Biomedical subjects
Publications and source records attributed to W L Hewitt.
A patient developed lethal suppurative thrombophlebitis and adjacent soft-tissue infection caused by Aeromonas. Potential risk factors included corticosteroid therapy and the use of warm tap water compresses at the site of intravenous catheter-related phlebitis. This case demonstrates the rapidly invasive characteristics of Aeromonas and the need for early surgical intervention in suppurative thrombophlebitis.
Osteitis pubis is a well-recognized painful inflammation involving the structures of the anterior half of the pelvic girdle, but its cause remains controversial. Biopsy and culture of the pubic bone in 3 patients with osteitis pubis after implantation of a urinary anti-incontinence device were consistent with pubic osteomyelitis which responded to antibiotic therapy. Infection was also found in almost all previously reported cases of osteitis pubis subjected to similar biopsy and culture. Bone biopsy and culture should be strongly considered before initiating frequently unsuccessful empirical therapy in patients with osteitis pubis.
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Piperacillin, a new semisynthetic penicillin, was compared with other semisynthetic penicillins, cephalosporins, and aminoglycosides by the agar dilution method against 3,600 isolates of facultative gram-negative bacilli, Bacteroides fragilis, and enterococci. At 64 mug/ml, piperacillin inhibited 90% of the isolates in each group of organisms tested except for Escherichia coli (83% inhibited by 64 mug/ml). Compared with carbenicillin, piperacillin had a 16-fold increase in activity by weight against Pseudomonas aeruginosa and the enterococcus, an 8-fold increase against Serratia marcescens, and a 4-fold increase against B. fragilis and Enterobacter species. Piperacillin was highly active against carbenicillin-resistant Klebsiella pneumoniae and inhibited many aminoglycoside-resistant organisms. Except for P. aeruginosa, the minimum bactericidal concentration of piperacillin was usually within one tube dilution of the minimum inhibitory concentration. Approximately one-third of the gram-negative bacilli were inhibited synergistically by piperacillin plus amikacin, but no synergy could be demonstrated against enterococci. Piperacillin's in vitro activity against gram-negative bacilli was similar to gentamicin's except that it also included B. fragilis, and piperacillin was decidedly superior to presently available penicillins against K. pneumoniae.
To determine if antimicrobial synergism might affect the results of treatment of gram-negative rod infections, 444 bacteremias from 1972 through 1974 were studied. On these, 173 were treated with two antibiotics to which the infecting organisms were sensitive. Clinical responses were observed in 80% of 83 cases where antibiotic activity was synergistic, as defined by a minimum inhibitory concentration (MIC) of each antibiotic in combination being one-fourth or less than the MICs of individual drugs. This response rate was significantly better than the 64% response seen in patients treated with nonsynergistic combinations (p less than 0.05). Synergism correlated with significantly better clinical responses in those patients with "rapidly fatal" and "ultimately fatal" underlying disease (p less than 0.005), neutropenia (p less than 0.001), shock (p less than 0.01) and Pseudomonas aeruginosa infections (p less than 0.05). These results suggest that the use of antibiotic combinations to treat patients with gram-negative rod bacteremia who have the poorest prognosis is clinically justified and the improved results may be related to the synergistic activity of antimicrobial agents.
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We report a radioimmunoassay for the new semisynthetic aminoglycoside netilmicin with a sensitivity of 480 pg per tube and a correlation coefficient of 0.94 between this radioimmunoassay and a microbioassay for measurement of netilmicin in serum.
Of 237 cases of gram-negative rod bacteremia observed at the UCLA Medical Center during a 12 month period, 52 (22 per cent) occurred while the patient was receiving antibiotics which inhibited the infecting organism by disc diffusion tests. One half of the plasma samples available from 42 such patients with "breakthrough" bacteremia had subinhibitory circulating antibiotic levels when cultures were positive. Sepsis documented within 72 hours of initiation of therapy was usually due to antibiotic-sensitive Esch. coli and was associated with inadequate antibiotic levels; the patient was usually treated with a penicillin or cephalosporin. The source of bacteremia was most frequently the urinary tract or the biliary tree. In contrast, sepsis occurring more than 72 hours after the administration of antibiotics was frequently caused by multiple antibiotic-resistant Esch. coli in patients treated with gentamicin in adequate dosage and was associated with leukopenia or undrained purulent collections. Therapy ultimately failed in 20 cases (48 per cent): in early "breakthrough" bacteremia, failure was associated with subinhibitory antibiotic levels, and in late "breakthrough" bacteremias with inadequate drainage or impaired host defenses.
Amikacin was used in 77 treatment courses at a dosage of >/=7.5 mg/kg every 8 h, and patients were monitored for ototoxicity by following serial audiograms, serum creatinine, and amikacin blood levels. Patients were leukopenic (58), were infected by gentamicin-resistant organisms (11), or had cystic fibrosis (8). Three patients developed tinnitus, but none had vertigo or nystagmus. Of 55 courses with pre- and post-treatment audiogram, 13 (24%) were associated with development of high-frequency hearing loss, which was usually bilateral. No patient had conversational hearing loss, and audiograms reverted to normal in three patients. Onset of cochlear damage occurred in one patient after therapy was stopped. The group with high-tone hearing loss, in comparison to the group without audiographic changes, received a larger mean total dose (24 versus 9.6 g), were treated for a longer duration (19 versus 9 days), and more frequently had previous aminoglycosides. Fifty-seven percent of patients with a "peak" serum level exceeding 32 mug/ml and 55% of patients with "trough" levels exceeding 10 mug/ml developed cochlear damage. There was no difference between the groups in age, body weight, previous cochlear damage, renal disease before or during therapy, or average daily dose. Both monitoring of blood levels and limiting duration of therapy may prevent amikacin ototoxicity.
