The patient is a man with pneumonia with isolated germ in blood culture and antibiogram. According to the data provided, it is a pneumococcus sensitive to penicillin (MIC < 0.125), so treatment is started with penicillin at high doses every 4 h, despite which the fever persists. If we analyze the case carefully, the treatment should be effective since the germ is totally sensitive to the drug and the dosage is adequate (so that high concentrations of the drug should be maintained at all times, remember that the efficacy of beta-lactams is time-dependent and the antibiotic concentrations in blood should be above the MIC permanently to achieve effectiveness and avoid the production of resistance). In such a case, what could be happening, probably, although the antibiotic is the right one, it is not reaching the infectious focus adequately because an empyema has probably occurred. We should rule out the existence of an empyema and drain it while continuing with the antibiotic treatment. If the dosage had not been adequate and the presence of drug resistance was possible, one option could have been to treat with ceftriaxone at high doses, since we should remember that streptococcus does not produce beta-lactamase and beta-lactam resistance is produced by another mechanism (using amoxicillin-clavulanate would not provide us with anything). With quinolone we do not increase the spectrum and it is evident that the poor evolution of the patient is not only a problem of time.

The patient is a man with pneumonia with isolated germ in blood culture and antibiogram. According to the data provided, it is a pneumococcus sensitive to penicillin (MIC < 0.125), so treatment is started with penicillin at high doses every 4 h, despite which the fever persists. If we analyze the case carefully, the treatment should be effective since the germ is totally sensitive to the drug and the dosage is adequate (so that high concentrations of the drug should be maintained at all times, remember that the efficacy of beta-lactams is time-dependent and the antibiotic concentrations in blood should be above the MIC permanently to achieve effectiveness and avoid the production of resistance). In such a case, what could be happening, probably, [HIDDEN] [HIDDEN] it is not reaching the infectious focus adequately because an empyema has probably occurred. We should rule out the existence of an empyema and drain it while continuing with the antibiotic treatment. If the dosage had not been adequate and the presence of drug resistance was possible, [HIDDEN], [HIDDEN] since we should remember that streptococcus does not produce beta-lactamase and beta-lactam resistance is produced by another mechanism (using amoxicillin-clavulanate would not provide us with anything). [HIDDEN] [HIDDEN] it is evident that the poor evolution of the patient is not only a problem of time.

A 50-year-old man with chronic bronchitis is admitted for pneumonia with positive blood culture for Streptococcus pneumoniae, with an MIC to penicillin of 0.0125 mg/l. Treatment was started with penicillin 2 million every 4h. On the fifth day, she still has a fever of 38ºC. Which of the following decisions do you think is correct?

I would change the treatment to ceftriaxone because of its greater efficacy.

I would add a quinolone to the treatment.

I would switch to amoxicillin/clavulanic acid.

It would rule out the presence of pleural empyema.

I would continue with the same treatment, assuming it is simply a timing issue.

[Would ampicillin alone again be enough for treating community-acquired pneumonias?].

MORE THAN SEMANTICS: The complexity of the problem raised by this apparently simple question becomes apparent if one examines the meanings behind the words. Globally, the frequency of pathogens known to cause community-acquired pneumonia has changed little over time: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumoniae. The real question is the emergence of S. Pneumoniae resistant strains. Currently, the frequency of penicillin or ampicillin resistant strains (less then 10%) is not associated with an increased rate of treatment failure or mortality. "High" doses (150-200 MU/kg/d for penicillin or 2 g t.i.d. for ampicillin) can still be expected to control suspected or certain resistant pneumococcal pneumonia. Would other antimicrobials be more effective? In France, "consensual" use of amoxicillin (1 g t.i.d.) "covers" 98% of the situations as resistant strains are found in only 2% of the adult cases. Thus, the lower frequency of pneumococcal resistance to cefotaxime or ceftriaxone (less than 0.5%) would not warrant their use in most cases of community-acquired pneumococcal pneumonia. Inversely, combination regimens with ampicillin or amoxicillin and cefotaxime or ceftriaxone or the amoxicillin-clavulanic acid association at standard doses provide good therapeutic alternatives for empirical prescriptions in cases with a high risk of infection other than pneumococcal infection (H.influenzae, methicillin-sensitive Staphylococcus aureus). The remarkable anti-pneumococcal activity of imipenem, vancomycin and teicoplanin should, for the time being, be reserved for selected patients with cross allergic reactions to penicillins and cephalosporins. In case of severe community-acquired pneumonia, a combination regimen should be the rule in order to "cover" as many bacteria as possible. In the "healthy" adult under 60 years of age, amoxicillin combined with a macrolide or a fluoroquinolone can be recommended. Bacteriological efficacy is not synonymous with cure. Secondary inflammatory processes and subsequent septic shock remain a major challenge.

A randomised, multicentre study of ceftriaxone versus standard therapy in the treatment of lower respiratory tract infections.

In this study the efficacy and cost-effectiveness of i.v. ceftriaxone 1 g once daily (CTX) was compared with standard i.v. antibiotic treatment (STD) for lower respiratory tract infections (LRTI). STD was given according to the guidelines of the American Thoracic Society and consisted of either cefuroxime 1500 mg three times daily (q8h), amoxicillin/clavulanic acid 1200 mg q8h or ceftriaxone 2 g once daily; each with or without a macrolide. After a minimum of 5 days i.v. therapy, patients could be switched to oral therapy. One hundred patients were enrolled in the study; 52 patients received CTX and 48 STD. Groups were comparable with respect to demographic and baseline characteristics. Seventy patients had a confirmed diagnosis of pneumonia. Twenty-nine patients had a severe type I exacerbation of chronic bronchitis. In one patient the diagnosis of LRTI could not be confirmed. In approximately 50% of the patients a microbiological diagnosis could be made. The most important isolated pathogens from sputum and blood were (positive blood cultures in brackets): Streptococcus pneumoniae 14 (9) and Haemophilus influenzae 16. Mean duration of i.v. therapy was 7.4 days in both groups. Average duration of hospitalisation was 15.0 days for CTX patients and 15.9 days for STD patients. Overall cure and improvement rate at the end of treatment was 47 (90%) for patients receiving ceftriaxone 1 g compared to 37 (77%) for patients receiving standard therapy. Pathogens were eradicated or presumed to be eradicated in 84% of the CTX patients and in 76% of the STD patients. Mean total costs per treatment were lower for CTX than for STD treatment: NLG 169 versus 458. These results show, that i.v. ceftriaxone 1 g once daily is as effective as standard therapy in the treatment of LRTI and that its use reduces treatment costs, in view of the multiple daily dosing regimens of most standard therapies.

Acute exacerbation of chronic obstructive pulmonary disease

More complicated bronchitis may be when the patient is more than 65 years old, has four or more exacerbations per year, has an FEV1/FVC ratio of less than 50% on spirometry, has failed to respond to previous antibiotic treatment, and/or has comorbidity. In these cases, treatment should be aimed at Gram-negative bacteria and the possibility of high antibiotic resistance should be considered. Sputum culture results are of great value in determining antibiotic resistance. First-line treatment is cefuroxime or co-amoxiclav. Third-line treatment, as well as treatment in penicillin-allergic patients, is a fluoroquinolone such as ciprofloxacin. An agent active against Streptococcus pneumoniae may have to be added.

