High-dose Amoxicillin Research Articles

Advanced Lemierre Syndrome Requiring Surgery

A 38-year-old homeless man was admitted with a 2-week history of a sore throat, increasing shortness of breath, and high fever. Clinical examination showed enlarged and tender submandibular and anterior cervical lymph nodes and a pronounced enlargement of the left peritonsillar region (Figure 1a). CT scan of the throat and the chest showed left peritonsillar abscess formation, occlusion of the left internal jugular vein with inflammatory wall thickening and perijugular soft tissue infiltration, pulmonary abscesses, and bilateral pleural effusions (Figures 1b-e, arrowed). Anaerobe blood cultures grew Fusobacterium necrophorum, leading to the diagnosis of Lemierre's syndrome. Treatment with high-dose amoxicillin and clavulanic acid improved the oropharyngeal condition, but the patient's general status declined further, marked by dyspnea and tachypnea. Repeated CT scans showed progressive lung abscesses and bilateral pleural empyema. Bilateral tonsillectomy, ligation of the left internal jugular vein, and staged decortication of bilateral empyema were performed. Total antibiotic therapy duration was 9 weeks, including a change to peroral clindamycin. Clinical and laboratory findings had returned to normal 12 weeks after surgery.The patient's history and the clinical and radiological findings are characteristic for Lemierre's syndrome. CT scans of the neck and the chest are the diagnostic methods of choice. F. necrophorum is found in over 80% of cases of Lemierre's syndrome and confirms the diagnosis. Prolonged antibiotic therapy is usually sufficient, but in selected patients, a surgical intervention may be necessary. Reported mortality rates are high, but in surviving patients, the recovery of pulmonary function is usually good.

Clinical efficacy and time to symptom resolution of 5-day telithromycin versus 10-day amoxicillin–clavulanate in the treatment of acute bacterial sinusitis

ABSTRACTObjective: This study compared the clinical efficacy, time to symptom resolution, and tolerability of a 5-day regimen of telithromycin with a 10-day regimen of high-dose amoxicillin–clavulanate in acute bacterial sinusitis (ABS).Research design and methods: In this multinational (41 centers in Canada, Germany, Greece, Portugal, and Turkey), open-label, noninferiority study, patients ≥18 years old (n = 298) with a clinical ( > 7 days' symptoms) and radiological (air/fluid level, total opacification, mucosal thickening ≥10 mm) diagnosis of ABS were randomized to receive telithromycin 800 mg once daily for 5 days or amoxicillin–clavulanate 875/125 mg twice daily for 10 days. Clinical efficacy and tolerability were assessed at the test-of-cure visit (days 17–21). Time to symptom resolution was based on patients' daily diary assessment of individual symptoms.Results: The per-protocol clinical success rate (primary endpoint) with telithromycin (88.6 % (109/123)) was noninferior to that with amoxicillin–clavulanate (88.8 % (111/125)) (95 % confidence interval: –8.9 to 8.5). In the modified intention-to-treat (mITT) population, the median time for 50 % reduction of total symptom scores was significantly shorter for telithromycin (4 days) vs. amoxicillin–clavulanate (5 days; p = 0.044); median times for 75 % reduction of total symptom scores were: telithromycin, 7 days; amoxicillin–clavulanate, 8 days (p = 0.115). The median time for reduction of total symptom scores to the absent/very mild category (mITT population) was 6 days for telithromycin vs. 8 days for amoxicillin–clavulanate (p = 0.04). All treatment-emergent adverse events (TEAEs) were mostly gastrointestinal and occurred in 20.7 % (30/145) of telithromycin-treated patients vs. 31.8 % (47/148) of amoxicillin–clavulanate-treated patients (p = 0.034). One serious AE was reported in the telithromycin group, but it was considered not to be related to treatment.Conclusions: This open-label, randomized study demonstrated that treatment of ABS with telithromycin resulted in comparable clinical efficacy, shorter times to symptom resolution, and fewer total TEAEs than treatment with amoxicillin–clavulanate.

