituent is ineffective on ap- proximately 50% of pneumococci strains with decreased susceptibility to penicillin. Use of this combination in AOM requires evaluation by additional studies.

• Cefotaxime and ceftriaxone are active against both H. Influenzae and pneumococci with decreased susceptibility to penicillin; they may be useful in severe forms of otitis media. • Patients with hypersensitivity to penicillin should be given the erythromycin-sulfasoxazole combination or an oral cephalosporin (cross reactions are infrequent).

• In patients with gastrointestinal symptoms, especially diarrhea, either oral cephalosporins or the erythromycin- sulfasoxazole combination can be used.

These therapeutic recommendations take into account the rapidly increasing resistance of pneum0cocci to penicillins. Changes in patterns of empiric treatment for acute otitis media need to be confronted with clinical results and with in- depth studies of any clinical failures.

II - S H O U L D A C U T E B R O N C H I T I S IN O T H E R HEALTHY A D U L T S O R IN C H R O N I C B R O N C H I T I S PATIENTS W I T H O U T RESPIRATORY FAILURE BE TREATED WITH ANTIMICROBIAL ?

• Acute bronchitis in healthy adults Acute bronchitis is defined as an acute inflammation of the bronchi and bronchioli. The vast majority of cases seem to be caused by viral agents. Comparative placebo-controlled trials have failed to provide objective evidence in support of the effectiveness of antimlcrobials in this condition. Withholding antimicrobial therapy is an acceptable approach.

Howeverl smokers with cough and production of purulent sputum for longer than seven clays and diffuse bronchial rales on auscultation may benefit from treatment with an aminopenicillin, a tetracycline or a macrolide. An inaccep- table attitude would be to give antimicrobials which may induce modifications in bacterial ecology when used abusively

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(fluoroquinolones, second-generation cephalosporins, third-generation cephalosporins...), expensive antimicrobials, or antimicrobials with poor tolerance profiles.

• Acute bronchitis in patients with chronic bronchitis (without respiratory failure) Chronic bronchitis is defined as cough with sputum production during three months each year for two consecutive years. Identification of the cause of acute bronchitis in a patient with chronic bronchitis is difficult. However, micro- biologic studies have documented the predominant role of two bacterial agents, i.e., S. pneurnoniae and H. in- fluenzae, although colonization of the mucosa and true infection need to be differentiated for these two commensal microorganisms.

• Which patients require treatment? Among the eight studies of an antimicrobial agent versus a placebo carried out using acceptable methodologies, only two support the effectiveness of active treatment; this benefit was substantial when at least two of the three symptoms indicating exacerbation (dyspnea, increased volume of bronchial secretions, and purulent sputum) were present initially.

In practice, because two of these symptoms are present in most cases of acute exacerbation of chronic bronchitis, use of an antimicrobial is the safest approach despite the lack of firm evidence that this treatment is beneficial in all pa- tients. Two facts argue in favor of this attitude: - differentiation of strictly bronchial infection and of infection involving the pulmonary parenchyma is difficult on the basis of clinical data only, and consequently a chest film is needed in doubtful cases; - in everyday practice, the impact of the bronchial condition on respiratory function cannot be readily evaluated.

• Which drug should be used? No recent studies have proved any given drug to be superior over the others. Consequently, use of the latest and most innovative agents in an attempt to cover all potential causative organisms is not warranted. Reasonable first-line treat- merits include aminopenicillins, first- generation cephalosporins, and macrolides, given orally. Persistence of symptoms for longer than seven days despite confirmation of the diagnosis (chest film: no pneumonia) and satisfactory symp- tomatic treatment (physiotherapy) should lead to second-line therapy with amoxicillin + clavulanic acid, an oral second- generation cephalosporin, or even a fluoroquinolone or an oral third-generation cephalosporin.

• How long? No treatment duration has been validated scientifically. Treatment is usually given for 8 to 10 days.

III - W H I C H A N T I M I C R O B I A L A G E N T S A R E A P P R O P R I A T E F O R F I R S T - L I N E T R E A T M E N T O F C O M M U N I T Y - A C Q U I R E D P N E U M O N I A ?

IN PATIENTS W H O FAIL TO RESPOND TO INITIAL THERAPY, H O W S H O U L D THE ANTIMICRO- BIAL REGIMEN BE MODIFIED TO TAKE INTO A C C O U N T CURRENT C H A N G E S AFFECTING CAUSATIVE AGENTS, IN PARTICULAR THE INCREASING RESISTANCE OF PNEUMOCOCCI ? IS THE USE OF MORE THAN ONE ANTIMICROBIAL WARRANTED ?

In every case, the initial treatment of community-acquired pneumonia is empiric. None of the products available to date are active against all the organisms capable of causing pneumonia.