[Failure of levofloxacin therapy in two cases of community-acquired pneumonia caused by fluoroquinolone-resistant Streptococcus pneumoniae and complicated with empyema].

Community acquired pneumonia (CAP) due to Streptococcus pneumoniae is a frequent cause of morbidity and mortality. We communicate two cases of CAP with complications. In both cases levofloxacin-resistant S. pneumoniae was isolated in pleural effusion. Patient 1: A 51-year-old man who had not received previous treatment with quinolones was admitted to the hospital for CAP and initially treated with levofloxacin (500 mg/24h iv). Four days later pleural effusion developed and fluid culture isolated levofloxacin-resistant S. pneumoniae (MIC > 32 .g/ml). The outcome was favorable following chest tube placement and treatment with beta-lactam antibiotics. Patient 2: A 73-year-old man with a history of chronic obstructive pulmonary disease was admitted due to CAP and was initially treated with levofloxacin (500 mg/24 h iv). He was transferred to our hospital after 10 days of treatment with this antibiotic, following the development of pleural effusion with isolation of levofloxacin-resistant S. pneumoniae (MIC = 12 .g/ml). The patient was treated with chest tube placement and beta-lactam antibiotics with a favorable outcome. Patients with CAP treated empirically must be closely followed, both clinically and radiologically, to facilitate early detection of complications due to bacterial resistance to the prescribed antibiotic. Patients with CAP who have received quinolones in the weeks before the development of pneumonia should not been treated empirically with these antibiotics because of the risk of resistance development.

[Treatment of community-acquired pneumonia in adults].

Appropriate antibiotic treatment reduces the duration of symptoms associated to pneumonia, the risk of complications and mortality. In most cases, it is not possible to identify the etiologic agent so antibiotic treatment is empirically prescribed. In Chile, one third of Streptococcus pneumoniae strain isolates has diminished susceptibility to penicillin; in-vitro erythromycin resistance is about 10-15% and cefotaxime resistance 2-10%. It is recommended to classify patients with community acquired pneumonia in four risk categories: Group 1: patients under 65 years without co-morbidities, in ambulatory attendance. oral amoxicillin 1 g TID, 7 days. Group 2: patients over 65 years and / or co-morbidities, in ambulatory attendance. oral amoxicillin/clavulanate 500/125 mg TID or 875/125 mg BID, or cefuroxime 500 mg BID, 7 days. Group 3: patients admitted to general wards with criteria of moderate severity. ceftriaxone 1-2 g once a day or cefotaxime 1 g TID, IV, 7-10 days. Group 4: patients with severe CAP that must be interned into ICU. ceftriaxone 2 g once a day or cefotaxime 1 g TID, IV, associated to erythromycin 500 QID, levofloxacin 500-1.000 mg once a day, or moxifloxacin 400 mg/once a day, IV, 10-14 days. In the presence of allergy to or treatment failure with betalactam drugs and/or positive serology for Mycoplasma, Chlamydia or Legionella sp it is recommended to add: erythromycin 500 mg QID, IV or oral, oral clarithromycin 500 mg BID, or oral azythromycin 500 mg once a day.

Aztreonam in patients with acute purulent exacerbations of chronic bronchitis: failure to prevent emergence of pneumococcal infections.

A group of 36 patients, all requiring hospital admission because of acute purulent exacerbations of chronic bronchitis, were treated with 1 or 2 g intramuscular injections of aztreonam for ten days. Patients with Streptococcus pneumoniae infections were excluded from the study. Sputum cultures before treatment revealed the other usual respiratory pathogens but repeat cultures on days 3, 10 and 17 sometimes yielded Str. pneumoniae, occasionally combined with Haemophilus influenzae or Branhamella catarrhalis. Ten patients had to be given other antimicrobial agents for Str. pneumoniae infections which developed during the study or follow-up periods. Pseudomonas aeruginosa failed to respond well to aztreonam. All the H. influenzae strains were sensitive to aztreonam (MIC 0.25 mg/l, or less) but all strains of Str. pneumoniae were resistant (MIC greater than 32 mg/l). Ps. aeruginosa strains were moderately resistant (MIC generally 4-16 mg/l) and Bran. catarrhalis strains only moderately sensitive (MICs generally 0.5-4 mg/l). Peak serum concentrations averaging approximately 37 mg/l were observed after the 1 g injections (55 mg/l after 2 g) and the corresponding mean peak concentrations in the sputum were 1.3 mg/l and 2.5 mg/l, respectively. The penetration from blood to sputum was thus approximately 3.5% and 4.6% after the 1 g and 2 g doses. No unwanted local or general reactions were observed. The disappointing clinical results (only 23 out of 36 patients with excellent or good clinical results) one week after the end of the treatment were mainly due to the emergence of pneumococcal infections during (and immediately after) therapy. Considering that Str. pneumoniae is still one of the most important organisms associated with acute purulent exacerbations of chronic bronchitis, and that conventional sputum cultures may not always reveal its presence, there is considerable doubt if aztreonam has any place in the treatment, especially as the results in Ps. aeruginosa infections have also been much poorer than expected.

InternalMed_Harrison

For outpatient management, amoxicillin (1 g every 8 h) provides effective treatment for virtually all cases of pneumococcal pneumonia. Neither cephalosporins nor quinolones, which are far more expensive, offer any advantage over amoxicillin. Levofloxacin (500–750 mg/d as a single dose) and moxifloxacin (400 mg/d as a single dose) also are highly likely to be effective in the United States except in patients who come from closed populations where these drugs are used widely or who have themselves been treated recently with a quinolone. Clindamycin (600–1200 mg/d every 6 h) is effective in 90% of cases and azithromycin (500 mg on day 1 followed by 250–500 mg/d) or clarithromycin (500–750 mg/d as a single dose) in 80% of cases. Treatment failure resulting in bacteremic disease due to macrolide-resistant isolates has been amply documented in patients given azithromycin empirically. As noted above, rates of resistance to all these antibiotics are relatively low in some countries and much

Community-acquired pneumonia

Children Treatment of CAP in children depends on the child's age and the severity of illness. Children under five are not usually treated for atypical bacteria. If hospitalization is not required, a seven-day course of amoxicillin is often prescribed, with co-trimaxazole as an alternative when there is allergy to penicillins. Further studies are needed to confirm the efficacy of newer antibiotics. With the increase in drug-resistant Streptococcus pneumoniae, antibiotics such as cefpodoxime may become more popular. Hospitalized children receive intravenous ampicillin, ceftriaxone or cefotaxime, and a recent study found that a three-day course of antibiotics seems sufficient for most mild-to-moderate CAP in children.

Clinical effectiveness of levofloxacin in patients with acute purulent exacerbations of chronic bronchitis: the relationship with in-vitro activity.

