Pharmacokinetics of two dosage regimens of ciprofloxacin during a two-week therapeutic trial in patients with cystic fibrosis.

Twenty-nine adult patients with cystic fibrosis received 750 or 1,000 mg of ciprofloxacin orally every 12 hours for two weeks. Pharmacokinetic data were collected on Days 1, 7, and 14. Pharmacokinetic analyses revealed minor differences between the dosage regimens, and results were similar on the first, seventh, and last day of therapy. Means for peak serum concentration (3.1 to 5.0 micrograms/ml), elimination half-life (4.8 to 5.3 hours), area under the time-concentration curve, and serum clearance (36.8 to 44.5 liter/hour) were similar to previously reported results for patients without cystic fibrosis. Sputum concentrations approximated serum values.

Randomized study of two dosage regimens of ciprofloxacin for treating chronic bronchopulmonary infection in patients with cystic fibrosis.

Twenty-nine adult patients with cystic fibrosis who had chronic bronchopulmonary infection were randomly assigned to receive 750 or 1,000 mg of oral ciprofloxacin every 12 hours for two weeks. Assessments for efficacy and safety were made on treatment Days 7 and 14 and one week following completion of therapy, and pharmacokinetic data were collected on Days 1, 7, and 14. Fifteen of 28 evaluable patients showed clinical improvement, and none had clinical deterioration. The higher dosage of ciprofloxacin did not enhance the clinical response. Statistically significant, stepwise changes in clinical scores, pulmonary function, and sputum concentrations of Pseudomonas aeruginosa and Staphylococcus aureus were noted, but regression toward initial values occurred by one week after treatment. Although all P. aeruginosa isolates were initially inhibited by 2 mg/liter of ciprofloxacin or less, 45 and 35 percent of isolates were resistant after 14 days of therapy and one week later, respectively. Outpatient oral ciprofloxacin therapy was commonly associated with clinical improvement in adult patients with cystic fibrosis who have chronic bronchopulmonary infection, regardless of the emergence of resistant P. aeruginosa, and adverse reactions were infrequent. Further studies must delineate the long-term consequences of the frequent emergence of bacterial resistance.

Potential of moxalactam and other new antimicrobial agents for bilirubin-albumin displacement in neonates.

The effects of several novel antibiotics on in vitro binding of bilirubin to human serum albumin were investigated. At physiologic bilirubin-albumin ratios and pH values, aztreonam, imipenem, azlocillin, enoxacin and ciprofloxacin did not compete with bilirubin at drug concentrations less than 900 micrograms/mL. Cefoperazone caused an apparent increase in unbound bilirubin only at concentrations greater than 35 microM (330 micrograms/mL). Moxalactam, however, caused a linear increase in unbound bilirubin, greater than that seen with sulfisoxazole, over the entire range of antibiotic concentrations. These results may have implications for the use of these newer antimicrobial agents in neonatal infections.

Aztreonam: clinical pharmacology.

Monocyclic beta-lactam antibiotics (monobactams) are structurally unique from the traditional bicyclic beta-lactams because of their single ring configuration. Aztreonam, the first of these monobactams, has been studied extensively in order to determine its pharmacologic and pharmacokinetic profile in adults and children with bacterial infections. It has been established, for example, that with intramuscular or intravenous dosing (30 to 50 mg/kg in children and 1 to 2 g in adults), serum concentrations above the minimum inhibitory concentrations of most aerobic Gram-negative bacteria can be maintained for up to 8 hours. Against a less susceptible pathogen such as Pseudomonas aeruginosa, every-6-hour dosing allows for preservation of the bactericidal effect, although longer intervals may be practical in low birth weight infants. The drug is primarily (80%) excreted by renal mechanisms and serum clearance varies with postnatal age. Distribution into body fluids is similar to that of other beta-lactams. For example in the presence of meningeal inflammation, cerebrospinal fluid concentrations are 17 to 33% of serum values. Urinary concentrations are high and prolonged with greater than 80% appearing as the active drug. Preliminary data from cystic fibrosis patients suggest that there are very minor pharmacokinetic differences in this population. The pharmacologic profile indicates that aztreonam may provide an appropriate alternative to traditional therapy for serious Gram-negative aerobic infections in infants and children.

