A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections.

Vitamin D has been shown to be an important immune system regulator. Vitamin D insufficiency during winter may cause increased susceptibility to upper respiratory tract infections (URIs). To determine whether vitamin D supplementation during the winter season prevents or decreases URI symptoms, 162 adults were randomized to receive 50 microg vitamin D3 (2000 IU) daily or matching placebo for 12 weeks. A bi-weekly questionnaire was used to record the incidence and severity of URI symptoms. There was no difference in the incidence of URIs between the vitamin D and placebo groups (48 URIs vs. 50 URIs, respectively, P=0.57). There was no difference in the duration or severity of URI symptoms between the vitamin D and placebo groups [5.4+/-4.8 days vs. 5.3+/-3.1 days, respectively, P=0.86 (95% CI for the difference in duration -1.8 to 2.1)]. The mean 25-hydroxyvitamin D level at baseline was similar in both groups (64.3+/-25.4 nmol/l in the vitamin D group; 63.0+/-25.8 nmol/l in the placebo group; n.s.). After 12 weeks, 25-hydroxyvitamin D levels increased significantly to 88.5+/-23.2 nmol/l in the vitamin D group, whereas there was no change in vitamin D levels in the placebo group. There was no benefit of vitamin D3 supplementation in decreasing the incidence or severity of symptomatic URIs during winter. Further studies are needed to determine the role of vitamin D in infection.

Therapeutic implications of antibacterial resistance in community-acquired respiratory tract infections in children.

The global spread of antibacterial resistance has important implications for the current and future management of bacterial respiratory tract infections in children. Data suggest that emerging resistance to commonly prescribed antibacterials, such as macrolides and trimethoprim-sulfamethoxazole, is beginning to impact the treatment of these infections, which include acute otitis media, tonsillitis/pharyngitis and community-acquired pneumonia. There is, therefore, a need for additional agents that are active against common respiratory tract pathogens, including resistant strains and are suitable for use in children. Infection control measures to curb the clonal spread of antibacterial resistance are also extremely important.

Community-acquired pneumonia. Diagnostic and therapeutic approach.

Optimal empiric therapy of CAP is with appropriate monotherapy (e.g., doxycycline, levofloxacin). Combination therapy is problematic because of potential side effects and high cost. Empiric coverage should have a high degree of activity against both typical and atypical pathogens. The antibiotic selected should have an excellent side-effect profile and be relatively inexpensive. Clinicians should be selective in their choice of antibiotic for CAP and choose an antimicrobial that has little or no resistance potential, is relatively inexpensive, and permits i.v.-to-PO switch monotherapy.

Nosocomial pneumonia. Diagnostic and therapeutic considerations.

Many patients with presumed nosocomial pneumonia probably have infiltrates on the chest radiograph, fever, and leukocytosis resulting from noninfectious causes. Because of the high mortality and morbidity associated with nosocomial pneumonias, however, most clinicians treat such patients with a 2-week empiric trial of antibiotics. Before therapy is initiated, the clinician should rule out other causes of pulmonary infiltrates, fever, and leukocytosis that mimic a nosocomial pneumonia (e.g., pre-existing interstitial lung disease, primary or metastatic lung carcinomas, pulmonary emboli, pulmonary drug reactions, pulmonary hemorrhage, collagen vascular disease affecting the lungs, or congestive heart failure). If these disorders can be eliminated from diagnostic consideration, a 2-week trial of empiric monotherapy is indicated. The clinician should treat cases of presumed nosocomial pneumonia as if P. aeruginosa were the pathogen. Although P. aeruginosa is not the most common cause of nosocomial pneumonia, it is the most virulent pulmonary pathogen associated with nosocomial pneumonia. Coverage directed against P. aeruginosa is effective against all other aerobic gram-negative bacillary pathogens causing hospital-acquired pneumonia. The clinician should select an antibiotic for empiric monotherapy that is highly effective against P. aeruginosa, has a good side-effect profile, has a low resistance potential, and is relatively inexpensive in terms of its cost to the institution. The preferred agents for empiric monotherapy for nosocomial pneumonia are cefepime, meropenem, and piperacillin. Single organisms are responsible for nosocomial pneumonia, not multiple pathogens. S. aureus rarely, if ever, causes nosocomial pneumonia but is mentioned frequently in studies based on cultures of respiratory tract secretions. S. aureus, unless accompanied by a necrotizing pneumonia with rapid cavitation within 72 hours, in the sputum indicates colonization rather than infection and should not be addressed therapeutically. Antibiotics associated with a high resistance potential should not be used as monotherapy or included in combination therapy regimens (i.e., ceftazidime, ciprofloxacin, imipenem, or gentamicin). Combination therapy is more expensive than monotherapy and is indicated only when P. aeruginosa is extremely likely, based on its characteristic clinical presentation, or is proved by tissue biopsy. Therapy should not be based on respiratory secretion cultures regardless of technique. Optimal combination regimens include cefepime or meropenem plus levofloxacin or piperacillin or aztreonam or amikacin. Nosocomial pneumonias usually are treated for 14 days. Lack of radiographic or clinical response to appropriate empiric nosocomial pneumonia monotherapy after 14 days suggests an alternate diagnosis. In these patients, a tissue biopsy specimen should be obtained to determine the cause of the persistence of pulmonary infiltrates unresponsive to appropriate antimicrobial therapy.