The objective of this randomized, double-blind study was to compare the clinical efficacy of levofloxacin at two different dosages with that of cefuroxime axetil in patients with acute purulent exacerbations of chronic bronchitis and, in particular, to assess the impact of the susceptibility to levofloxacin on the clinical findings. In total, 124 evaluable patients were treated for 7 days with oral levofloxacin 250 mg or 500 mg od, or cefuroxime axetil 250 mg bd. Sputum cultures were monitored pre-treatment, and at 1 and 7 days after the end of treatment. The susceptibility of Streptococcus pneumoniae isolates was tested by agar dilution in Columbia blood agar and by disc diffusion, but all other isolates were tested solely by the disc diffusion method. A greater number of infections were eradicated by levofloxacin than by cefuroxime axetil: infections were eradicated in 68% of patients receiving the 500 mg dosage and in 63% of those taking 250 mg levofloxacin, whereas the eradication rate with the comparator drug was much lower (48%). Against all pre-treatment S. pneumoniae isolates (n = 39), the MICs of levofloxacin were between 0.25 and 2 mg/L (geometric mean 0.95 mg/L), similar to those of the post-treatment strains (n = 32; mean 1.11 mg/L). All except one of the S. pneumoniae isolates were susceptible to penicillin G (MIC < or = 0.06 mg/L), and the remaining isolate was inhibited by 0.5 mg/L of penicillin G, but was fully susceptible to levofloxacin. Some pretreatment strains of Pseudomonas aeruginosa were resistant to levofloxacin, but many more resistant strains were encountered afterwards. All strains of Moraxella catarrhalis and Haemophilus influenzae were highly susceptible to levofloxacin in the disc diffusion tests. All the antimicrobial agents used in the study were well tolerated: only two patients discontinued treatment because of adverse drug effects. The results of this study indicated that, although there were some failures in patients with S. pneumoniae and P. aeruginosa infections, resistance to levofloxacin did not emerge rapidly among strains of S. pneumoniae during therapy with levofloxacin, and that natural resistance among pneumococci, H. influenzae and M. catarrhalis was rare.

Scarlet fever

The antibiotic of choice is Penicillin V which is taken by mouth in pill form. Children who are not able to take pills can be given amoxicillin which comes in a liquid form and is equally effective. Duration of treatment is 10 days. Benzathine penicillin G can be given as a one time intramuscular injection as another alternative if swallowing pills is not possible. If the person is allergic to the family of antibiotics which both penicillin and amoxicillin are a part of (beta-lactam antibiotics), a first generation cephalosporin is used. Cephalosporin antibiotics, however, can still cause adverse reactions in people whose allergic reaction to penicillin is a Type 1 Hypersensitivity reaction. In those cases it is appropriate to choose clindamycin or erythromycin instead. Tonsillectomy, although once a reasonable treatment for recurrent streptococcal pharyngitis, is not indicated, as a person can still be infected with group A streptococcus without their tonsils.

[Pharmacodynamic basis for the use of amoxicillin-clavulanic acid in respiratory infections due to Streptococcus pneumoniae: In vitro studies in an experimental model].

Amoxicillin-clavulanic acid is a first choice treatment for respiratory tract infections caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. In a previous study we observed its high efficacy against penicillin-susceptible and intermediate-resistant strains of S. pneumoniae. We aimed to study the efficacy of this antibiotic against three strains of S. pneumoniae (susceptible, intermediate and resistant to penicillin) in a mouse model of pneumonia, and to determine the influence of the time of starting treatment and the in vitro postantibiotic effect. We also determined the serum levels of the antimicrobial agent in the mice, and correlated the pharmacodynamic parameters (Cmax/MIC, AUC/MIC and T>MIC) with the survival rate to establish the best predictor of efficacy. MICs with amoxicillin-clavulanic acid were 0. 03 mg/l, 0.25 mg/l and 2 mg/l for the penicillin-susceptible, -intermediate and -resistant strains, respectively. The ED90 were approximately 5 mg/kg for susceptible strains, 25 mg/kg for the intermediate and 50 mg/kg for the resistant strains. We observed a lower survival rate (approximately 55%) when the treatment began 31 h after infection than when it began 5 h (100%) and 19 h (approximately 90-100%) afterwards. Serum levels were dose dependent and the correlation with the pharmacodynamic parameters showed a significant association between survival and the T>MIC (r = 0.946). In vitro postantibiotic effects with 1, 4 and 10 times the MIC were 0.96 to 1.69 h for susceptible strains, 0.38 to 1.23 h for intermediate, and 1.52 to 2. 20 h for resistant strains. These results show the high efficacy of this antibiotic combination against strains with variable susceptibility to penicillin, with this activity being related mainly to the T>MIC of the microorganism. The postantibiotic effect would prolong the effect of the antibiotic in the dosing interval. These parameters and antimicrobial effects are important in terms of the clinical application of this antimicrobial agent.

[Diagnostic and therapeutic strategies in exacerbations of chronic bronchitis in city practice].

The consensus conference convened by the French Language Society for Infectious Disease at Lille in 1991 stressed the fact that two germs were most often the cause of exacerbation in chronic bronchitis (Streptococcus pneumoniae and Haemophilus influenzae) and that antibiotic therapy was the "safe solution" and that the first intention treatment should be either penicillin A, a first generation cephalosporin or a macrolide for the first 8-10 days. A chest x-ray was recommended if there was the slightest doubt about co-existing parenchymal disease with a reevaluation around the 7th day and a prescription of penicillin A plus a beta-lactamase inhibitor or a second or third generation cephalosporin in case of failure. The aim of this study was to assess the diagnostic and therapeutic attitudes of general practitioners when faced with exacerbation in chronic bronchitis in an adult of 60 without severe signs and to find out the antibiotic of first choice and also the antibiotic to be used if the first treatment failed. One hundred doctors were drawn at random from a list of general practitioners in Bordeaux. They were requested to reply to a questionnaire on the strategy of first choice antibiotic and the means of reassessment of the treatment after it had been instituted and the strategy used when faced with a patient who did not improve after the initial treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Resistance of Streptococcus pneumoniae to penicillin. "Bacteriological" resistance/"clinical" resistance].

From January 1988 to December 1992, 143 Streptococcus pneumoniae strains have been isolated at a significant level from 136 patients hospitalized in the pulmonary care unit of CHI Créteil. The clinical presentations were: 83 pneumonia (P), 48 acute bronchitis (B) and 12 colonizations (C). Fourteen strains were found to be penicillin resistant (MIC > 0.125 mg. l-1): 11 P, 2 B, 1 C. Two patients were lost of view after the beginning of the treatment: a pneumonia (Serotype 23F, MIC = 2 mg. l-1) and a bronchitis (Serotype 23F, MIC = 2 mg. l-1). Treatment was pristinamycine for one and amoxicilline alone or associated to clavulanic acid for the other 13. We observed the failure of the treatment in two. A pneumonia (Serotype 23, MIC = 2 mg. l-1) was treated before hospitalization by josamycine (3 days), then cefpodoxime (4 days) and amoxicillin-clavulanic acid (1.5 gr/d during 7 days). Healing was obtained with the increase to 3 gr/d. The other failure was a pneumonia without improvement after 11 days with 3 gr/d of amoxicilline. The treatment was stopped during 5 days and a protected brushing was performed. A Streptococcus Pneumoniae (Serotype 23F, MIC = 8 mg. l-1) was isolated. The clinical status rapidly improved with erythromycine (3 gr/d) to which the strain was susceptible. "Bacteriological" Resistance to penicillin is demonstrated (10 percent in our sample, 17 percent in France during 1991). However amoxicillin to a sufficient dosage is still enough ("Clinical" Resistance < 1 percent in our sample) for the treatment of respiratory infections except when the MIC is at a high level.

