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Biomedical subjects

S A Lerner

Publications and source records attributed to S A Lerner.

At least 55 records · Page 3Linked to original sources
PubMed1986

Comparative study of ototoxicity and nephrotoxicity in patients randomly assigned to treatment with amikacin or gentamicin.

Fifty-four patients treated with gentamicin and 52 patients treated with amikacin were evaluated for nephrotoxicity and ototoxicity in a prospective, randomized, blinded comparative trail. According to our definition of nephrotoxicity (an increase in serum creatinine levels to at least 50 percent and 0.5 mg/dl above the baseline value), nephrotoxicity occurred in eight (15 percent) of the patients who were treated with gentamicin and none of the patients who were treated with amikacin (p = 0.006). Using several other definitions of nephrotoxicity, the differences in incidence between the treatment arms were not significant. Nephrotoxicity appeared to be associated with impaired baseline renal function, greater age, and the presence of bacteremia. Ototoxicity occurred in six (11 percent) of the 54 gentamicin-treated patients; auditory toxicity occurred in three patients, and toxic changes were observed in three of the 33 patients who could also be evaluated for vestibular toxicity. Similarly, ototoxicity was observed in seven (13 percent) of the 52 amikacin-treated patients; auditory toxicity occurred in four patients, and of the 34 patients who could also be evaluated for vestibular toxicity, three exhibited vestibular toxicity without auditory toxicity are one experienced vestibular effects in addition to those affecting the cochlea. We observed a modest association of ototoxicity with nephrotoxicity and with an elevated mean trough aminoglycoside serum level. The results of this study indicate that amikacin may be less nephrotoxic than gentamicin in humans; however, the broad applicability of this finding to other patient populations is uncertain.

Adolescent↗
PubMed1986

Mechanisms of action of chloroalanyl antibacterial peptides. Identification of the intracellular enzymes inactivated on treatment of Escherichia coli JSR-O with the dipeptide beta Cl-LAla-beta Cl-LAla.

The dipeptide beta Cl-LAla-beta Cl-LAla is an antibacterial agent designed to utilize bacterial peptide transport for intracellular delivery of the alanine racemase inactivator beta Cl-LAla. The minimum inhibitory concentrations (MICs) for the peptide against Gram-negative species grown on enriched agar medium range from 1.56 to 12.5 micrograms/ml; MICs are increased to greater than 100 micrograms/ml when D-alanine is included in the medium, indicating that alanine racemase is, in fact, inhibited in sensitive species. When susceptible Gram-negative cells are grown on a minimal medium, D-alanine supplementation alone does not increase the MICs for beta Cl-LAla-beta Cl-LAla, but complete protection is afforded by supplementation with D-alanine, L-valine, L-leucine, and L-isoleucine. In liquid culture, the peptide is: bactericidal and lytic against Escherichia coli JSR-O growing in enriched medium or in minimal medium supplemented with the branched-chain amino acids; only inhibitory against these cells growing in minimal medium supplemented with D-alanine; and ineffective against these cells in minimal medium containing the branched-chain amino acids plus D-alanine. Cells exposed to beta Cl-LAla-beta Cl-LAla (with the protection of the four amino acids) have specific activities of both alanine racemase and transaminase B that are lower than those of cultures not treated with the peptide. Finally, E. coli JSR-O alanine racemase experiences time-dependent loss of activity when exposed to the dipeptide in the presence of aminopeptidases; the dipeptide alone is not an inactivator of the racemase in vitro. These results suggest the following mechanism of action for beta Cl-LAla-beta Cl-LAla: transport of the dipeptide into the cell; intracellular hydrolysis to give accumulation of beta Cl-LAla; and subsequent inactivation of targeted enzymes. Whether inactivation of the racemase or of the transaminase determines the pathophysiologic effects of the peptide depends on the composition of the growth medium.

Alanine Racemase↗
PubMed1986

Chloroalanyl antibiotic peptides: antagonism of their antimicrobial effects by L-alanine and L-alanyl peptides in gram-negative bacteria.