Clinical experience with aztreonam.

Aztreonam, the first of the new class of monobactams, has a narrow and specific range of bactericidal activity; it is highly active against Gram-negative aerobic pathogens but is essentially inactive against Gram-positive or anaerobic bacteria. Several unique features indicate that aztreonam may provide an attractive choice for the treatment of serious Gram-negative infection in adults and children. Clinical study in adults has shown aztreonam to be highly effective against infections of the urinary and lower respiratory tracts, the musculoskeletal system and the female genitourinary tract. It also has proved useful in neutropenic patients, including those with cancer, and for treatment of bacterial peritonitis, gonorrhea, cellulitis and wound infections. Reported clinical and microbiologic cure rates have been comparable to those associated with traditional therapeutic approaches (85 to 100%). In the treatment of children with urinary tract infection as well as other types of infections, aztreonam therapy in a dosage of 30 mg/kg given every 6 to 8 hours was associated with satisfactory clinical and microbiologic cure rates. There appear to be specific clinical situations for which aztreonam may be an appropriate alternative to more toxic therapies, although comparative trials are needed to delineate the exact place of aztreonam in the armamentarium against bacterial infection.

Second episodes of Haemophilus influenzae type b disease following rifampin prophylaxis of the index patients.

Patients treated for Haemophilus influenzae type b disease frequently remain nasopharyngeal carriers of that organism and fail to develop protective concentrations of serum antibody. It has been suggested that rifampin prophylaxis of the index patient may prevent recurrence of disease by eliminating type b Haemophilus carriage. We report nine children who developed second episodes of disease 1 week or more after receiving rifampin prophylaxis. The median interval between the last dose of rifampin and admission to the hospital for the second episode was 70 days (range, 9 to 138). Analysis of biotypes and outer membrane protein polyacrylamide gel electrophoresis patterns of paired isolates from eight cases revealed that the second episodes in two of the children were caused by acquisition of new type b Haemophilus strains, whereas the second episodes in the remaining six children were caused by isolates which were indistinguishable from the respective isolates from the first episodes. Rifampin prophylaxis of the index patient may prevent some episodes of recurrent disease. However, in some patients who have received prophylaxis, second episodes can occur, probably as a result of reacquisition of the organism from contacts who did not receive rifampin or from acquisition of new type b strains.

Comparative trial of cefprozil vs. amoxicillin clavulanate potassium in the treatment of children with acute otitis media with effusion.

A total of 137 children with acute otitis media with effusion were randomly allocated to treatment with cefprozil (30 mg/kg/day divided into two equal doses), an investigational cephalosporin or amoxicillin clavulanate potassium (40 mg/kg/day divided into three equal doses) for 10 days. The most common pathogens obtained from middle ear cavities by tympanocentesis were Streptococcus pneumoniae (33%), Haemophilus influenzae (19.6%) and Moraxella catarrhalis (8.3%). Patients were scheduled for follow-up visits at midtreatment, at end of therapy and at 30 days. Of the 137 children 122 were evaluable. Five of 60 patients (8.3%) treated with cefprozil and 14 of 62 patients (22.5%) treated with amoxicillin clavulanate potassium were considered therapeutic failures because of persistence of symptoms and/or isolation of the original pathogen or superinfection (P = 0.05). Rates of relapse, reinfection and persistent middle ear effusion as documented by tympanogram were comparable in both groups. When persistent middle ear effusion was analyzed by pneumatic otoscopy, 64 of 103 affected ears (62.1%) treated with cefprozil and 80 of 105 affected ears (76.1%) treated with amoxicillin clavulanate potassium were abnormal (P = 0.04). Loose stools were more common in children treated with amoxicillin clavulanate potassium than in children treated with cefprozil (P = 0.0004). Based on the efficacy results from this study, the lower gastrointestinal side effects and the convenience of twice-a-day dosing, we believe that cefprozil in a dosage of 30 mg/kg/day divided every 12 hours represents a potential alternative for the treatment of acute otitis media with effusion in children.