[An analysis of 99 consecutive shifts in the selection of antibiotics used in therapy in a medical department].

During 208 days 2836 patients were admitted to Sundby Hospital, medical ward. A total of 734 antibiotic cures were initiated. About 632 (22-23%) of the patients had antibiotic treatment. Penicillin, ampicillin and sulfamethizole were the most frequently used antibiotics. The use of erythromycin was 42-50% and 64-78% of that of penicillin and ampicillin respectively. Antibiotic treatment was changed in 99 cures in 73 patients. Fifty-seven of ninety-nine (43-71%) shifts were based on culture or serology and 42/99 (29-57%) shifts were based on clinical evaluation including microscopy and urinary stix. In 26 of the latter 42 cases positive culture or serology was obtained after the antibiotic was changed. Thirteen of the 26 shifts improved treatment, six were unlucky and seven indifferent, thus giving a net advantage of 13-6 = 7 of 26 shifts. This net advantage was due to shifts from penicillin. In ten cases the antibiotic was shifted to erythromycin due to suspected atypical pneumonia, but only one case was verified. In ten antibiotic shifts in pneumonia patients the etiologic agents were not identified. In 4/99 shifts in 4/73 patients relevant specimens were not obtained. The antibiotic most often changed compared with its total use was ampicillin (32/152 congruent to 1/5 of initiated cures) and shifts from ampicillin were more often (21/32) based on culture than shifts from penicillin (16/36) (p < 0.1). Initial supplementation of ampicillin with aminoglycosides was retrospectively relevant in 13/28 cases. Cephalosporines (p < 0.001) and dicloxacillin (p < 0.02) were significantly more often used as second drug, whereas penicillin was most often used as first drug (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin/clavulanic acid: a review of its use in the management of paediatric patients with acute otitis media.

Amoxicillin/clavulanic acid (Augmentin), Augmentin ES-600 is a well established, orally administered combination of amoxicillin (a semisynthetic antibacterial agent) and clavulanic acid (a beta-lactamase inhibitor). Amoxicillin/clavulanic acid shows good activity against the main pathogens associated with acute otitis media (AOM), including penicillin-susceptible and -intermediate strains of Streptococcus pneumoniae, and beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis. It has moderate activity against penicillin-resistant S. pneumoniae; a high-dose formulation has been developed with the aim of providing better coverage for penicillin-resistant strains. Amoxicillin/clavulanic acid (conventional formulations, mostly 40/10 mg/kg/day in three divided doses) produced clinical response rates similar to those of oral cephalosporin comparators and similar to or significantly greater than those for intramuscular ceftriaxone in randomised trials in paediatric patients with AOM (mean age approximately 2 to 5 years). Clinical response rates were generally similar for amoxicillin/clavulanic acid and macrolide comparators (mean patient age approximately 1 to 6 years), although significantly better clinical and bacteriological responses were seen versus azithromycin in one randomised trial (mean patient age approximately 1 year). The high-dose formulation of amoxicillin/clavulanic acid (90/6.4 mg/kg/day in two divided doses) eradicated a high proportion of penicillin-resistant S. pneumoniae (penicillin MICs 2 or 4 mg/L) in a large noncomparative trial in children with AOM (upper limit of the US indication for S. pneumoniae is 2 mg/L). Amoxicillin/clavulanic acid is generally well tolerated. A low total incidence of adverse events (3.6%) and no serious events were reported from a large paediatric postmarketing study. The most frequently reported adverse events in children are mild gastrointestinal disturbances. Diarrhoea is generally less frequent with twice-daily than with three-times-daily treatment. The new high-dose formulation showed similar tolerability to a conventional twice-daily formulation (45/6.4 mg/kg/day) in a well controlled trial. Amoxicillin/clavulanic acid is a well established broad-spectrum antibacterial treatment which is effective and well tolerated in the treatment of AOM in paediatric patients. The high-dose combination should prove valuable in treating AOM caused by penicillin-intermediate and -resistant S. pneumoniae (approved in the US for penicillin MIC < or =2 mg/L). Based on recent recommendations and the available data, high-dose amoxicillin/clavulanic acid can be considered a treatment of choice for recurrent or persistent paediatric AOM (after failure of amoxicillin alone) where involvement of resistant pathogens is suspected.

[Objectives for antibiotic therapy in acute exacerbations of chronic bronchitis].

ANTIBIOTIC EFFICACY: According to early studies, antibiotics have moderate efficacy in acute exacerbation of chronic bronchitis. The lack of efficacy is particularly clear for patent exacerbation with marked alteration of respiratory function. Recent studies have shown that newer compounds exhibit an efficacy similar (no proven superiority) to comparison compounds (75 to 95% favorable outcome with treatment). The recommendations of the IVth Consensus Conference on Anti-infectious Therapy thus propose first line antibiotic therapy for patients with a forced expiratory volume in 1 second (FEV1) between 80 and 35% and broader spectrum and new antibiotics in case of failure of the first line treatment for patients with severe obstruction or frequently recurrent exacerbation. Using exacerbation-free interval, reduction in the number of exacerbations, duration of treatment and/or hospital stay as evaluation criteria, interesting results are obtained with amoxicillin/clavulanic acid, azithromycin, and ciprofloxacin. Independent factors predictive of therapeutic failure are, according to one study, FEV1 less than 35%, ambulatory administration of oxygen, more than 4 acute exacerbations within 24 months, history of pneumonia or sinusitis, and requirement for long-term corticosteroid therapy. Factors predictive of recurrence are, according to another study, dependence on oxygen therapy, prolonged corticosteroid therapy, smoking, and/or heart disease. Cost effectiveness is particularly interesting with ciprofloxacin, especially in more severe patients. It is important to target antibiotic therapy for acute exacerbation of chronic bronchitis specifically for patients who will truly benefit, adapting the prescribed compound to the bacterial target.

E test for studying in vitro activity of seven antimicrobial agents against penicillin-susceptible and penicillin-resistant pneumococci.

To evaluate the comparative activity of seven oral antimicrobial agents against 100 strains of Streptococcus pneumoniae (S. pneumoniae). Total 100 strains of S. pneumoniae were collected from general hospitals in Beijing from June 1996 to June 1997. E test method was used to detect the minimum inhibitory concentration (MIC) values of the following seven drugs against S. pneumoniae: penicillin, amoxicillin/clavulanate, cefaclor, cefuroxime, ceftriaxone, azithromycin and ofloxacin. The breakpoint of susceptibility categories was defined according to NCCLS. 74% of isolates were susceptible (S, MIC 0.06 mg/L) to penicillin, and 5% were penicillin resistant (R, MIC 2 mg/L). The intermediately resistant (I, MIC 0.1-1 mg/L) rate to penicillin was 21%. The total rates of R or I were 26% for penicillin, 6% for both amoxicillin/clavulanate and ceftriaxone, 9% for cefuroxime, 66% and 68% for azithromycin and ofloxacin respectively. Overall 94%, 94% and 91% of the pneumococcal isolates were susceptible to amoxicillin/clavulanate, ceftriaxone and cefuroxime respectively. S. pneumoniae was highly resistant to azithromycin tested as a representative of macrolides (MIC50 and MIC90 both > 256 mg/L, R rate 66%), and had a highly intermediately resistant rate to ofloxacin (I rate 62%). Our data suggest that in vitro activity of oral amoxicillin/clavulanate was as good as ceftriaxone and cefuroxime. It can be considered as an alternative compound in the treatment of community acquired pneumoniae and other respiratory tract infections caused by multiresistant S. pneumoniae.