Trends in Otitis Media Treatment Failure and Relapse

The goals were to describe trends in acute otitis media, treatment failure, and relapse and in high-dose amoxicillin use and to determine whether treatment of acute otitis media with high-dose amoxicillin was associated with treatment failure or relapse. We conducted a retrospective study of acute otitis media visits made between 1996 and 2004 by children 2 months to 12 years of age in a large group practice, using computerized data. We defined acute otitis media as an otitis media visit with antibiotics dispensed (preceded by 30 days without otitis media visits), treatment failure as initiation of treatment with a second antibiotic before the first prescription was finished, and relapse as initiation of antibiotic treatment after the first prescription was finished but within 30 days after the index acute otitis media episode. The primary independent measure was high-dose amoxicillin (>70 mg/kg per day). We evaluated changes over time and determined whether high-dose amoxicillin use was associated with otitis media treatment failure or relapse. We identified 111,335 acute otitis media visits over a 9-year period. The incidence of acute otitis media decreased from 385.1 visits per 1000 enrollees in 1996 to 188.8 visits per 1000 enrollees in 2004. The proportion of acute otitis media visits treated with high-dose amoxicillin increased from 1.7% in 1996 to 41.9% in 2004. Both otitis media treatment failure and relapse rates decreased from 1996 to 2004 (from 3.9% to 2.6% and from 9.2% to 8.9%, respectively). The odds of treatment failure or relapse did not differ between acute otitis media episodes treated with high-dose and low-dose amoxicillin. During the past decade, acute otitis media, treatment failure, and relapse became less common and high-dose amoxicillin use increased. However, high-dose amoxicillin treatment did not reduce the risk of individual infections resulting in adverse outcomes.

Ambulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomised equivalency trial

WHO case management guidelines for severe pneumonia involve referral to hospital for treatment with parenteral antibiotics. If equally as effective as parenteral treatment, home-based oral antibiotic treatment could reduce referral, admission, and treatment costs. Our aim was to determine whether home treatment with high-dose oral amoxicillin and inpatient treatment with parenteral ampicillin were equivalent for the treatment of severe pneumonia in children. This randomised, open-label equivalency trial was done at seven study sites in Pakistan. 2037 children aged 3-59 months with severe pneumonia were randomly allocated to either initial hospitalisation and parenteral ampicillin (100 mg/kg per day in four doses) for 48 h, followed by 3 days of oral amoxicillin (80-90 mg/kg per day; n=1012) or to home-based treatment for 5 days with oral amoxicillin (80-90 mg/kg per day in two doses; n=1025). Follow-up assessments were done at 1, 3, 6, and 14 days after enrollment. The primary outcome was treatment failure (clinical deterioration) by day 6. Analyses were done per protocol and by intention to treat. This trial is registered, ISRCTN95821329. In the per-protocol population, 36 individuals were excluded from the hospitalised group and 37 from the ambulatory group, mainly because of protocol violations or loss to follow-up. There were 87 (8.6%) treatment failures in the hospitalised group and 77 (7.5%) in the ambulatory group (risk difference 1.1%; 95% CI -1.3 to 3.5) by day 6. Five (0.2%) children died within 14 days of enrollment, one in the ambulatory group and four in the hospitalised group. In each case, treatment failure was declared before death and the antibiotic had been changed. None of the deaths were considered to be associated with treatment allocation; there were no serious adverse events reported in the trial. Home treatment with high-dose oral amoxicillin is equivalent to currently recommended hospitalisation and parenteral ampicillin for treatment of severe pneumonia without underlying complications, suggesting that WHO recommendations for treatment of severe pneumonia need to be revised.

Treating severe pneumonia in children: we can do better

In today's Lancet, Tabish Hazir and colleagues 1 Hazir T Fox LM Bin Nisar Y for the New Outpatient Short-Course Home Oral Therapy for Severe Pneumonia (NO-SHOTS) Study GroupAmbulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomised equivalency trial. Lancet. 2008; 371: 49-56 Summary Full Text Full Text PDF PubMed Scopus (138) Google Scholar present findings that should change the management of severe pneumonia in children in developing countries. Previously, a large multicentre study in Asia, Africa, and Latin America had shown that an oral antibiotic was as effective as a parenteral antibiotic in hospitalised children with severe pneumonia who did not have other serious disease. 2 Addo-Yobo E Chisaka N Hassan M for the Amoxicillin Penicillin Pneumonia International Study (APPIS) groupOral amoxicillin versus injectable penicillin for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study. Lancet. 2004; 364: 1141-1148 Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar Hazir's finding that oral treatment outside a hospital is safe and efficacious is a milestone. The potential impact here is enormous, particularly for the many children with severe pneumonia who are referred to hospitals but never reach them. Ambulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomised equivalency trialHome treatment with high-dose oral amoxicillin is equivalent to currently recommended hospitalisation and parenteral ampicillin for treatment of severe pneumonia without underlying complications, suggesting that WHO recommendations for treatment of severe pneumonia need to be revised. Full-Text PDF