A radioimmunoassay (RIA) has been developed using 125I-amikacin. Amikacin was iodinated by a modified BOLTON and HUNTER method. Dextran-charcoal was used to separate bound from free drug. The standard curve was linear on a logit-log plot in the range of 0.5 ng to 4 ng amikacin per tube. There was no cross-reactivity of amikacin antisera to the amino-glycosides gentamicin, tobramycin, netilmicin, and sisomicin but a 70% cross-reaction was observed with kanamycin, the compound from which amikacin is synthetically derived. Correlation of the RIA with a microbioassay for the determination of serum amikacin levels in 18 patient samples was excellent (r = 0.94). This new RIA technique is more sensitive, rapid, versatile, and less costly than the RIA using 3H-amikacin, and is far more sensitive and faster than microbioassay.
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Three aminoglycoside antibiotics and two penicillins were compared for their in vitro activity against 60 isolates of Serratia, Pseudomonas, Proteus mirabilis, and indole-positive Proteus sp. Testing was done by the agar dilution method using Mueller-Hinton broth solidified with 1.5% agar. The activity of amikacin, aminodeoxybutirosin, and gentamicin against Proteus and Pseudomonas, as related to their peak blood levels, showed no significant differences. Amikacin was the most active against Serratia marcescens. Results using Mueller-Hinton media in broth dilution tests correlated with the agar dilution method except for Pseudomonas aeruginosa. The minimal inhibitory concentration for aminoglycosides in agar was considerably greater than the minimal inhibitory concentration in Mueller-Hinton broth, and the disparity was related to the higher divalent cation concentration of agar. BL-P1654 and carbenicillin were similar except that carbenicillin was much more active against indole-positive Proteus sp. Additionally, the ratio of bactericidal to bacteriostatic concentrations of BL-P1654 was considerably greater than for carbenicillin.
The acetylating radioenzymatic assay of aminoglycosides was modified by using [(3)H]acetyl coenzyme A as cosubstrate. This modification reduces the cost of the method by at least one-half without sacrificing rapidity or accuracy.
Gentamicin blood levels were monitored in 86 patients. Twenty-one patients had valley levels over 2 mug/ml and 36% of these patients developed abnormal serum creatinine or a further rise in creatinine. No patient had a rise in creatinine without a valley level over 2. The peak levels in patients with valleys over 2 were above 10 mug/ml in only one case, whereas four patients had peaks over 10 mug/ml without nephrotoxicity. The mean peak blood levels in patients with a normal creatinine were dose related. An initial dose of 2.0, 1.5, and 1.3 or less mpk (mg/kg) yielded mean peak blood levels of 5.2, 4.7, and 3.7, respectively. To assure an initial peak blood level over 4 mug/ml a loading dose of 2 mpk was required. A rise in peak and valley levels during therapy appeared dose related, being observed in all patients treated with 4.5 mpk daily but not in those receiving 3.0 mpk daily. A radioenzymatic assay was used to validate the standard agar diffusion assay method. The results from the two assays were statistically identical. Valley blood levels of gentamicin may be useful for predicting accumulation of gentamicin which in turn may be correlated with early renal impairment before potentially toxic serum levels of gentamicin develop.
Gentamicin is an aminoglycoside antibiotic widely used to treat gram-negative bacillary infections. Because it has a low therapeutic index, monitoring of serum levels may help to insure adequacy of dosage and avoid toxicity. Microbiological assays are relatively slow and can be complicated by the presence of other antimicrobials. Radioimmunoassay (RIA) and acetylating radio-enzymatic assay (ARA) are new methods for gentamicin assay which offer the following advantages: rapidity (less than 3 hours); no interference by other antibiotics; RIA is extremely sensitive and ARA is versatile (being useful in the measurement of other aminoglycosides). Correlation coefficients determined by linear regression analysis of assays on 36 patient samples performed in duplicate on 2 different days demonstrated no significant difference in measurement of gentamicin by each of the methods. Factors such as numbers of specimens, cost, and time involved will affect the decision of the method to be applied in individual laboratories.
Untoward clinical effects in man of drugs or chemicals as food residues might occur from direct pharmacological action, stimulation of hypersensitivity, or effects on cell regulatory processes. Antimicrobial residues might also influence the normal bacterial microflora of the skin, mucous membranes, and gastromintestinal tract. No direct evidence exists to incriminate antimicrobial drug food residues in any of these events. The permissible residues of antimicrobial substances are so low and the assay procedures for detecting them so sensitive that adequate surveillance should preclude harmful effects in man from these agents. Problems still remain with respect to potential carcinogenicity of drugs and chemicals as food residues.
Infections with Pseudomonas aeruginosa and Serratia marcescens are often difficult to treat because of the narrow therapeutic ratio of available antimicrobials. Synergistic inhibitory and bactericidal activity for gentamicin and carbenicillin against P. aeruginosa has been documented in vitro. The purpose of this study was to compare 4 methods of determining in vitro synergism between several aminoglycosides and penicillins. The agar dilution method using an inoculum replicator was employed, and a drug combination showing inhibition equal to or less than one-fourth of the individual minimal inhibitory concentrations was termed synergistic. Combinations using amikacin and BL-P1654 showed synergism against a greater per cent of strains of P. aeruginosa and S. marcescens than combinations using gentamicin or carbenicillin. Additionally, the "checkerboard" broth dilution method using both minimal inhibitory concentration and minimal bactericidal concentration as endpoints and killing curves according to the methods of Jawetz was studied. Comparison of the results of these 4 methods showed excellent correlation, verifying the consistency of the 4 techniques for determining in vitro synergism.