Challenging questions in treating bronchitis.

Whatever facts we gather and no matter how many we have, you and I must eventually put the journal down and pick up our stethoscope, pen, and prescription pad and go to work. Hopefully we can do better than, "Therapy is not uniform and specific antibiotic regimens are usually selected based on local tribal custom." We can discard an old paradigm, "The absence of data bears no relation to the strength of opinion." Personally, I have used these new scientific data before I reached my conclusion. I have developed 10 points to structure my new approach. I invite you to compare my conclusions to yours. 1. In acute bronchitis, in otherwise healthy adults, my preference is to not prescribe an antibiotic. If I do, it is not over the phone. You should want to see and examine the patient. If there are no helpful hints to etiology, I choose a newer macrolide for those under age 50 and use a short course, five-seven days. For patients over age 50, especially if they are "healthy smokers," consider a short course of cefuroxime. (You can see, even in these acute bronchitis patients, you want an antibiotic effective against today's pathogens.) 2. In all chronic bronchitis patients, prevention of further damage to the airways should be attempted by instituting a program of smoking cessation and appropriate immunizations against influenza and pneumococcus. 3. Treatment outcomes will also improve if we recognize that in some patients the progressing SOB, cough, and increasing sputum production are due to congestive heart failure and not due to infection. I try to think about congestive heart failure in all of my patients, but especially in those with known heart disease and cardiomegaly on their chest x-ray. 4. Routine pulmonary function testing is important in smoking patients. Physicians underestimate the degree of obstruction present when they rely on physical exam alone. Hopefully long before the patient's acute illness you have established whether or not obstruction is present. This information helps identify the high risk patient for not only recurrent bouts of infection but also those at increased risk for lung cancer. 5. We will have more success in treating AECB when we elect to use an antibiotic only for patients with at least two of the following three cardinal symptoms: increased dyspnea, increased sputum production, and increased purulent sputum. COPD patients have many days when they feel more SOB. To use this or any one sign as the sole indication for starting an antibiotic has been proven not to make a statistically significant difference in outcome in most patients. Also, the value of prophylactic antibiotic therapy has not been established. 6. When airflow obstruction is moderately severe or more pronounced, AECB should usually be treated with oral steroids. Other measures such as chronic bronchodilator therapy, supplemental and home oxygen use, and pulmonary rehabilitation have been extensively reviewed elsewhere.

In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations.

The in vivo activities of amoxicillin and amoxicillin-clavulanate against 17 strains of Streptococcus pneumoniae with penicillin MICs of 0.12-8.0 mg/liter were assessed in a cyclophosphamide-induced neutropenic murine thigh infection model. Renal impairment was produced by administration of uranyl nitrate to prolong the amoxicillin half-life in the mice from 21 to 65 min, simulating human pharmacokinetics. Two hours after thigh infection with 10(5) to 10(6) CFU, groups of mice were treated with 7 mg of amoxicillin per kg of body weight alone or combined with clavulanate (ratio, 4:1) every 8 h for 1 and 4 days. There was an excellent correlation between the MIC of amoxicillin (0.03 to 5.6 mg/liter) and (i) the change in log10 CFU/thigh at 24 h and (ii) survival after 4 days of therapy. Organisms for which MICs were 2 mg/liter or less were killed at 1.4 to 4.2 and 1.6 to 4.1 log10 CFU/thigh at 24 h by amoxicillin and amoxicillin-clavulanate, respectively. The four strains for which MICs were >4 mg/liter grew 0.2 to 2.6 and 0.6 to 2. 3 logs at 24 h despite therapy with amoxicillin and amoxicillin-clavulanate, respectively. Infection was uniformly fatal by 72 h in untreated mice. Amoxicillin therapy resulted in no mortality with organisms for which MICs were 1 mg/liter or less, 20 to 40% mortality with organisms for which MICs were 2 mg/liter, and 80 to 100% mortality with organisms for which MICs were 4.0-5.6 mg/liter. Lower and higher doses (0.5, 2, and 20 mg/kg) of amoxicillin were studied against organisms for which MICs were near the breakpoint. These studies demonstrate that a reduction of 1 log10 or greater in CFU/thigh at 24 h is consistently observed when amoxicillin levels exceed the MIC for 25 to 30% of the dosing interval. These studies would support amoxicillin (and amoxicillin-clavulanate) MIC breakpoints of 1 mg/liter for susceptible, 2 mg/liter for intermediate, and 4 mg/liter for resistant strains of S. pneumoniae.

[Amoxicillin as a 1st choice: 275 acute focal pneumopathies treated on an outpatient basis].

From December 1986 to January 1988, 100 General Practitioners and Pneumologists working outside hospital included in open unmatched series 275 patients who were diagnosed as having pneumonia at home. The study consisted of 53.2% men with an average age of 49.3 plus or minus 19.3. Their temperature on the first day (J1) was in 72.7% of cases greater than 38.5 degrees Centigrade. The doctors felt that the general state was good in 66.5% of the cases. Cough was present in 83.5% of cases but was dry in one out of every two. The patients received Amoxycillin in a dose of 2 grams per day orally (66.9%), or by injection (33.1%). On the third day (J3) 90% of the patients had a temperature below 38.5 degrees Centigrade. Their general state was improved in 94.6% of cases. The diagnosis of pneumonia at home was confirmed radiologically on 219 of the films available, confirming the good specificity of the clinical diagnosis of pneumonia at home. Ten patients were hospitalised. The apparent treatment of Amoxycillin was given in 247 cases (89.8% of cases). In 28 cases (10.2%) the treatment was changed by the addition or substitution of a Macrolide (15), or another antibiotic (5), and in 80 cases a change of treatment was not specified. 25 of these 28 cases were reviewed on the 14th day (J14) and no failures were observed after the change of treatment. In 247 patients in whom the treatment with Amoxycillin was followed 336 were reviewed on the 15th day and there had been four failures. Three were intolerant to the drug and there was one relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Levofloxacin: a review of its use in the treatment of bacterial infections in the United States.