Quinolones: clinical use and formulary considerations.

Quinolones are broad-spectrum antibiotics active primarily against aerobic gram-negative organisms. All quinolones have activity against oral anaerobes, but only trovafloxacin provides coverage against Bacteroides fragilis, the primary anaerobe of the abdomen/pelvis. In addition, quinolones are very active against atypical pulmonary pathogens, e.g., Legionella, but trovafloxacin is the least active against Chlamydia. As with other antibiotics, the selection of quinolones depends not simply on the degree of microbiologic activity but also on safety profile and cost. Ciprofloxacin and trovafloxacin are associated with central nervous system side effects. Photosensitivity reactions may occur with sparfloxacin. Trovafloxacin is associated with more adverse reactions than any other quinolone, and its gastrointestinal side effects are most frequent among the quinolones. Resistance potential is highest with ciprofloxacin and lowest with levofloxacin. Sparfloxacin and grepafloxacin are available only as oral formulations. Among the parenteral quinolones, ciprofloxacin and trovafloxacin are the most expensive, levofloxacin, the least expensive. Levofloxacin is preferred for general use alone or in combination because it has virtually no side effects, induces no resistance, and is the least expensive and most versatile quinolone currently available.

Problems arising in antimicrobial therapy due to false susceptibility testing.

In vitro antibiotic susceptibility testing provides clinicians with guidelines to assess microbial sensitivities to various antibiotics. However, susceptibility testing is a laboratory procedure which does not always reflect the in vivo situation. False susceptibility testing is often due to methodological/disk concentration problems. In vitro versus in vivo discrepancies may also occur because of problems with varying pH/antibiotic concentration at the infection site. Clinicians should use susceptibility testing as a guide, but must rely upon the patient's clinical response as the ultimate in vivo susceptibility test.

Cefepime.

Because of the popularity of some third-generation cephalosporins, emergence of resistant organisms (e.g., selected Enterobacteriaceae) that produce inducible and extended-spectrum beta-lactamases has been a problem. Cefepime's twice-a-day dosage schedule and enhanced activity against Enterobacteriaceae and gram-positive organisms give it several advantages over older drugs. The clinical efficacy of cefepime has been demonstrated in comparative and noncomparative trials in the United States and Europe. Cefepime with twice-daily dosing has been useful in the treatment of lower respiratory tract infections, urinary tract infections, skin and skin structure infections, and in serious infection, including those with associated bacteremia. Cefepime is comparable to ceftazidime in clinical and bacteriologic response rates when both agents are administered three times a day in febrile neutropenic patients. Cefepime is also active against organisms that show resistance to other agents. Several studies have shown that cefepime retains its activity against E. cloacae and E. coli strains resistant to other cephalosporins and against many strains of P. aeruginosa resistant to ceftazidime. Cefepime exhibits a low level of cross-resistance with third-generation cephalosporins and a low propensity for selection of resistant mutants and offers a low potential for the induction of bacterial resistance, which complicates the course of many patients treated with single-agent third-generation therapy. Cefepime should be used in place of ceftazidime based on resistance potential, activity against resistant organisms, and cost.