A large number of structurally diverse di- and tripeptides containing the alanine racemase inactivator beta-chloro-L-alanine (beta-Cl-LAla) have been synthesized, and their antibacterial properties in vitro have been evaluated. The dipeptides 1, 3-6, and 8-17 and the tripeptide 20 are all broad-spectrum antibacterial agents with considerable potency against both Gram-positive and Gram-negative species, but none of these peptides improves dramatically on the antibiotic efficacy of the previously described beta-Cl-LAla-beta-Cl-LAla, 9 (Cheung, K. S.; Wasserman, S. A.; Dudek, E.; Lerner, S. A.; Johnston, M. J. Med. Chem. 1983, 26, 1733). Gram-negative microorganisms, such as Escherichia coli, Hemophilus influenzae, Shigella flexneri, and Enterobacter species are consistently resistant to any haloalanyl peptide containing an alanyl residue, such as the dipeptide LAla-beta-Cl-LAla (2) and the tripeptides LMet-LAla-beta-Cl-LAla (7), LAla-LAla-beta-Cl-LAla (18), and LVal-LAla-beta-Cl-LAla (19). Correspondingly, these same organisms are protected from the bactericidal effects of 9 by supplementation of the growth medium with LAla or LAla-LAla. Escherichia coli JSR-O exposed to 9, but protected from lysis by sucrose stabilization, has only about 10% the normal level of intracellular alanine racemase activity. But when these cells are cultured in the presence of 9 with LAla supplementation, or in the presence of 2 with no supplementation, the alanine racemase levels are only about 20-30% below control values. These findings suggest that the resistance of Gram-negative species to chloroalanyl peptides containing alanyl units arises from the ability of LAla to protect the targeted racemase from inactivation by beta-Cl-LAla in vivo, an event which otherwise leads to cell death and lysis. Inactivation of alanine racemase in Gram-positive organisms appears not to be the cellular event that confers sensitivity of these species to a haloalanyl peptide.

Alanine↗
PubMed1986

A model for predicting nephrotoxicity in patients treated with aminoglycosides.

We have previously identified risk factors for nephrotoxicity in 204 patients receiving aminoglycosides. We added data on an additional 134 patients from the University of Chicago who were treated for longer periods (13.1 +/- 9.4 days) to determine if duration of therapy was also a risk factor. In the combined populations, nephrotoxicity developed in 59 (17.5%) of 338 patients, and duration of therapy was the factor most strongly associated with nephrotoxicity (P less than .0001). A new predictive model was developed that was then tested prospectively on 175 consecutive medical and surgical patients who had plasma levels of aminoglycoside measured. The new model accurately identified 14 of 15 patients with nephrotoxicity (sensitivity = 93%) and 106 of 160 without nephrotoxicity (specificity = 66%). A bedside scoring system accurately identified high-risk and low-risk patients. We believe these data add to the understanding of the clinical correlates of aminoglycoside nephrotoxicity and aid in the identification of high-risk patients.

Aminoglycosides↗
PubMed1986

Auxotypes, penicillin susceptibility, and serogroups of Neisseria gonorrhoeae from disseminated and uncomplicated infections.

We examined auxotypes, penicillin susceptibility, and outer membrane serogroups of 137 strains of Neisseria gonorrhoeae isolated from patients with disseminated gonococcal infection (DGI) and 137 control strains from patients with uncomplicated gonorrhea. We analyzed separately the data for strains isolated from systemic sites in patients with DGI and for strains from local sites in patients with the clinical syndrome of DGI (SDGI) who had negative systemic cultures. We found the nutritional requirement for arginine, hypoxanthine, and uracil (AHU auxotype) significantly more often among DGI strains than among SDGI strains. By using commercially available serogrouping reagents to detect outer membrane protein antigens, we found that regardless of strain auxotype, dissemination correlated best with the presence of protein IA antigens. We did not find that gonococci isolated from DGI are highly susceptible to penicillin. Susceptibility to low concentrations of penicillin correlated only with the AHU requirement, not with serogroup or isolation from a patient with DGI or SDGI.

Agglutination Tests↗
PubMed1986

Emergence of resistance to imipenem during therapy for Pseudomonas aeruginosa infections.

We studied the mechanism of resistance to imipenem in three clinical isolates of Pseudomonas aeruginosa. Two of these isolates arose from imipenem-susceptible strains isolated during therapy with imipenem and were associated with treatment failure. One of these two strains had previously been broadly resistant to beta-lactams; the second acquired resistance to imipenem alone. One isolate of the third strain was resistant to imipenem but susceptible to other antipseudomonal beta-lactams. No isolate contained beta-lactamase activity capable of hydrolyzing imipenem at a detectable rate. Studies of the penicillin-binding proteins of all isolates revealed no differences in the number of proteins, molecular weight of, affinity for penicillin, or affinity for imipenem in any isolate. In each case the resistant isolate lacked one or more outer membrane proteins that were present in a susceptible isolate of the same strain. The observed alterations in outer membrane proteins may be associated with diminished permeability of the bacterial outer membrane to imipenem and may be the major factor responsible for resistance in these isolates.