Emergence of a Multiresistant Serotype 19A Pneumococcal Strain Not Included in the 7-Valent Conjugate Vaccine as an Otopathogen in Children

Concern has been raised about the possible emergence of a bacterial strain that is untreatable by US Food and Drug Administration (FDA)-approved antibiotics and that causes acute otitis media (AOM) in children. To monitor continuing shifts in the strains of Streptococcus pneumoniae that cause AOM, with particular attention to capsular serotypes and antibiotic susceptibility, following the introduction of a pneumococcal 7-valent conjugate vaccine (PCV7). Prospective cohort study using tympanocentesis to identify S pneumoniae strains that caused AOM in children receiving PCV7 between September 2003 and June 2006. All children were from a Rochester, New York, pediatric practice. Determination of serotypes and antibiotic susceptibility of S pneumoniae causing AOM. Among 1816 children in whom AOM was diagnosed, tympanocentesis was performed in 212, yielding 59 cases of S pneumoniae infection. One strain of S pneumoniae belonging to serotype 19A was a new genotype and was resistant to all antibiotics approved by the FDA for use in children with AOM. This strain was identified in 9 cases (2 in 2003-2004, 2 in 2004-2005, and 5 in 2005-2006). Four children infected with this strain had been unsuccessfully treated with 2 or more antibiotics, including high-dose amoxicillin or amoxicillin-clavulanate and 3 injections of ceftriaxone; 3 had recurrent AOM; and for 2 others, the infection was their first in life. The first 4 cases required tympanostomy tube insertion after additional unsuccessful antibiotic therapies. Levofloxacin was used in the subsequent 5 cases, with resolution of infection without surgery. In the years following introduction of PCV7, a strain of S pneumoniae has emerged in the United States as an otopathogen that is resistant to all FDA-approved antibiotics for treatment of AOM in children.

A Canadian perspective on the American Academy of Pediatrics guidelines for acute otitis media