Ribavirin effect on pulmonary function in young infants with respiratory syncytial virus bronchiolitis.

To assess the effect of ribavirin on pulmonary function in infants with respiratory syncytial virus bronchiolitis, we performed a randomized (nonmatched), double blinded, placebo-controlled study of 19 infants with RSV bronchiolitis. Infants with underlying respiratory, cardiac or immunologic disease were excluded. Patients were given ribavirin (10) or placebo (9) via an aerosol generator for 18 hours/day for 3 days. Pulmonary function (dynamic compliance, total lung resistance) was calculated using a pneumotachographic method on Days 1, 2 and 7. Differences between groups on clinical criteria were not found. Approximately one-half of each group showed increased compliance and decreased lung resistance after 24 to 48 hours of therapy. By Day 7 compliance had increased 30% in the placebo group and 210% in the ribavirin-treated infants (P = 0.05). Significant differences in the rate of change of lung resistance were not seen by Day 7. We conclude that previously noted improvements in the early course of respiratory syncytial virus bronchiolitis treated with ribavirin do not appear to be a result of measurable changes in pulmonary function. However, paradoxical increases in airway resistance were not found in patients treated with ribavirin.

Invasive Haemophilus influenzae type B infections: a continuing challenge.

Invasive Haemophilus influenzae type b infections are a major cause of severe infections in children between 2 months and 5 years of age. Meningitis, arthritis, pneumonia, cellulitis, osteomyelitis, and epiglottitis affect approximately 25,000 patients annually and are a major cause of mortality and morbidity in children. H. influenzae type b clinical syndromes, diagnostic methods, epidemiology, immunity, and treatment are discussed in this review. Although potent antibiotics have long been available for treatment, mortality and morbidity rates have not declined substantially in the last 15 years. Prevention of disease is therefore a continuous medical challenge. Secondary cases can be prevented by identification of the high-risk groups and the application of appropriate techniques, including antimicrobial prophylaxis. Primary prevention is the major goal of current research. H. influenzae type b vaccines currently are available for protection of infants 18 months of age and older. Prevention of primary and secondary disease and future developments, including new vaccine strategies, are stressed.

Comparison of quantitative polymerase chain reaction, acid fast bacilli smear, and culture results in patients receiving therapy for pulmonary tuberculosis.

Quantitative-competitive polymerase chain reaction (QPCR) was performed on serial sputum samples from 22 consecutive cases of acid fast bacilli (AFB) smear-positive pulmonary tuberculosis. Of 94 specimens, 55, 72, and 83% were positive by culture, AFB smear, and QPCR, respectively. Of 52 culture-positive specimens, 6% were negative by PCR, and 13% were negative by AFB smear. Of 42 culture-negative specimens, AFB smear and QPCR were positive in 55 and 61%, respectively. AFB smear and QPCR results were strongly correlated (r = 0.75, p < 0.001), but each correlated less strongly with culture (r = 0.54, p < 0.005 for smear and r = 0.52, p < 0.005 for QPCR). When patients were classified by microbiologic response, responders tended to have less DNA in their sputum and shorter time to a negative PCR result compared to nonresponders. These data do not suggest a great advantage of QPCR over AFB smear for predicting culture results in patients with pulmonary tuberculosis.

In vitro activity of teicoplanin compared with vancomycin against methicillin-resistant Staphylococcus aureus derived from cystic fibrosis sputum.

We evaluated the in vitro activity of teicoplanin compared with vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) derived from cystic fibrosis (CF) sputum. Teicoplanin had a slightly lower median minimum inhibitory concentration (MIC) for these strains (0.25 micrograms/ml) than did vancomycin (0.5 micrograms/ml). Inoculum size increased the MICs similarly for both drugs, and pH variations did not significantly affect their activity. The presence of serum and sputum in the growth media decreased the activity of both drugs, although this was more pronounced for teicoplanin which is highly protein bound. We conclude that teicoplanin has activity against this pathogen and might be evaluated in clinical protocols designed to address this emerging clinical problem.

Phaeohyphomycosis of the maxilloethmoid sinus caused by Drechslera spicifera: a new fungal pathogen.