First-line antimicrobial regimens have been validated through years of use rather than during clinical trials. The refe- rence products are penicillin G and amoxicillin for pneumococci and macrolides for intracellu]ar bacteria and myco- plasmas. Experience has also led the amoxicillin-clavulanic acid combination to be accepted as a reference first-line treatment when pneumococci, S. aureus, gram-negative bacilli and anaerobes are suspected. This also applies to first- generation cephalosporins, except for anaerobes. Some of the earliest antimicrobia]s can no longer be used as first- line treatment: tetracyclines, cotrimoxazo]e, chloramphenicol.

Recent epidemiologic data show that the incidence of pneumococcal pneumonia is growing in the community as well as in inpatients, regardless of previous health status. The incidence of M. pneurnoniae pneumonia is higher among younger patients. Additional data are needed on the Incidence of C. pneumoniae pneumonia in France. Legionella

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pneumophllia probably causes less than 5% of all pneumonias. S. aureus and the enterobacterias account for 10% to 20% of pneumonias in subjects above 75 years of age and debilitated patients. Anaerobes should be considered in subjects with swallowing disorders. Pneumonia due to H. Influenzae is exceedingly rare.

No clinical or roentgenologic criteria are accurate for predicting the causative agent. Selection of an empirical anti- microbial regimen consequently rests on epidemiologic data and on host factors. This also applies to hospital-acqui- red pneumonia pending culture results. Severe symptoms may lead to first-line use of extended-spectrum antimicro- bial regimens. Changes in acquired resistance mainly concern pneumococcal strains: 20% are resistant to macrolides and resistance to penicillins was documented in 16% of all strains tested in 1991, versus only 3% of strains recovered from patients with pneumonia and a positive blood culture, which were inhibited by less than 4 mg/l penicillin.

None of the new molecules which can be used orally seems superior over reference drugs. Fluoroquinolones exhibit the same activity as macrolides on intracellular agents and on M. pneumonlae. The only beta-lactams wih MIC 90 va- lues consistent with clinical effectiveness against resistant pneumococci are amoxicillin, cefatoxime, ceftriaxone, and imipenem. In the Spanish clinical trials, no clinical failures were recorded with these beta-lactams. Commercially avai- lable quinolones are not indicated in this condition. Glycopeptides, rifampin, and pristinamycin are also consistently active in vitro.

• Apparently healthy adults with no features indicating severe disease There is no call to change the usual strategy which consists in administration of an amoxicillin or a macrolide. In confir- med pneumonia, use of an antimicrobial with consistent activity on pneumococci is indispensable: amoxicillin is the an- tibiotic of first choice in this situation. The dosage usually given in France is 1 g three times a day. In young adults with mild disease suggesting atypical pneumonia, a macrolide is recommended. In every case, treatment should be reap- praised after 48 to 72 hours. If there is no clinical response, the patient should be given the alternative initial anti- microbial, instead of or in addition to the first agent used. A chest film should be performed routinely in patients with persistent symptoms. Rapid worsening of symptoms requires hospitalization.

• Debilitated high-risk adults The spectrum of the antimicrobial regimen should be broadened to include pneumococci, gram-negative bacilli (141ebslella pneumoniae, E. co/i) and S. aureus. Several agents are suitable, including the amoxicillin-clavulanic acid combination and oral cephalosporins, but none offers complete effectiveness. None of the data from the literature in- dicate superiority of any given agent over the other drugs. When aspiration pneumonia due to a swallowing disorder is suspected, the amoxicillin-clavulanic acid combination shoul be used (anaerobes).

In these high-risk subjects, failure of conventional therapy due to infection by a pneumococcus with decreased sus- ceptibility to penlcillins is to be feared. In such cases, use of increased dosages of amoxicillin or administration of cef- triaxone should be considered. The risk of L. pneumophilla pneumonia may lead to use of a macrolide or of a fluo- roqulnolone, either initially or in patients who fail to respond to first4ine treatment.

• P a t i e n t s h o s p i t a l i z e d f o r s e v e r e s y m p t o m s

Microbiologic studies are indispensable. Parenteral antimicrobial therapy should be given immediately and drugs used should cover all the possible causative agents, while awaiting bacteriological results. Use of a combination of agents is needed in these patients : amoxicillin-clavulanic acid or third-generation cephalosporin + macrolide or fluoroquinolone. In patients with confirmed pneumococcal disease, given current patterns of resistance, use of treatments other

• than penicillin G (300 000 IU/kg/day) or high-dose amoxicillin (150 mg/kg/day) seems unwarranted.

In every case, effectiveness should be evaluated daily on the basis of clinical findings and microbiological data. When bacteriological results are available, drugs with confirmed effectiveness on the bacteria recovered should be given.

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