In 2004, the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP) published guidelines on the management of acute otitis media (AOM) (1). These are summarized in Table 1. The guidelines contain new recommendations for both empirical and second-line antibiotic treatments; however, some of the drugs recommended are not available in Canada. What are these recommendations, and what are the options for the prescribing Canadian physician? TABLE 1 The American Academy of Pediatrics otitis media guidelines The AAP/AAFP clinical practice guideline is a comprehensive document that covers diagnosis and management, including weighing the option of observation and symptomatic treatment, pain control, prevention measures, as well as appropriate choices for antibacterial medications. We will address the recommended antibiotics and explain why these drugs are recommended, as well as provide options for drugs that are not available in Canada. The first major new recommendation in the AAP/AAFP guidelines is an increase in the empirical treatment dose of amoxicillin. Specifically, the guidelines recommend that for most children, if an antibacterial agent is to be used, then the first-line agent to be prescribed should be amoxicillin at 80 mg/kg/day to 90 mg/kg/day. This was based on a Centers for Disease Control and Prevention (CDC) recommendation that the empirical treatment dose of amoxicillin should be increased from 40 mg/kg/day to 45 mg/kg/day, to 80 mg/kg/day to 90 mg/kg/day, owing to the rising prevalence of drug-resistant Streptococcus pneumoniae (DRSP) (2). In general, one cannot just increase the dose of a drug to overcome resistance; however, the mechanism of penicillin resistance is such that increasing the dose of amoxicillin results in serum levels that can overcome the resistance. This is based on in vitro data, not clinical trials. Penicillin susceptibility is geographically dependent, both in the United States and Canada. Thus, the CDC guidelines acknowledge that patients at very low risk for DRSP may still be treated with a regular dose of amoxicillin. This refers to patients older than two years of age, those without antibiotic exposure in the past three months and those with no daycare attendance. Moreover, since the publication of these guidelines, new data have emerged from the United States showing a change in the relative frequency of the different isolates causing AOM as a result of conjugated pneumococcal vaccine use. A significant drop (greater than 10%) in the rates of DRSP in certain communities was reported, especially in areas in which the vaccine has had universal recommendations (3); an overall decrease in the frequency of S pneumoniae isolates relative to Haemophilus influenzae (4) causing AOM was also reported. The Canadian Paediatric Society is currently revising the Canadian guidelines for first-line antibiotic treatment of AOM. In the interim, it would seem prudent to weigh all the risk factors (eg, age, daycare attendance, previous antibiotic exposure and geographical rate of drug resistance), as well as vaccination status (5) in the decision to choose high- versus standard-dose amoxicillin. It is important to remember that high-dose amoxicillin could cause diarrhea as an adverse effect. In patients with severe illness (moderate to severe ear pain and fever of 39°C or higher) and in those who fail to respond to initial management within 48 h to 72 h, the guidelines recommend the use of high-dose amoxicillin-clavulanate in two divided doses, in a 14:1 formulation (90 mg/amoxicillin component to a 6.4 mg/clavulin component). The addition of clavulanate is effective against the beta-lactamase-producing strains of H influenzae or Moraxella catarrhalis, which are thought to be the pathogens responsible for disease in those who fail initial amoxicillin treatment. Because this formulation is not available in Canada, one may prescribe the 7:1 Clavulin (GlaxoSmithKline Inc, Canada) product containing 45 mg/kg/day of the amoxicillin component and an additional amoxicillin dose of 45 mg/kg/day for a combined total of 90 mg/kg/day of amoxicillin. Clavulin-200 and -400 suspensions (7:1) are given every 12 h (6). If this treatment fails, the guidelines recommend a three-day course of parenteral ceftriaxone, owing to its superior efficacy against S pneumoniae compared with the oral antibiotics.

Management of Acute Otitis Media by Primary Care Physicians: Trends Since the Release of the 2004 American Academy of Pediatrics/American Academy of Family Physicians Clinical Practice Guideline

In 2004, the American Academy of Pediatrics and the American Academy of Family Physicians released a clinical practice guideline on the management of acute otitis media that included endorsement of an observation option for selected cases and recommendations of specific antibiotics. We sought to describe primary care physicians' current management of acute otitis media to compare it with the guideline's recommendations and describe trends since 2004. We used a mail survey from March through June 2006 within the Slone Center Office-Based Research Network, a national practice-based pediatric research network. The response rate was 299 (62.7%) of 477. The observation option was considered reasonable by 83.3%, compared with 88.0% in 2004, and was used in a median of 15% of acute otitis media cases over the previous 3 months. The most common physician-identified barriers to the use of the observation option were parental reluctance (83.5%) and the cost and difficulty of follow-up of children who do not improve (30.9%). In terms of antibiotic choices for acute otitis media, agreement with the guideline's antibiotic recommendation for 4 common clinical scenarios was as follows: high-dose amoxicillin for acute otitis media with nonsevere symptoms (57.2%), high-dose amoxicillin-clavulanate for acute otitis media with severe symptoms (12.7%), high-dose amoxicillin-clavulanate for cases that failed to respond to amoxicillin (42.8%), and intramuscular ceftriaxone for cases that failed to respond to treatment with amoxicillin-clavulanate (16.7%). Each of these proportions declined from 2004. Most primary care physicians accept the concept of an observation option for acute otitis media but use it only occasionally. Antibiotics prescribed for acute otitis media differ markedly from the guideline's recommendations, and the difference has increased since 2004.