Levofloxacin (Levaquin) is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and atypical respiratory pathogens. It is active against both penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. The prevalence of S. pneumoniae resistance to levofloxacin is <1% overall in the US.A number of randomised comparative trials in the US have demonstrated the efficacy of levofloxacin in the treatment of infections of the respiratory tract, genitourinary tract, skin and skin structures. Sequential intravenous to oral levofloxacin 750mg once daily for 7-14 days was as effective in the treatment of nosocomial pneumonia as intravenous imipenem/cilastatin 500-1000mg every 6-8 hours followed by oral ciprofloxacin 750mg twice daily in one study. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once daily for 7-14 days achieved clinical and bacteriological response rates similar to those with comparator agents, including amoxicillin/clavulanic acid, clarithromycin, azithromycin, ceftriaxone and/or cefuroxime axetil and gatifloxacin. A recent study indicates that intravenous or oral levofloxacin 750mg once daily for 5 days is as effective as 500mg once daily for 10 days, in the treatment of mild to severe CAP. Exacerbations of chronic bronchitis and acute maxillary sinusitis respond well to treatment with oral levofloxacin 500mg once daily for 7 and 10-14 days, respectively. Oral levofloxacin was as effective as ofloxacin in uncomplicated urinary tract infections and ciprofloxacin or lomefloxacin in complicated urinary tract infections. In men with chronic bacterial prostatitis treated for 28 days, oral levofloxacin 500mg once daily achieved similar clinical and bacteriological response rates to oral ciprofloxacin 500mg twice daily. Uncomplicated skin infections responded well to oral levofloxacin 500mg once daily for 7-10 days, while in complicated skin infections intravenous and/or oral levofloxacin 750mg for 7-14 days was at least as effective as intravenous ticarcillin/clavulanic acid (+/- switch to oral amoxicillin/clavulanic acid) administered for the same duration. Levofloxacin is generally well tolerated, with the most frequently reported adverse events being nausea and diarrhoea; in comparison with some other quinolones it has a low photosensitising potential and clinically significant cardiac and hepatic adverse events are rare. Levofloxacin is a broad-spectrum antibacterial agent with activity against a range of Gram-positive and Gram-negative bacteria and atypical organisms. It provides clinical and bacteriological efficacy in a range of infections, including those caused by both penicillin-susceptible and -resistant strains of S. pneumoniae. Levofloxacin is well tolerated, and is associated with few of the phototoxic, cardiac or hepatic adverse events seen with some other quinolones. It also has a pharmacokinetic profile that is compatible with once-daily administration and allows for sequential intravenous to oral therapy. The recent approvals in the US for use in the treatment of nosocomial pneumonia and chronic bacterial prostatitis, and the introduction of a short-course, high-dose regimen for use in CAP, further extend the role of levofloxacin in treating bacterial infections.

Performance in practice: bacteriological efficacy in patients with drug-resistant S. pneumoniae.

Using pharmacokinetic/pharmacodynamic principles, pharmacokinetically enhanced amoxicillin/clavulanate 2000/125 mg twice daily was designed to provide adequate levels of amoxicillin over the 12-h dosing interval to eradicate penicillin-resistant Streptococcus pneumoniae (PRSP, penicillin MICs > or = 2 mg/L) with amoxicillin MICs of at least 4 mg/L. The clinical efficacy of amoxicillin/clavulanate 2000/125 mg was evaluated in patients with respiratory tract infections caused by S. pneumoniae, including isolates with elevated penicillin (2-8 mg/L) MICs. Data from 10 clinical studies were combined: seven randomised (1:1), double-blind, controlled trials (efficacy intent-to-treat [ITT]N = 3376): amoxicillin/clavulanate 2000/125 mg twice daily vs. levofloxacin 500 mg once daily in acute bacterial sinusitis (ABS); levofloxacin 500 mg once daily in acute exacerbations of chronic bronchitis (AECB); clarithromycin 500 mg twice daily in AECB; amoxicillin/clavulanate 875/125 mg twice daily/three times daily and 1000/125 mg three times daily in community-acquired pneumonia (CAP) and three noncomparative studies (efficacy ITT N = 3024): two in ABS, one in CAP. The bacteriological per-protocol (PP) population at follow up (days 14-39) comprised 1295 patients for amoxicillin/clavulanate 2000/125 mg and 241 for comparators. With amoxicillin/clavulanate 2000/125 mg at follow-up, outcome was successful (clinical success and eradication/presumed eradication) in 85/90 (94.4%) patients with S. pneumoniae in comparative studies and 421/445 (94.6%) in noncomparative studies, and with comparators 58/70 (82.9%) were successes. In the amoxicillin/clavulanate 2000/125 mg group at follow up, 52/552 S. pneumoniae isolates were resistant to penicillin. At follow up, 50/52 (96.2%) patients with PRSP were successes, including 6/7 with amoxicillin MICs of 4 mg/L and 7/8 with amoxicillin MICs of 8 mg/L. Success rates for amoxicillin/clavulanate 2000/125 mg against PRSP were similar for CAP (96.0%[24/25]), AECB (100%[3/3]) and ABS (95.8%[23/24]). There were six PRSP isolates in the comparator group (two isolates were from one patient), and three of five patients in this group were successes. In conclusion, amoxicillin/clavulanate 2000/125 mg demonstrated combined clinical/bacteriological success against 50/52 patients with PRSP, including 13/15 strains with amoxicillin MICs of 4-8 mg/L. These results for the pharmacokinetic-enhanced formulation of amoxicillin/clavulanate 2000/125 mg are in line with the high efficacy against PRSP predicted using pharmacokinetic/pharmacodynamic parameters.

Acute exacerbation of chronic obstructive pulmonary disease

"Simple" COPD is generally where a person 65 years or less, has fewer than four exacerbations per year, has minimal or moderate impairment in respiratory function and no comorbid disease. In patients with "simple" COPD, therapy should be targeted towards Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and possibly pathogens of atypical pneumonia. The first-line treatment is a beta-lactam antibiotic such as amoxicillin. The choice will depend on resistance patterns. In patients with penicillin allergy, doxycycline or trimethoprim are preferred.

Bacteriologic efficacy of a three-day intramuscular ceftriaxone regimen in nonresponsive acute otitis media.

To determine the bacteriologic efficacy of ceftriaxone in nonresponsive acute otitis media in children. In a prospective study 92 patients ages 3 to 36 months (median, 11 months) with culture-proved nonresponsive acute otitis media were studied from January, 1995, through August, 1997. The patients were treated with intramuscular ceftriaxone (50 mg/kg/l/day) for 3 days. Middle ear fluid was aspirated for culture by tympanocentesis on day of enrollment (Day 1); a second tap was performed on Days 4 to 10. Additional middle ear fluid cultures were obtained if clinical relapse occurred. Bacteriologic failure was defined by positive culture on Days 4 to 10. Patients were followed until Day 17+/-2. Susceptibility was measured by E test. The main drugs administered before enrollment were amoxicillin (38%), amoxicillinclavulanate (25%) and cefaclor (20%). Organisms recovered (n=105) were: Haemophilus influenzae, 54; Streptococcus pneumoniae, 47; Moraxella catarrhalis, 2; and Streptococcus pyogenes, 2. Thirty-four (72%) of the 47 S. pneumoniae isolates were intermediately resistant to penicillin (MIC 0.1 to 1.0 microg/ml), but all were susceptible to ceftriaxone (MIC < 0.5 microg/ml). Bacteriologic eradication was achieved in 100 of 105 (95%) cases: 54 of 54 (10O%) H. influenzae, 43 of 47 (92%) S. pneumoniae, 1 of 2 (50%) M. catarrhalis and 2 of 2 (100%) S. pyogenes. Bacteriologic success (with no relapse) occurred in 13 of 13 (100%) penicillin-susceptible S. pneumoniae vs. 28 of 34 (82%) S. pneumoniae intermediately resistant to penicillin (4 cases of bacteriologic failure and 2 cases of relapse). A 3-day intramuscular ceftriaxone regimen is efficacious for the treatment of nonresponsive acute otitis media. The optimal duration of treatment in cases of nonresponsive acute otitis media and whether ceftriaxone is efficacious for the treatment of nonresponsive otitis media caused by S. pneumoniae highly resistant to penicillin is yet to be determined.