"Phaeohyphomycosis" refers to soft tissue and systemic infections caused by dematiacious septate fungi. Drechslera spicifera, a dematiacious fungus, rarely pathogenic in humans was found to cause maxilloethmoid sinus disease in two immunocompetent children. The clinical presentation was similar to noninvasive aspergillosis. Intracavitary surgical excision without adjuvant chemotherapy resulted in apparent cure. The microbiologic and clinicopathologic aspects of this mycotic sinus disease are reviewed and discussed in relation to the entire spectrum of human disease reported which has been attributed to this organism.

Parainfluenza type 3 meningitis. Report of two cases and review of the literature.

The authors present two immunocompetent children with parainfluenza type 3 meningitis. In each case, the outcome was favorable without detectable complications. The authors reviewed the literature, showing that central nervous system (CNS) involvement by parainfluenza viruses has rarely been described but may present with a variety of neurologic syndromes. Pediatricians and laboratory personnel should recognize that these viruses, commonly known to produce respiratory syndromes, can also be a cause of CNS infections. If additional studies confirm these observations, clinicians and virology laboratories may consider whether early hemadsorption testing to detect myxoviruses is warranted.

Clinical profile of pediatric patients hospitalized with respiratory syncytial virus infection.

To update the clinical profile of pediatric patients hospitalized with RSV infection, we retrospectively reviewed the records of 246 children (male:female ratio 1.44:1) admitted during one season to a tertiary-care hospital. The most common admitting diagnoses were bronchiolitis (37.4%), pneumonia (32.5%), and possible septicemia (13%). Median age was 3 months; median length of stay, three days. Twice as many minorities were admitted with RSV infection as all other admissions during the same year. Family history of asthma, while common (35%), did not affect length of stay or complications. Of the 38 (15%) patients requiring intensive care, 29 (76%) underwent ventilation. Patients with underlying cardiopulmonary disease had more complications, were more likely to require intensive care (about 50%), and had significantly longer hospital stays than others. All three patients (1.2%) who died had congenital heart disease. Common risk factors included young age, chronic cardiopulmonary disease, male sex, and possibly family history of asthma. Although the most typical clinical diagnoses remain bronchiolitis and pneumonia, a systemic illness resembling the sepsis syndrome has emerged at our institution as a significant clinical presentation.

Salmonella, Shigella, and Campylobacter: common bacterial causes of infectious diarrhea.

Salmonella, Shigella, and Campylobacter species are the most common causes of acute bacterial enteritis in the United States. These pathogens should be considered seriously in children who progress rapidly from secretory to inflammatory diarrhea syndrome or in whom diarrhea persists beyond 5 to 6 days. Furthermore, children who appear more toxic than their state of dehydration would suggest should be suspected of having an acute bacterial etiology for their diarrhea. Systemic, extraintestinal dissemination of these organisms is uncommon, with the exception of salmonella infection during the first year of life and in immunocompromised hosts. In this latter situation, culture of blood and other appropriate body fluids should be considered, along with empiric systemic antibiotic therapy. When antibiotics are warranted in patients with shigella or campylobacter infection, oral therapy is usually sufficient. Careful attention to handwashing and personal hygiene is always appropriate to prevent further spread of these organisms. The very low infectious dose of shigella infection mandates an even more compulsive attention to these latter recommendations when this organism is implicated.

Cefprozil.

Cefprozil is a new, orally bioavailable, cephalosporin with significant activity against the bacteria commonly associated with upper and lower respiratory tract infection, and skin and soft tissue infections. Its absorption and elimination dynamics suggest once- or twice-daily dosing. The low-rate of gastrointestinal and dermatologic side effects associated with cefprozil administration suggest that it may have a significant role in the management of patients with these infections. Children with pharyngitis or urinary tract infection are more appropriately treated with antibiotics having a narrower spectrum of activity. With a variety of newer cephalosporins being marketed in the early 1990s, it will be important for the clinician to examine the data from ongoing comparative clinical trials to determine which antibiotic is best for a patient with a specific infection and whether the added cost justifies its use.