Prior antibiotics and risk of antibiotic-resistant community-acquired urinary tract infection: a case–control study

To assess the effect of previous antibiotic use on the risk of a resistant Escherichia coli urinary tract infection (UTI), we undertook a case-control study with prospective measurement of outcomes in 10 general practices in the UK. Urinary samples from all patients with symptoms suggestive of UTIs were sought, and those with a laboratory-proven E. coli infection were interviewed and their medical records examined. Case patients were those with ampicillin- or trimethoprim-resistant infections and control patients had infections that were susceptible to antibiotics, including ampicillin and trimethoprim. Risk of ampicillin-resistant E. coli infection in 903 patients was associated with amoxicillin prescriptions of >or=7 days duration in the previous 1 month [odds ratio (OR)=3.91, 95% CI 1.64-9.34] and previous 2-3 months (2.29, 1.12-4.70) before illness onset. For prescriptions <7 days duration, there was no statistically significant association. Higher doses of amoxicillin were associated with lower risk of ampicillin resistance. For trimethoprim-resistant E. coli infections, the OR was 8.44 (3.12-22.86) for prescriptions of trimethoprim of >or=7 days in the previous month and 13.91 (3.32-58.31) for the previous 2-3 months. For trimethoprim prescriptions of <7 days, the OR was 4.03 (1.69-9.59) for the previous month but prescribing in earlier periods was not significantly associated with resistance. Within the community setting, exposure to antibiotics is a strong risk factor for a resistant E. coli UTI. High-dose, shorter-duration antibiotic regimens may reduce the pressure on the emergence of antibiotic resistance.

Amoxicillin is effective against penicillin-resistant Streptococcus pneumoniae strains in a mouse pneumonia model simulating human pharmacokinetics.

High-dose oral amoxicillin (3 g/day) is the recommended empirical outpatient treatment of community-acquired pneumonia (CAP) in many European guidelines. To investigate the clinical efficacy of this treatment in CAP caused by Streptococcus pneumoniae strains with MICs of amoxicillin > or =2 microg/ml, we used a lethal bacteremic pneumonia model in leukopenic female Swiss mice with induced renal failure to replicate amoxicillin kinetics in humans given 1 g/8 h orally. Amoxicillin (15 mg/kg of body weight/8 h subcutaneously) was given for 3 days. We used four S. pneumoniae strains with differing amoxicillin susceptibility and tolerance profiles. Rapid bacterial killing occurred with an amoxicillin-susceptible nontolerant strain: after 4 h, blood cultures were negative and lung homogenate counts under the 2 log(10) CFU/ml detection threshold (6.5 log(10) CFU/ml in controls, P < 0.01). With an amoxicillin-intermediate nontolerant strain, significant pulmonary bacterial clearance was observed after 24 h (4.3 versus 7.9 log(10) CFU/ml, P < 0.01), and counts were undetectable 12 h after treatment completion. With an amoxicillin-intermediate tolerant strain, 24-h bacterial clearance was similar (5.4 versus 8.3 log(10) CFU/ml, P < 0.05), but 12 h after treatment completion, lung homogenates contained 3.3 log(10) CFU/ml. Similar results were obtained with an amoxicillin-resistant and -tolerant strain. Day 10 survival rates were usually similar across strains. Amoxicillin with pharmacokinetics simulating 1 g/8 h orally in humans is bactericidal in mice with pneumonia due to S. pneumoniae for which MICs were 2 to 4 microg/ml. The killing rate depends not only on resistance but also on tolerance of the S. pneumoniae strains.

Effective regimens for the treatment of Helicobacter pylori infection

Successful Helicobacter pylori eradication therapy remains a challenge in medical practice. Currently, a proton pump inhibitor-based triple therapy containing clarithromycin, amoxicillin or nitroimidazole for 7 days is the recommended first-line treatment approach with an expected eradication success rate of ∼ 80%. As a second-line treatment option in the case of failure, a ranitidine bismuth citrate-based quadruple therapy is currently recommended curing another 80% of patients, leaving a subset of patients with persistent H. pylori infection. For these patients, promising rescue options have been evaluated including regimens that contain rifabutin, quinolones, furazolidone or high-dose amoxicillin. The role of susceptibility testing is still under discussion. It is not generally recommended prior to first-line treatment but guidelines propose a role for culture and antibiotic sensitivity testing after failure of the second attempt. Meanwhile, data on the geographic distribution of resistance pattern are available and may guide therapeutic decisions with regard to the combination of antibiotics chosen for the individual patients aiming at 100% cure rate in each individual patient.