Efficacy and safety of twice-daily pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg) in the treatment of adults with community-acquired pneumonia in a country with a high prevalence of penicillin-resistant Streptococcus pneumoniae.

This randomized, double-blind, non-inferiority trial evaluated the efficacy and safety of pharmacokinetically enhanced amoxicillin/clavulanate 2000/125 mg twice daily versus amoxicillin/clavulanate 875/125 mg three times daily, both given orally for 7 or 10 days, in the treatment of adults with community-acquired pneumonia in Spain, a country with a high prevalence of penicillin-resistant Streptococcus pneumoniae. Following 2:1 randomization, 566 patients (intent-to-treat population) received either amoxicillin/clavulanate 2000/125 mg (n = 374) or amoxicillin/clavulanate 875/125 mg (n = 192). Among the patients who did not deviate from the protocol (clinical per-protocol population), clinical success at day 21-28 post-therapy (test of cure; primary efficacy endpoint) was 92.4% (266/288) for amoxicillin/clavulanate 2000/125 mg and 91.2% (135/148) for amoxicillin/clavulanate 875/125 mg (treatment difference, 1.1; 95% confidence interval, -4.4, 6.6). Bacteriological success at test of cure in the bacteriology per-protocol population was 90.8% (79/87) with amoxicillin/clavulanate 2000/125 mg and 86.0% (43/50) with amoxicillin/clavulanate 875/125 mg (treatment difference 4.8; 95% confidence interval, -6.6, 16.2). At test of cure, amoxicillin/clavulanate 2000/125 mg was clinically and bacteriologically effective against 7/7 penicillin-resistant Streptococcus pneumoniae (MIC > or = 2 mg/L) isolates (including three amoxicillin non-susceptible strains) and amoxicillin/clavulanate 875/125 mg against 5/5 isolates (including one amoxicillin non-susceptible strain). Both treatment regimens were well tolerated. Amoxicillin/clavulanate 2000/125 mg was at least as effective clinically and as safe as amoxicillin/clavulanate 875/125 mg in the treatment of community-acquired pneumonia in adults in a country with a high prevalence of penicillin-resistant S. pneumoniae and has a more convenient twice daily posology.

[Proceedings: Long-term therapy with antibiotics in chronic bronchitis].

Longterm therapy of chronic bacterial bronchitis assumes two forms: (a) therapy of acute exacerbations, and (b) continuous longterm prophylaxis, chiefly during the 4-7 winter months. Longterm prophylaxis should be confined exclusively to patients with two or more severe annual exacerbations. The commonest pathogens, Haemophilus influenzae and pneumococci, are usually sensitive to ampicillin and amoxycillin, cotrimoxazole (Bactrim or Eusaprim) and tetracyclines.

Therapeutic options for pneumococcal pneumonia in Turkey.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Streptococcus pneumoniae continues to be the most important causative agent in CAP. This article reviews options for the empiric treatment of pneumococcal pneumonia in Turkey based on local epidemiologic data. This was a retrospective review of studies evaluating antimicrobial susceptibility patterns among clinical isolates of S pneumoniae in Turkey from 2000 onward. Relevant studies were identified through literature searches of both Turkish (Ulakbim and Pleksus) and international (MEDLINE) databases using the search terms S pneumoniae and Turkey. Only antibiotics likely to be used in pneumococcal pneumonia were evaluated. The minimum concentration required to inhibit 90% of isolates (MIC(90)) for each antibiotic was obtained by averaging all reported values to arrive at a single value for the entire country. The MIC(90) for penicillin was 1 g/mL; among all isolates of S pneumoniae, 6.4% were penicillin resistant and 30.9% showed intermediate susceptibility. The MIC(90)s and overall rates of resistance (combined intermediate susceptibility and resistance) for the other antibiotics studied were as follows: cefaclor, 4 microg/mL (26.3%); cefuroxime, 2 microg/mL (15.4%); ceftriaxone, 0.25 microg/mL (0.75%); imipenem, 0.06 microg/mL (0%); erythromycin, 2 microg/mL (13.9%); clarithromycin, 2 microg/mL (13.7%); azithromycin, 2 microg/mL (13.8%); telithromycin, 0.06 microg/mL (no published breakpoints); trimethoprim-sulfamethoxazole, 4 microg/mL (63.8%); tetracycline, 16 microg/mL (24.6%); ciprofloxacin, 2 microg/mL (no published breakpoints); ofloxacin, 2 microg/mL (4%); levofloxacin, 1 microg/mL (0%); gemifloxacin, 0.06 microg/mL (no published breakpoints); and moxifloxacin, 0.06 microg/mL (0%). Penicillin G, at standard parenteral doses, has been shown to achieve concentrations above the MIC for >40% to 100% of the dosing interval, depending on the MIC of the isolate. Based on pharmacodynamic studies, the MIC(90) for penicillin in Turkey should easily be exceeded with the use of penicillin G 3 mU QID. In vitro, susceptibility is generally greater to amoxicillin than to penicillin, with average amoxicillin MIC values approximately 1 dilution lower than those for penicillin. Amoxicillin's better pharmacodynamic/pharmacokinetic properties relative to penicillin make it a reasonable option for the treatment of CAP. In pharmacodynamic studies, amoxicillin 1 g TID achieved and maintained serum concentrations of 2 to 4 microg/mL for at least 40% of the dosing interval. A new formulation of amoxicillin/clavulanate given 2000/125 mg BID is expected to eradicate isolates of S pneumoniae at an amoxicillin MIC < or = 4 microg/mL. Based on data from Turkish surveillance studies performed from 2000 onward, high-dose parenteral penicillin G and parenteral/oral amoxicillin may be initial choices for the empiric treatment of uncomplicated pneumococcal pneumonia in Turkey. If these agents cannot be used for any reason, other options include parenteral cefuroxime, ceftriaxone, cefotaxime, newer quinolones, macrolides, and telithromycin. Due to elevated rates of resistance in Turkey, trimethoprim-sulfamethoxazole and tetracyclines are not recommended for empiric use in these infections.

[Treatment and prevention of pneumococcal pneumonia].

Streptococcus pneumoniae is the most commonly identified pathogen in patients with community-acquired pneumonia. 40% of isolated strains in France are of decreased sensibility to penicillin, two third being multiresistant to antibiotics. However, high doses of some beta-lactams are effective in vivo against the majority of circulating strains (MIC > 2 mg/L). For this reason according to French guidelines amoxicillin (3 g/day) is the first line recommended treatment. Telithromycin is an alternative, or ceftriaxone (1 g/day) in more severe cases. If the level of resistance increases (MIC > 4 mg/L) guidelines would be revisited. Effectiveness of pneumococcal vaccination has been confirmed in cases of bacteriemic pneumococcal pneumonia (elderly patients included). Vaccine is recommended among persons with comorbiditie(s) and 65 years old population.

