William L. Hewitt

Gentamicin Blood Levels: a Guide to Nephrotoxicity

Gentamicin blood levels were monitored in 86 patients. Twenty-one patients had valley levels over 2 μg/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 μg/ml in only one case, whereas four patients had peaks over 10 μg/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 μg/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.

Comparative efficacy and toxicity of amikacin/carbenicillin versus gentamicin/carbenicillin in leukopenic patients: A randomized prospective trail

Abstract Between July 1974 and August 1976, 157 leukopenic patients who had a neoplastic disease or bone marrow failure syndrome were assigned at random to receive either amikacin (7.5 mg/kg every 8 hours)/carbenicillin (100 mg/kg every 4 hours) or gentamicin (2 mg/kg loading, 1.5 mg/kg every 8 hours)/ carbenicillin on admission to the hospital or on completion of a previous course of antibiotic therapy. Fever and evidence suggesting gram-negative rod infection prompted initiation of therapy, and its duration was determined by the patients clinical course and culture data. A total of 155 courses of amikacin therapy and 140 courses of gentamicin therapy were given. The over-all clinical response rate was 75 per cent for both antibiotic regimens. Cure of urinary tract or soft tissue infections was observed in over 90 per cent of the cases. In gram-negative bacillemias only 15 of 23 patients (65 per cent) treated with amikacin and 10 of 17 patients (59 per cent) given gentamicin survived. Two bacteremic patients with gentamicin-resistant (but amikacin-sensitive) rods were assigned at random to receive gentamicin; they died. Improved survival in both treatment groups was associated with the use of combinations of drugs that interacted synergistically in vitro. There was no significant difference in the incidence of ototoxicity and nephrotoxicity. For patients with infections due to an organism susceptible to both amikacin and gentamicin, a regimen which incorporates carbenicillin and either drug is equally effective, but empiric use of amikacin is indicated when there is a reasonable possibility of infection due to gentamicin-resistant organisms.

Coccidioidal Meningitis: AN ANALYSIS OF THIRTY-ONE CASES AND REVIEW OF THE LITERATURE

Clinical and laboratory features of 31 patients with coccidioidal meningitis seen from January 1964 through December 1976 with follow-up through 1979 are reported and data on 114 patients from the literature reviewed. History of exposure to C. immitis, a wide age range, and, in about one third, underlying conditions are noteworthy. Dissemination to the meninges usually occurs within the first few months although diagnosis is frequently delayed. Presenting symptoms and signs of coccidioidal meningitis are varied but signs of chronic meningitis or suggestion of hydrocephalus are prominent. Evidence of acute infection is unusual even with widespread disease. Diagnosis is usually made by demonstration of coccidioidal CF antibodies in the CSF although they are not found in all patients. Some show other direct evidence of C. immitis. Special diagnostic techniques such as CAT scanning for evidence of basilar meningitis or hydrocephalus are valuable. Amphotericin B remains the drug of choice despite the need for long-term therapy and the problems with intrathecal administration. Reservoirs are only occasionally useful but shunts are frequently lifesaving despite complications. Factors associated with a bad prognosis are hydrocephalus, non-Caucasian race, or presence of an underlying disease.

Ototoxicity of Amikacin

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 μg/ml and 55% of patients with “trough” levels exceeding 10 μg/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.

Piperacillin Therapy for Serious Bacterial Infections

Abstract Piperacillin, a new semisynthetic penicillin derivative, is active against many Klebsiella pneumoniae resistant to carbenicillin and ticarcillin as well as being more active against organisms susceptible to all three antibiotics. It was evaluated as single-agent therapy in 59 patients, including 20 with septicemia. Despite the severely compromised condition of most patients (48 percent with rapidly or ultimately fatal underlying disease, 52 percent in critical or poor condition and 63 percent with renal failure), 89 percent of the patients responded favorably (infection cured or diminished) to piperacillin. Nine of 10 patients with previous aminoglycoside toxicity responded. Definite or probable side effects, usually diarrhea or hypersensitivity reactions, occurred in 12 of 59 patients but were mild and reversible. Piperacillin-resistant organisms emerged during therapy in seven patients and were associated with treatment failure in one patient and superinfection in four others. Piperacillin is effective therapy for serious infections caused by susceptible organisms, especially in patients in whom further aminoglycoside therapy may be undesirable because of renal failure or previous aminoglycoside toxicity.

Activity of Five Aminoglycoside Antibiotics In Vitro Against Gram-Negative Bacilli and Staphylococcus aureus

The in vitro susceptibility to BB-K8, butirosin, gentamicin, sisomicin, and tobramycin of seven groups of clinically significant gram-negative bacilli and Staphylococcus aureus was assessed by using the International Collaborative Study-World Health Organization criteria. The activity of gentamicin, sisomicin, and tobramycin generally paralleled each other. Sisomicin was the most potent compound by weight and usually demonstrated the most rapid rate of killing. BB-K8 and butirosin were less potent, but higher serum levels may be achieved with these agents. BB-K8 generally showed the greatest ratio between achieveable mean peak serum levels and concentrations needed to inhibit [Formula: see text] of each group of organisms tested. Additionally, BB-K8 was active against six of seven highly gentamicin-resistant strains. All of these antibiotics showed diminished activity at pH 6.4 but only gentamicin and sisomicin showed occasionally enhanced activity at pH 8.4.

Infectious osteitis pubis

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.

Comparative in vitro activity of moxalactam, cefotaxime, cefoperazone, piperacillin, and aminoglycosides against gram-negative bacilli.

The in vitro activities of four new beta-lactam antimicrobial agents (moxalactam, cefotaxime, cefoperazone, and piperacillin) and the aminoglycosides against 744 recent clinical isolates of facultative gram-negative bacilli were compared simultaneously by the agar dilution method. The major in vitro difference of these newer beta-lactam compounds appeared to be their antipseudomonal activity; cefoperazone was the most active, whereas cefotaxime had the least potency. The aminoglycosides, however, had the most effective in vitro activity on a weight basis against Pseudomonas aeruginosa.

In Vitro Studies of Piperacillin, a New Semisynthetic Penicillin

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 μg/ml, piperacillin inhibited 90% of the isolates in each group of organisms tested except for Escherichia coli (83% inhibited by 64 μg/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. Piperacillins in vitro activity against gram-negative bacilli was similar to gentamicins except that it also included B. fragilis, and piperacillin was decidedly superior to presently available penicillins against K. pneumoniae.

Combined use of gentamicin and carbenicillin.

Abstract High concentrations of carbenicillin can decrease the antibacterial activity of gentamicin in vitro over a period of time. Experiments in dogs and humans with normal renal function show th...