Efficacy, tolerability, and parent reported outcomes for cefdinir vs. high-dose amoxicillin/clavulanate oral suspension for acute otitis media in young children

ABSTRACTObjectives: To compare efficacy, tolerability, and parental satisfaction of cefdinir and high-dose amoxicillin/clavulanate oral suspensions given to young children with non-refractory acute otitis media (AOM) based on clinical endpoints and outcomes measures.Research design and methods: This was an investigator-blinded, multicenter study in which 318 children 6 months through 6 years of age with a clinical diagnosis of AOM were randomized to receive 10 days of either cefdinir (14 mg/kg divided BID) or high-dose amoxicillin/clavulanate (90/6.4 mg/kg divided BID).Main outcome measures: Investigators evaluated clinical response at an end-of-therapy (EOT) office visit conducted on day 12–15. Outcomes of satisfaction, tolerability, and adherence were also assessed at that visit using an Otitis Parent Questionnaire.Results: The treatment groups were similar at baseline with respect to patient demographics. At the EOT visit, for cefdinir and amoxicillin/clavulanate, respectively, intent-to-treat (ITT) clinical cure rates were 82% (129/158) and 85% (134/158) ( p = 0.547; 95% confidence interval [CI] –11.7 to 5.4) and per-protocol cure rates were 82% (123/150) and 90% (129/143) ( p = 0.045; 95% CI –16.4 to 0.0). This difference was driven primarily by reduced cefdinir response in patients with recurrent AOM (p = 0.010) and those younger than 24 months (p = 0.039). Comparing cefdinir with amoxicillin/clavulanate, parents more often reported significantly better ease of use (89% vs. 57%; p < 0.0001), better taste (85% vs. 39%; p < 0.0001), and better adherence (at least 95% of doses) (82% vs. 61%; p < 0.0001). Diarrhea/loose stools were more common in the amoxicillin/clavulanate group than in the cefdinir group (28% vs. 18%, respectively; p = 0.0341). One patient in the cefdinir group and eight patients in the amoxicillin/clavulanate group withdrew from the study prematurely due to at least one adverse event ( p = 0.0364). Study limitations included assessment of clinical recurrence by telephone call rather than office visit, exclusion of children with refractory AOM, and no assessment of middle ear microbiology.Conclusions: Among young children with non-refractory AOM, cefdinir was as efficacious as high-dose amoxicillin/clavulanate in the ITT group, but somewhat less effective in per-protocol analysis. From the parental perspective, cefdinir was easier to administer, had a better taste, caused less diarrhea, and resulted in higher treatment adherence than high-dose amoxicillin clavulanate.

Index of Suspicion in the Nursery

A 10-day old male infant in the neonatal intensive care unit (NICU) has a small amount of purulent drainage from his right eye, but no other signs of infection. His respiratory rate is 40 to 64 breaths/min, with oxygen saturations of more than 90% in room air and no significant episodes of apnea. His pulse is 140 to 164 beats/min, with no significant episodes of bradycardia, and his temperatures are recorded at 97.7° to 98.1°F (36.5° to 36.7°C) in a heated bed. He is tolerating feedings of expressed human milk through a feeding tube and has gained weight consistently since the sixth postnatal day, although he is still approximately 100 g below birthweight. His only medication is caffeine for apnea of prematurity, which was started on the second postnatal day. The patient was born at 29 4/7 weeks’ gestation to a 35-year-old, G2P1→2 woman who developed preterm labor that was resistant to tocolysis with magnesium and nifedipine. The infant was delivered vaginally and resuscitated in the delivery room with supplemental oxygen via facemask. Apgar scores were 7 at 1 minute and 8 at 5 minutes. His birthweight was 1,660 g. He was admitted to the NICU because of preterm birth and mild respiratory distress syndrome. Laboratory tests upon admission included a complete blood count (CBC) and blood cultures, and ampicillin and gentamicin administration was initiated. His initial CBC revealed a white blood cell count of 14.3×103/mcL (14.3×109/L), with 58% neutrophils, 3% bands, 25% monocytes, and 14% lymphocytes. He received a total of four doses of ampicillin and two doses of gentamicin over the first two postnatal days; antibiotics were discontinued when initial blood cultures showed no growth at 48 hours. He did not require intubation; he was maintained initially on continuous positive airway pressure and then …

How Do Antimicrobial Agents Lead to Resistance in Pathogens Causing Acute Respiratory Tract Infections?