[Pneumococcal pneumonia resistant to penicillin].

The authors report a case of community-acquired pneumonia in a patient with chronic obstructive lung disease. The initial antibiotic therapy consisted of an amoxicillin-clavulanic acid combination and intravenous macrolides. Twenty-four hours after admission, blood cultures were positive for pneumococcus. Pending the results of disc sensitivity tests, the antibiotic therapy was modified and amoxicillin alone was prescribed. Clinical deterioration then developed rapidly, as the pathogen was amoxicillin-resistant. Subsequently, the patient recovered under erythromycin therapy. As illustrated by this case, the emergence of pneumococci resistant, or showing low sensitivity to penicillins raises the problem of the antibiotic therapy to be used against community-acquired lung diseases.

Development of a new experimental model of penicillin-resistant Streptococcus pneumoniae pneumonia and amoxicillin treatment by reproducing human pharmacokinetics.

The increase of penicillin-resistant Streptococcus pneumoniae (PRSP) pneumonia results in a greater risk of antibiotic treatment failure. In vitro data are not sufficient predictors of clinical efficacy, and animal models may be insufficiently contributive, since they often use immunocompromised animals and do not always respect the human pharmacokinetics of antibiotics. We developed an experimental PRSP pneumonia model in immunocompetent rabbits, by using intrabronchial instillation of PRSP (MIC = 4 mg/liter), without any adjuvant. This reproducible model was used to assess amoxicillin efficacy by reproducing human serum pharmacokinetics following 1-g oral or intravenous administrations of amoxicillin every 8 h. Evaluation was performed by using clinical, CT scan, macroscopic, histopathologic, and microbiological criteria. Experimental pneumonia in untreated rabbits was similar to untreated severe human bacteremic untreated pneumonia; in both rabbits and humans, (i) cumulative survival was close to 50%, (ii) red or gray lung congestion and pleuritis were observed, and (iii) lung and spleen concentrations reached 5 and 4 log(10) CFU/g. A 48-h treatment resulted in a significant bacterial clearance in the lungs (1.53 versus 5.07 log(10) CFU/ml, P < 0.001) and spleen (1.00 versus 4.40 log(10) CFU/ml, P < 10(-6)) and a significant decrease in mortality (0% versus 50%, P = 0.02) in treated versus untreated rabbits. No difference was observed on macroscopic and histopathologic lesions between treated and untreated rabbits (P = 0.36 and 0.78, respectively). Similar results were obtained by using a fully penicillin-susceptible S. pneumoniae strain (MIC = 0.01 mg/liter). Our findings suggest that (i) this new model can be contributive in the evaluation of antibacterial agents and (ii) 1 g of amoxicillin three times a day may be sufficient to treat PRSP pneumonia in immunocompetent humans.

Efficacy of high doses of oral penicillin versus amoxicillin in the treatment of adults with non-severe pneumonia attended in the community: study protocol for a randomised controlled trial.

Streptococcus pneumoniae is the bacterial agent which most frequently causes pneumonia. In some Scandinavian countries, this infection is treated with penicillin V since the resistances of pneumococci to this antibiotic are low. Four reasons justify the undertaking of this study; firstly, the cut-off points which determine whether a pneumococcus is susceptible or resistant to penicillin have changed in 2008 and according to some studies published recently the pneumococcal resistances to penicillin in Spain have fallen drastically, with only 0.9% of the strains being resistant to oral penicillin (minimum inhibitory concentration>2 μg/ml); secondly, there is no correlation between pneumococcal infection by a strain resistant to penicillin and therapeutic failure in pneumonia; thirdly, the use of narrow-spectrum antibiotics is urgently needed because of the dearth of new antimicrobials and the link observed between consumption of broad-spectrum antibiotics and emergence and spread of antibacterial resistance; and fourthly, no clinical study comparing amoxicillin and penicillin V in pneumonia in adults has been published. Our aim is to determine whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of uncomplicated community-acquired pneumonia. We will perform a parallel group, randomised, double-blind, trial in primary healthcare centres in Spain. Patients aged 18 to 65 without significant associated comorbidity attending the physician with signs and symptoms of lower respiratory tract infection and radiological confirmation of the diagnosis of pneumonia will be randomly assigned to either penicillin V 1.6 million units thrice-daily during 10 days or amoxicillin 1,000 mg thrice-daily during 10 days. The main outcome will be clinical cure at 14 days, defined as absence of fever, resolution or improvement of cough, improvement of general wellbeing and resolution or reduction of crackles indicating that no other antimicrobial treatment will be necessary. Any clinical result other than the anterior will be considered as treatment failure. A total of 210 patients will be recruited to detect a non-inferiority margin of 15% between the two treatments with a minimum power of 80% considering an alpha error of 2.5% for a unilateral hypothesis and maximum possible losses of 15%. This pragmatic trial addresses the long-standing hypothesis that the administration of high doses of a narrow-spectrum antibiotic (penicillin V) in patients with non-severe pneumonia attended in the community is not less effective than high doses of amoxicillin (treatment currently recommended) in patients under the age of 65 years. EudraCT number 2012-003511-63.

Usefulness of betalactam therapy for community-acquired pneumonia in the era of drug-resistant Streptococcus pneumoniae: a randomized study of amoxicillin-clavulanate and ceftriaxone.

Empirical antibiotic therapy of community-acquired pneumonia (CAP) has been complicated by the worldwide emergence of penicillin resistance among Streptococcus pneumoniae. The impact of this resistance on the outcome of patients hospitalized for CAP, empirically treated with betalactams, has not been evaluated in a randomized study. We conducted a prospective, randomized trial to assess the efficacy of amoxicillin-clavulanate (2 g/200 mg/8 hr) and ceftriaxone (1 g/24 hr) in a cohort of patients hospitalized for moderate-to-severe CAP. Three-hundred seventy-eight patients were randomized to receive amoxicillin-clavulanate (184 patients) or ceftriaxone (194 patients). Efficacy was assessed on Day 2, after completion of therapy and at long term follow-up. There were no significant differences in outcomes between treatment groups, both in intention-to-treat and per-protocol analysis. Overall mortality was 10.3% for amoxicillin-clavulanate and 8.8% for ceftriaxone (NS). There were 116 evaluable patients with proven pneumococcal pneumonia. Rates of high-level penicillin resistance (MIC of penicillin > or = 2 microg/mL) were similar in the two groups (8.2 and 10.2%). Clinical efficacy at the end of therapy was 90.6% for amoxicillin-clavulanate and 88.9% for ceftriaxone (95% C.I. of the difference: -9.3 to +12.7%). No differences in outcomes were attributable to differences in penicillin susceptibility of pneumococcal strains. Sequential i.v./oral amoxicillin-clavulanate and parenteral ceftriaxone were equally safe and effective for the empirical treatment of acute bacterial pneumonia, including penicillin and cephalosporin-resistant pneumococcal pneumonia. The use of appropriate betalactams in patients with penumococcal pneumonia and in the overall CAP population, is reliable at the current level of resistance.