Adult↗
PubMed1986

High-level amikacin resistance in Escherichia coli due to phosphorylation and impaired aminoglycoside uptake.

Plasmid pMP1-1 in Escherichia coli L-0 encodes aminoglycoside (AG) 3'-phosphotransferase II [APH(3')-II]. This enzyme modifies and confers high-level resistance to kanamycin. Although amikacin is a substrate for APH(3')-II, strain L-0(pMP1-1) is susceptible to amikacin. Plasmid pMP1-2 is a spontaneous mutant of pMP1-1 which determines increased APH(3')-II activity for amikacin, apparently as a result of an increase in the copy number of the plasmid. From amikacin-susceptible, gentamicin-susceptible transformants and transconjugants that bear the APH(3')-II gene on plasmid pMP1-1 or pMP1-2 or cloned into multicopy plasmid pBR322, we selected spontaneous mutants at concentrations of amikacin or gentamicin that were two to four times higher than the MICs of these antibiotics. In each case, whether they were selected by using amikacin or gentamicin, the mutants exhibited modest (two- to eightfold) increases in the MIC of gentamicin and major (64- to 128-fold) increases in the MIC of amikacin. Using these laboratory strains of E. coli, we examined the effects on AG susceptibility of the interaction of AG-modifying enzyme activity and generalized AG uptake. Increasing the level of activity of an AG phosphotransferase in these strains lowered their susceptibility to AGs which were substrates for which the enzyme had low Kms. However, an increase in AG-modifying activity alone did not result in large increases in the MICs for poor substrates of the enzyme. In strains which lacked AG-modifying enzymes, a decrease in the rate of AG uptake increased the MICs modestly for a broad spectrum of AGs. When a strain bore the phosphotransferase, a decrease in generalized AG uptake could raise the MIC further, not only for low-Km substrates, but even for AG substrates for which the enzyme had high Kms. Thus, increased modifying activity, together with a diminished rate of uptake, could produce even higher MICs for poor AG substrates.

Amikacin↗
PubMed1985

Lack of accumulation of exogenous adenylyl dihydrostreptomycin by whole cells or spheroplasts of Escherichia coli.

Accumulation of purified adenylylated dihydrostreptomycin (DHS-AMP) was examined in two strains of Escherichia coli. E. coli JSRO-N was plasmid free and aminoglycoside (AG) susceptible; E. coli JSRO-N(pSAD1) contained a plasmid-encoded AG adenylyltransferase which modifies DHS and streptomycin and confers resistance to both of these drugs. Although both whole cells and spheroplasts of JSRO-N accumulated free DHS, we were not able to demonstrate uptake of DHS-AMP by this strain. Whole cells and spheroplasts of JSRO-N(pSAD1) accumulated DHS at a much slower rate than that observed in JSRO-N. This was presumably due to the activity of the adenylyltransferase in JSRO-N(pSAD1). However, this low rate of accumulation of DHS was still higher than the uptake of DHS-AMP by either JSRO-N or JSRO-N(pSAD1). Thus, the rate of accumulation of DHS-AMP was even lower than that of DHS during the slow, initial, energy-dependent phase of AG uptake seen in JSRO-N(pSAD1). We also found that when either JSRO-N or JSRO-N(pSAD1) was incubated with barely inhibitory or subinhibitory concentrations of DHS, rapid uptake of DHS could be stimulated by the addition of an inhibitory concentration of another AG, such as amikacin. Uptake of DHS-AMP could not be similarly enhanced by the addition of amikacin. Our results indicate that DHS-AMP is not accumulated by whole cells or spheroplasts of E. coli. These results are consistent with the postulated intracellular location of AG-modifying enzymes.

Chromatography, Thin Layer↗
PubMed1985

Correlation of aminoglycoside resistance with the KmS and Vmax/Km ratios of enzymatic modification of aminoglycosides by 2''-O-nucleotidyltransferase.

A clinical isolate, Serratia marcescens 75, was found to be susceptible to netilmicin and yet had a high level of aminoglycoside 2''-O-nucleotidyltransferase activity for netilmicin. Kinetic studies of the partially purified enzyme revealed substrate inhibition for gentamicin and tobramycin at concentrations greater than 10(-2) mM, but this was not observed for netilmicin. The MICs of the aminoglycosides tested exhibited a good inverse correlation with the Km values for the enzyme and a direct correlation with the Vmax/Km ratios of the enzyme.

Aminoglycosides↗
PubMed1985

Emergence of resistance to beta-lactam antibiotics in Pseudomonas aeruginosa during treatment with new beta-lactams.