Aztreonam.

Aztreonam is a monocyclic beta-lactam antibiotic that is active exclusively against the aerobic gram-negative bacilli. It is not ototoxic or nephrotoxic and so is used as an alternative to aminoglycosides in a variety of clinical situations. In polymicrobial infections or when used for empiric therapy, aztreonam must be combined with other antimicrobial agents active against gram-positive and anaerobic species. Aztreonam is often effective against resistant strains of gram-negative organisms, which are often involved in nosocomial infections. Overuse of aztreonam should be avoided to prevent the emergence of resistant P. aeruginosa strains. Except in the treatment of P. aeruginosa infections, aztreonam should not be added to beta-lactam regimens for additional gram-negative coverage.

Vancomycin.

Vancomycin is a nontoxic glycopeptide antibiotic most often used to treat serious gram-positive infections, C. difficile diarrhea/colitis, and endocarditis and hemodialysis shunt prophylaxis. Vancomycin should not be added to drug regimens for gram-positive coverage, and the empiric use of vancomycin should be discouraged to avoid the emergence of VRE. Vancomycin serum levels are no longer necessary or cost effective in most patients because vancomycin is not nephrotoxic.

Aminopenicillins in urology.

The use of ampicillin and amoxicillin remains a mainstay of urologic prophylaxis and therapy, however ampicillin's effectiveness against aerobic gram-negative bacilli, especially Escherichia coli has steadily decreased over time due to increasing beta-lactamase-induced resistance. Presently, up to 40-60 percent of E. coli may be ampicillin resistant. Since there have been no major resistance problems with enterococci, ampicillin remains the preferred anti-enterococcal antibiotic in penicillin-tolerant patients. Ampicillin/beta-lactamase inhibitor combinations are preferred when penicillins are used to treat ampicillin resistant aerobic gram-negative bacillary urinary tract infections (UTIs). One response to the problem of resistance has been short-course or single-dose therapy for uncomplicated cystitis in immunocompetent adults, which is less likely to cause side effects, bacterial resistance, or alterations in bowel flora. Another response has been to combine the aminopenicillins with beta-lactamase inhibitors such as clavulanate or sulbactam.

Amoxicillin/clavulanate therapy of respiratory tract infections: a microbiologic perspective.

The development of beta-lactamase-producing strains of the common respiratory tract pathogens Hemophilus influenzae and Moraxella catarrhalis has caused increasing resistance to a number of antimicrobial agents, including ampicillin and amoxicillin, that are traditionally used to treat respiratory tract infections. Because antimicrobial therapy for upper and lower respiratory tract infections is usually empiric, an understanding of beta-lactamase-mediated resistance and its implications for antibiotic therapy is critical for the successful treatment of these infections.

Ampicillin/sulbactam in lower respiratory tract infections: a review.

The pathophysiology and microbiology of lower respiratory tract infections are outlined and diagnostic and therapeutic problems considered. The use of sulbactam/ampicillin in the treatment of these infections is evaluated. The two drugs have similar pharmacokinetic characteristics; predictable and dose-dependent peak serum concentrations of both agents are achieved after parenteral administration. More than 90% of strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella sp, Escherichia coli, and Acinetobacter sp were inhibited by ampicillin/sulbactam concentrations of 16/8 micrograms/ml. Serum concentrations of ampicillin and sulbactam were 18 to 28 micrograms/ml and 13 micrograms/ml, respectively, after intramuscular administration of 1 gm/0.5 gm of ampicillin/sulbactam and 58 micrograms/ml and 30 micrograms/ml, respectively, after intravenous administration of the same dose. Good distribution of ampicillin/sulbactam into lung tissue, sputum, and bronchial fluid has been demonstrated. In over 2,250 patients treated with ampicillin/sulbactam, the rate of discontinuance of treatment because of side effects was less than 1%. Satisfactory clinical and bacteriologic outcome has been reported in over 80% of patients treated with ampicillin/sulbactam. The cost of ampicillin/sulbactam treatment is generally lower than that of other comparable antibiotic regimens.