Melvin I. Marks

Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.

Comparison of a β-lactam alone versus β-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis

We determined whether a β-lactam and an aminoglycoside have efficacy greater than a β-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. Study design: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. Results: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P = .034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P < .001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. Conclusion: We conclude that the combination of a β-lactam and an aminoglycoside produces a longer clinical remission than a β-lactam alone and slightly better initial improvement. (J Pediatr 1999;134:413-21)

Aerosolized ribavirin treatment of respiratory syncytial virus infection in infants hospitalized during an epidemic

Thirty-three infants wtih predisposing conditions and/or severely symptomatic with respiratory syncytial virus (RSV) infection were treated with aerosolized ribavirin during a 12-week period at Oklahoma Childrens Memorial Hospital. These patients were compared with 97 untreated patients with RSV infection hospitalized during the same epidemic. Despite preconditions which selected for a more seriously ill treatment group, patients who received ribavirin showed prompter resolution of the illness than did untreated controls. Greatest clinical improvement in treated patients occurred between the first and second days of ribavirin therapy; mean ribavirin treatment duration was 4.5 days. Ten of 22 ribavirin-treated patients continued to excrete RSV after conclusion of antiviral therapy. No adverse hematologic, renal or metabolic effects occurred with ribavirin therapy. Our experince with ribavirin therapy during a major epidemic confirms and extends the results of previous controlled evaluations demonstrating this treatment safe and effective in high risk and seriously ill infants with RSV bronchiolitis and bronchopneumonia.

Synergistic action of amphotericin B and rifampin against Rhizopus species.

A 16-year-old diabetic patient developed Rhizopus pneumonia and was initially treated with amphotericin B for 7 days. Because of clinical deterioration of the patient, rifampin was added empirically. The patient improved clinically, and lung tissue removed surgically 8 weeks later showed no fungal elements by histopathological studies or by culture. An in vitro study of amphotericin B alone and in combination with rifampin against the isolate from the patient and 11 additional isolates of Rhizopus spp. was designed. The activity of amphotericin B in the presence of rifampin (10 or 5 micrograms/ml) increased fourfold against 9 of 10 clinical and 1 of 2 environmental isolates. Amphotericin B activity in the presence of 2 micrograms of rifampin per ml increased fourfold against 6 of 10 clinical isolates and increased twofold against an additional 3 clinical isolates. Amphotericin B in the presence of 1 microgram of rifampin per ml inhibited 9 of 10 isolates at a concentration of one-half the MIC of amphotericin B alone. These findings were confirmed by dose-response curves calculated from fungal dry weight determinations of Rhizopus spp. incubated in serial dilutions of amphotericin B combined with rifampin. These observations demonstrate in vitro, and possibly in vivo, synergy between amphotericin B and rifampin against Rhizopus spp.

Oral chloramphenicol in the treatment of Haemophilus influenzae meningitis

We conducted a prospective, randomized evaluation of oral chloramphenicol administration for completion of therapy of Haemophilus influenza type b meningitis in 44 children: 21 received drug by this route after the second day of therapy, the remainder continued to receive the drug intravenously. Resolution of clinical manifestations and cerebrospinal fluid indicators of meningitis was equivalent with both routes in 43 patients. One infant failed to achieve efficacious serum concentrations by either route of administration. Paired analysis of the area under the serum concentration versus time curve in 13 patients after oral and intravenous administration indicated equivalent bioavailability. Neutropenia was the only observed drug-related toxicity and correlated with the highest observed serum concentration. We conclude that: (1) chloramphenicol can be used by the oral route to complete treatment of H. influenzae type b meningitis; (2) a dose of 75 mg/kg/day is effective and less likely than higher doses to cause neutropenia; and (3) the measurement of serum chloramphenicol concentrations is important, regardless of route of administration.

Cefuroxime versus ampicillin plus chloramphenicol in childhood bacterial meningitis: A multicenter randomized controlled trial

In a multicenter randomized trial, 107 children with bacterial meningitis were initially given either cefuroxime or ampicillin plus chloramphenicol. Patients were alternately assigned to 7- or 10-day courses of the designated antimicrobial regimen. CSF isolates included Haemophilus influenzae type b (89, of which 25% were beta-lactamase positive), Streptococcus pneumoniae, and Neisseria meningitidis. Although mean CSF bactericidal titers against Haemophilus isolates were 1:6 in each treatment group, H. influenzae was cultured from CSF in four of 39 patients receiving cefuroxime, 24 to 48 hours after initiation of therapy, compared with none of 40 patients given ampicillin plus chloramphenicol (P = 0.11). Clinical cure rates were similar (95%); one death occurred in each group. One child given cefuroxime had persistent meningitis after 5 days of therapy, and mastoiditis with secondary bacteremia developed in one on day 10. Three patients had relapse or reinfection. One patient who received cefuroxime for 10 days had a relapse of epiglottitis 17 days later, and of the patients given ampicillin plus chloramphenicol, one had a relapse of meningitis 1 week after 7 days of therapy, and bacteremia developed in one 42 days after completion of 10 days of therapy. No increase in either in-hospital complications or relapses occurred with a 7-day treatment course. Proof of the equivalence of the antibiotic regimens and the efficacy of 7-day courses of treatment, as well as the consequences of delayed CSF sterilization, will require additional investigation.