In 12 patients treated with cefsulodin for Pseudomonas aeruginosa infections, resistance to cefsulodin developed in the infecting strains of two patients who failed to improve clinically. In both cases, cross-resistance also appeared for a broad spectrum of new antipseudomonal beta-lactams, except imipenem. The resistant isolate from one patient had a new constitutive beta-lactamase for cephalothin which also had modest activity for cefsulodin, ceftazidime, and carbenicillin. Furthermore, all of the non-hydrolyzed beta-lactams appeared to be bound by a beta-lactamase in this isolate. The origin and role in beta-lactam resistance of the observed beta-lactamase activity are obscure. The resistant isolate from the other patient had no demonstrable beta-lactamase activity that could account for the beta-lactam resistance. In five patients treated with imipenem for P. aeruginosa infections, resistance to imipenem developed in the strains of two patients who failed to improve clinically. The strain from one patient was already resistant to all other antipseudomonal beta-lactams before imipenem therapy. The initial strain from the other patient was broadly susceptible, and it developed resistance only to imipenem. Prior to imipenem therapy, another patient, who had P. aeruginosa endocarditis, had isolates from blood with three different susceptibility patterns: susceptible to all antipseudomonal beta-lactams, resistant to all but imipenem, and resistant to imipenem alone. There was no demonstrable beta-lactamase activity to account for imipenem resistance in any of the isolates in these patients. None of the resistant P. aeruginosa isolates had a change in penicillin-binding proteins from those of their susceptible counterparts that might explain the development of resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Stability and cost analysis of clindamycin-gentamicin admixtures given every eight hours.

Stability and costs of a mixture of clindamycin and gentamicin in a single carrier solution for every-eight-hour i.v. administration were analyzed. Duplicate solutions containing clindamycin 900 mg (as the phosphate salt) and gentamicin 100 mg (as the sulfate salt) in 5% dextrose injection 150 mL in flexible plastic containers were prepared. Samples withdrawn at 0-24 hours were visually inspected and assayed for content of both drugs. Clindamycin concentrations were determined by high-performance liquid chromatography and gentamicin concentrations by fluorescence-polarization immunoassay. Preparation and administration times were measured in two trials to determine cost differences between every-eight-hour administration of the two-antibiotic mixture and separate administration of the two drugs (four daily doses of clindamycin and three of gentamicin). No precipitate was seen. Concentrations of both drugs after 24 hours were greater than 90% of initial concentrations. Total daily costs (per patient) for labor, drug, and carrier solution were $3.08 less when the two drugs were mixed and administered every eight hours. At the concentrations studied, clindamycin and gentamicin mixed together in 5% dextrose injection are stable for 24 hours. Administration of this drug mixture every eight hours is safe and less costly than separate administration of the two drugs.

Chromatography, High Pressure Liquid↗
PubMed1984

Biphasic systemic anaphylactic reaction: three illustrative cases.

We report on three patients with early mild systemic reactions triggered by administration of rabies vaccine, immunotherapy with rye grass extract, or yellow jacket sting. After appropriate treatment, these early cutaneous and respiratory symptoms improved considerably, but then flared up three and one half to four hours later. All three patients had specific IgE antibodies against their offending allergen.

Adult↗
PubMed1983

Chloralanyl and propargylglycyl dipeptides. Suicide substrate containing antibacterials.

A set of dipeptides containing the amino acid residues beta-chloroalanine and propargylglycine, which are mechanism-based inactivators of purified microbial enzymes (alanine racemase and cystathionine gamma-synthase, respectively), have been synthesized, and their antibacterial properties in vitro have been evaluated. Dipeptides containing a single beta-chloro-L-alanyl residue (e.g., 3, 5, 9, and 10) or a single L-propargylglycyl residue (e.g., 12 and 15) are potent antibacterials. The in vitro antibiotic activity of beta-chloro-L-alanine and of L-propargylglycine is increased as much as 4000-fold by incorporation of these residues into a dipeptide. Compounds that contain only a single enzyme-inactivating amino acid together with a second L-alanyl residue (3, 5, 12, and 15) have a restricted range of activity: of the species tested, only Streptococcus agalactiae, Staphylococcus aureus, and Staphylococcus epidermidis are sensitive. However, peptides that contain two suicide-substrate residues [e.g., beta-Cl-LAla-beta-Cl-LAla (8) or LppGly-LppGly (18)] are broad-spectrum antibacterials; as many as 12 different species of the 16 surveyed are sensitive. Dipeptides that contain an amino-terminal L-methionyl (9) or an L-norvalyl (10) residue and a carboxy-terminal beta-chloro-L-alanyl unit are also effective against a large number of organisms; the spectra of activity are like those seen for 8 and 18. A "mixed" dipeptide [beta-Cl-LAla-LppGly, (21)] gives apparent synergism of antibiotic action of beta-chloro-L-alanine and of L-propargylglycine when these two residues are incorporated into a single structure. Peptides of the D,D configuration (4, 6, 13, 16, and 20) and ones of L,D stereochemistry (e.g., 7) are not antibacterials. Peptides containing one (11 and 14) and two (17) D,L-propargylglycyl residues are unresolved sets of diastereomers; the mixtures of compounds are between two- and fourfold less active than the correspondingly resolved L,L dipeptides (12, 15, and 18). These findings are consistent with a mechanism of action for these antibiotics involving stereoselective processing of the peptidyl unit in vivo.