Whereas the principles of successful antimicrobial treatment-hit hard, hit early, and combine drugs-are well established for infections like tuberculosis and human immunodeficiency virus infection, they are not as well established for treatment of acute respiratory infections (ARIs) in which the target organisms are typically carried as commensals in the nasopharynx, drug resistance may be all-or-none or incremental, and (except for fluoroquinolones), resistance usually requires acquisition of foreign DNA. For these pathogens, most notably Streptococcus pneumoniae, any use of an effective antibiotic is likely to promote resistance at the population level, but different antimicrobial classes do so in different ways and to different degrees. Data on the effects of different classes on susceptible and nonsusceptible bacterial flora are reviewed, and the consequences for selecting resistance are discussed. It is concluded that, with certain caveats, these considerations support prescribing of high-dose amoxicillin (when necessary) for ARIs, although continued monitoring for the emergence of strains against which this high dose has no effect (increasing minimal inhibitory concentration) is needed. Other strategies, such as reserving certain highly effective antibiotics for use in severe cases and avoiding their routine use in children who are the reservoir of transmission of many ARI pathogens, should be considered. These considerations argue strongly against the use of fluoroquinolones for routine treatment in pediatrics.

Empiric First-line Antibiotic Treatment of Acute Otitis in the Era of the Heptavalent Pneumococcal Conjugate Vaccine

Our goal was to estimate the local prevalence of Streptococcus pneumoniae nonsusceptible to penicillin and amoxicillin after widespread use of the heptavalent pneumococcal vaccine and to revise community-specific recommendations for first-line antibiotic treatment of acute otitis media. We conducted serial prevalence surveys between 2000 and 2004 in the offices of community pediatricians in St Louis, Missouri. Study participants were children <7 years of age with acute upper respiratory infections. Children treated with an antibiotic in the past 4 weeks were excluded. S pneumoniae was isolated from nasopharyngeal swabs using standard techniques. Isolates with a penicillin minimum inhibitory concentration >2 microg/mL were considered to be S pneumoniae nonsusceptible to amoxicillin. There were 327 patients enrolled in the study. Between 2000 and 2004, vaccine coverage with > or =3 doses of heptavalent pneumococcal vaccine increased from 0% to 54%, but nasopharyngeal carriage of S pneumoniae was stable at 39%. The prevalence of S pneumoniae nonsusceptible to penicillin fell from 25% to 12% among patients, did not vary if <2 years of age, was reduced in children with > or =3 doses of heptavalent pneumococcal vaccine, and increased in child care attendees but reduced in attendees who had > or =3 doses of heptavalent pneumococcal vaccine. The prevalence of S pneumoniae nonsusceptible to amoxicillin in patients remained <5%. In our community, widespread use of heptavalent pneumococcal vaccine has reduced the prevalence of S pneumoniae nonsusceptible to penicillin, and the prevalence of S pneumoniae nonsusceptible to amoxicillin remains low (<5%). If antibiotic treatment is elected for children with uncomplicated acute otitis media, we recommend treatment with standard-dose amoxicillin (40-45 mg/kg per day) for children with > or =3 doses of heptavalent pneumococcal vaccine, regardless of age and child care status. High-dose amoxicillin should be used for children with <3 doses of heptavalent pneumococcal vaccine and those treated recently with an antibiotic.

Pharmacokinetics of amoxicillin administered in drinking water to recently weaned 3- to 4-week-old pigs with diarrhea experimentally induced by Escherichia coli O149:F4