Nosocomial infantile gastroenteritis associated with minirotavirus and calicivirus

A prospective study was carried out to determine the epidemiology and etiology of acute gastroenteritis on the general infant ward of The Montreal Childrens Hospital in the late fall of 1976. Diarrhea occurred in 41 of 165 infants (25%), with probable nosocomial acquisition in 26 patients. Two infants each had two episodes of diarrhea, and one had three. A putative pathogen was found in 31 of 45 case episodes (69%). Virus-like particles were present in 28 of 45 patients, and in 24 of 74 asymptomatic room contacts. Particles belonging to six morphologic classes were identified: adenovirus, rotavirus, minirotavirus, calicivirus, picorna-parvovirus, and coronavirus. More than one agent was identified in 12 infants with diarrhea and in five asymptomatic room contacts. No wardwide etiologic pattern was evident, but minirotavirus or calicivirus or both were associated with diarrhea in 20 patients, accompanied by vomiting in 15 of these infants. Moreover, spread of individual agents was almost entirely limited to minirotavirus and calicivirus, with diarrhea in six of ten, and four of seven, virus positive room contacts, respectively. These viruses were also identified in stools from 12 infants without diarrhea, seven of whom had repeated vomiting. Data support the etiologic role of minirotavirus and calicivirus in diarrhea or vomiting or both in hospitalized infants.

In vitro activity of BMY-28142 against pediatric pathogens, including isolates from cystic fibrosis sputum.

The antibacterial activity of BMY-28142, a new aminothiazole cephalosporin, was measured by standardized broth microdilution and agar dilution methods against 450 gram-positive and gram-negative bacteria isolated from pediatric infections, including acute pulmonary exacerbations of cystic fibrosis. BMY-28142 activity was compared with that of aminoglycosides, beta-lactams, chloramphenicol, trimethoprim-sulfamethoxazole, vancomycin, and clindamycin. The activity of BMY-28142 in combination with other antimicrobial agents against Pseudomonas aeruginosa was also determined. Furthermore, the effects of inoculum and pH on BMY-28142 activity were evaluated. BMY-21842 was active against most of the gram-positive and gram-negative isolates, with the exception of methicillin-resistant Staphylococcus aureus and Pseudomonas cepacia. The combination of BMY-28142 with tobramycin was often synergistic, and combinations of BMY-28142 with either polymyxin B or imipenem were usually antagonistic. BMY-28142 antibacterial activity could be adversely affected at extremes of medium pH and by high inoculum densities.

Soft-Tissue Infections Caused by Mycobacterium fortuitum Complex Following Penetrating Injury

Soft-tissue infections caused by rapidly growing mycobacteria may follow penetrating trauma. We present four immunologically normal patients in whom soft-tissue infections with Mycobacterium fortuitum developed after they stepped on nails. Their presentations were clinically indistinguishable from puncture wound infections caused by Pseudomonas aeruginosa and Staphylococcus aureus. The acid-fast organisms grew on standard bacteriologic media within three to five days. Speciation and antimicrobial susceptibility testing was performed. The primary mode of therapy was surgical; adjunctive antimicrobial therapy is recommended only for extensive or chronic infections and in immunocompromised hosts. All four of our patients had good outcomes after therapy.

Antimicrobial susceptibility testing of Streptococcus pneumoniae by micro-broth dilution.

Thirty-three clinical isolates of Streptococcus pneumoniae were tested for susceptibility to penicillin and ampicillin by a standard agar dilution method. Results were compared to those obtained using a micro-broth dilution technique in which Mueller-Hinton broth was supplemented with 5% difibrinated whole sheep blood. Among the 33 strains, 2 were resistant (minimal inhibitory concentration, 8 micrograms/ml), 10 were relatively resistant (minimal inhibitory concentration, 0.12 to 0.5 micrograms/ml), and 20 were susceptible (minimal inhibitory concentration, less than or equal to 0.06 micrograms/ml) to penicillin by both methods. Only one stain showed a two-dilutional-step difference by micro-broth and agar dilution testing resulting in categorization as relatively resistant by the former method but susceptible by the latter. A 1-microgram oxacillin disk correctly identified 11 of the 12 resistant strains. The micro-broth dilution technique is a reliable, simple method for penicillin or ampicillin susceptibility testing of pneumococci and economically feasibile to perform manually or with a semiautomated system.