Alanine↗
PubMed1983

Characteristics of pathogenic Neisseria spp. isolated from homosexual men.

Oropharyngeal, urethral, and rectal cultures for pathogenic Neisseria spp. were collected from 815 homosexual men attending a community clinic in Chicago. Meningococci were characterized by serogrouping and antimicrobial susceptibility testing. Gonococci were auxotyped, and susceptibilities to penicillin and tetracycline were determined. Of the 815 men tested, 42.5% carried meningococci in the oropharynx. Gonococci were recovered from the urethra, rectum, and oropharynx of 18.5, 16.3, and 5.6%, respectively. Meningococci were also recovered from the urethra (6 patients) and the rectum (15 patients). Some of these isolates were identical to the isolates from the oropharynges of the same patients, whereas others were distinct from the oropharyngeal isolates by serogroup or antimicrobial susceptibilities. Serogroups B, W135, and C comprised over 90% of the meningococci. Almost 80% of the gonococcal strains required minimal inhibitory concentrations greater than 0.06 micrograms of penicillin per ml, whereas greater than 90% of the meningococci were inhibited at this concentration. Auxotyping demonstrated three major auxotypes: Zero (required none of the nutrients tested), 60%; arginine requiring, 19.4%; and proline requiring, 12.3%. Only four strains (1.2%) required arginine, hypoxanthine, and uracil.

Arginine↗
PubMed1982

Schooling behavior of tadpoles: a potential indicator of ototoxicity.

Fish and tadpoles in schools use hair cells of their lateral line system to assess their position in relation to neighbors. This suggests that pharmaceutical agents that damage hair cells in the mammalian inner ear may also alter geometry in fish and tadpole schools. We used a computer-based image analysis system to examine the effect of the ototoxic aminoglycoside antibiotic, streptomycin, on school geometry for tadpoles of the African clawed frog Xenopus laevis. Tadpoles exposed to streptomycin in the surrounding water show a general tendency toward clumping, and an increase in the distance over which they orient parallel to neighbors, compared to controls. These behavioral responses appear in 18 min or less, and are evident in some tadpoles exposed to concentrations as low as 5 micrograms/ml. Results suggest that analysis of spatial relations in tadpole schools could serve as a method for rapidly detecting ototoxic potential of agents suspected of damaging hair cells.

Animals↗
PubMed1982

Decreased susceptibility to 4'-deoxy-6'-N-methylamikacin (BB-K311) conferred by a mutant plasmid in Escherichia coli.

Escherichia coli MP6 contains a plasmid that encodes aminoglycoside 3'-phosphotransferase II, which phosphorylates kanamycin and confers high-level kanamycin resistance, Amikacin is a minor substrate of this enzyme, but MP6 is susceptible to amikacin. Strain MP10 has a spontaneous mutation in the plasmid of MP6 that increases the aminoglycoside 3'-phosphotransferase II activity not only against kanamycin but also against amikacin. This mutation is also responsible for the appearance of resistance to amikacin in MP10. Resistance to 4'-deoxy-6'-N-methylamikacin (BB-K311) by enzymatic modification has not been reported previously. As with amikacin, MP6 was susceptible to BB-K311 and its aminoglycoside 3'-phosphotransferase II did not phosphorylate this amikacin derivative appreciably. We found that the plasmid-borne mutation in MP10, however, localized by being cloned with a 3.7-megadalton HindIII fragment containing the aminoglycoside 3'-phosphotransferase II gene, resulted in increased phosphorylation of BB-K311 and resistance to it. Thus, the mutation distinguishing MP6 and MP10 has increased the activity of an existing aminoglycoside-modifying enzyme and produced new bacterial resistance to two previously minor substrates of the enzyme.

Amikacin↗