To measure effects of Escherichia coli O149:F4-induced diarrhea on water consumption and pharmacokinetics of amoxicillin after administration in drinking water. 24 recently weaned 24- to 28-day-old crossbred pigs. 10 pigs were inoculated with E. coli O149:F4; all 10 pigs subsequently developed diarrhea. Pigs were medicated by administration of amoxicillin in the drinking water (0.75 mg/mL) for a 4-hour period on 2 consecutive days. Fourteen age-matched noninfected healthy pigs (control group) were medicated in a similar manner. Blood samples were obtained from both groups daily, and plasma concentrations of amoxicillin were analyzed by use of high-performance liquid chromatography. Diarrhea reduced the area under the plasma concentration-versus-time curve (AUC) and maximum plasma concentration (C(max)) of amoxicillin on the first day of medication by 56% and 63%, respectively. The AUC of amoxicillin on the second day of medication for diarrheic pigs did not differ significantly from that of control pigs on the first day of medication. E. coli-induced diarrhea reduced the AUC of amoxicillin and time that plasma concentration of amoxicillin was > 0.025 microg/mL and, hence, less likely to have a therapeutic effect on the first day of administration in drinking water. On the assumption that plasma concentrations may indirectly reflect concentrations at the site of infection, analysis of our results suggests that higher doses of amoxicillin may be appropriate for administration in drinking water during a 4-hour period on the first day that pigs have diarrhea attributable to E. coli O149:F4.

Beginning Antibiotics for Acute Rhinosinusitis and Choosing the Right Treatment

Acute bacterial sinusitis (ABS) is an extremely common problem in both children and adults. There are three clinical presentations of acute sinusitis: (1) onset with persistent symptoms (nasal symptoms or cough or both for > 10 but < 30 d without evidence of improvement); (2) onset with severe symptoms (high fever and purulent nasal discharge for 3-4 consecutive days); and (3) onset with worsening symptoms (respiratory symptoms, with or without fever, which worsen after several days of improvement). Images to confirm the presence of acute sinusitis are necessary in older children (> 6 years) and adults to enhance the certainty of diagnosis. The predominant bacterial species that are implicated in acute sinusitis are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in children. In the last decade, there has been an increasing prevalence of penicillin-resistant S. pneumoniae, and beta-lactamase-producing H. influenzae and M. catarrhalis. Although there has been some controversy in the literature regarding the effectiveness of antibiotics in the treatment of ABS, most studies in which the diagnosis of acute bacterial sinusitis is confirmed with images and appropriate anti-biotics are prescribed show superior outcomes in recipients of antibiotics. Therapy may be initiated with high-dose amoxicillin or amoxicillin-clavulanate. In penicillin-allergic patients or those who are unresponsive to amoxicillin, amoxicillin-clavulanate is appropriate. Alternatives include cefuroxime, cefpodoxime, or cefdinir. In cases of serious drug allergy, clarithromycin or azithromycin may be prescribed. The optimal duration of therapy is unknown. Some recommend treatment until the patient becomes free of symptoms and then for an additional 7 d.

A Randomized, Multicenter, Double Blind, Double Dummy Trial of Single Dose Azithromycin Versus High Dose Amoxicillin for Treatment of Uncomplicated Acute Otitis Media

A Randomized, Multicenter, Double Blind, Double Dummy Trial of Single Dose Azithromycin Versus High Dose Amoxicillin for Treatment of Uncomplicated Acute Otitis Media

Comparison of Amoxicillin with Alternative Agents for the Treatment of Acute Otitis Media in Children

Expert panels have recommended high-dose amoxicillin (80-90 mg/kg/day) as the therapy of choice for uncomplicated acute otitis media in children. This recommendation is based primarily on pharmacokinetic data predicting bacteriologic cure of most middle ear infections by using amoxicillin at the recommended dosage. However, comparisons of aminopenicillin-containing regimens with alternative treatments, particularly azithromycin, have not consistently demonstrated superiority of the former, even in recent trials with stringent designs. Moreover, amoxicillin exposure may perturb nasopharyngeal colonization more profoundly than do alternative agents. These perturbations may theoretically promote the dissemination of beta-lactam-resistant pneumococci in the community more than other drugs approved for use in otitis media. Such findings suggest that several factors should be considered when choosing an agent to treat otitis media and that reexamination of high-dose amoxicillin as the superior first-line agent for this condition might be warranted.

A Randomized, Multicenter, Double Blind, Double Dummy Trial of Single Dose Azithromycin Versus High Dose Amoxicillin for Treatment of Uncomplicated Acute Otitis Media

A Randomized, Multicenter, Double Blind, Double Dummy Trial of Single Dose Azithromycin Versus High Dose Amoxicillin for Treatment of Uncomplicated Acute Otitis Media