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R A Bonomo

Publications and source records attributed to R A Bonomo.

35 records · Page 2Linked to original sources
PubMed1997

Oral antibiotics in the nineties: new drugs and new challenges in primary care.

The primary care physician is faced with a bewildering array of new oral antimicrobials to treat common infections. These agents promise to be extremely effective as replacements for time-honored drugs, as prophylaxis, and for the treatment of infections previously requiring prolonged intravenous therapy. The overuse of the newer macrolides, quinolones, and beta-lactam beta-lactamase inhibitors may prove to be ecologically and economically costly. It is feared that the selective pressure from these broad spectrum agents may burden society with an even greater problem of multiply resistant community-acquired pathogens. The specific therapeutic and economic advantages and disadvantages of each class should be considered and the decision to employ these agents should be highly individualized.

Administration, Oral↗
PubMed1997

OHIO-1 beta-lactamase mutants: Asp179Gly mutation confers resistance to ceftazidime.

The Asp179Gly mutant of the OHIO-1 beta-lactamase, an SHV enzyme, was constructed to investigate the effect of disruption of the omega loop on beta-lactamase activity in this class A enzyme. In Escherichia coli DH5 alpha the strain possessing the Asp179Gly mutation of the OHIO-1 beta-lactamase demonstrated increased susceptibility to all beta-lactams except ceftazidime and ceftriaxone. The minimum inhibitory concentrations for ceftazidime and ceftriaxone increased from 0.25 and 0.015 microgram/ml to 4.0 and .25 micrograms/ ml respectively. For ceftazidime, a substrate not hydrolyzed by the wild-type enzyme (K(m) > or = 500 microM), the K(m) of the Asp179Gly mutant beta-lactamase was measured to be 7 microM and the Vmax was 0.13 microM/min. The minimum inhibitory concentrations, K(m), and Vmax for all other beta-lactams decreased. Our analysis of this OHIO-1 beta-lactamase mutant suggests that disruption of the salt bridge in the omega loop by substitution of a glycine at position 179 markedly decreases the catalytic efficiency of the enzyme.

Aspartic Acid↗
PubMed1997

Tazobactam is a potent inactivator of selected inhibitor-resistant class A beta-lactamases.

The beta-lactam beta-lactamase inhibitor combinations (ampicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate and piperacillin/tazobactam) were tested against selected inhibitor-resistant class A beta-lactamases of the TEM and OHIO-1 varieties. Minimum inhibitor concentrations (MIC) revealed that the Escherichia coli DH5 alpha transconjugate strains that possessed the OHIO-1 beta-lactamase, Met69Ile mutant of the OHIO-1 beta-lactamase, TEM-30 (Arg244Ser) and TEM-31 (Arg244Cys) beta-lactamase were most susceptible to piperacillin and piperacillin/tazobactam. Kinetic experiments with each beta-lactamase demonstrated that tazobactam was 10-25-fold more potent than clavulanate or sulbactam against TEM-30 and TEM-31 beta-lactamase. Tazobactam was also as effective as clavulanate against the Met69Ile mutant of the OHIO-1 beta-lactamase. Among the clinically available beta-lactams and beta-lactamase inhibitors, piperacillin/tazobactam appears to be the most potent combination against selected inhibitor-resistant strains of TEM and OHIO-1 beta-lactamase.

Ampicillin↗
PubMed1997

Risk factors associated with permanent access-site infections in chronic hemodialysis patients.

OBJECTIVE: To determine the epidemiological risk factors associated with permanent access-site (PAS) infection in a population of chronic hemodialysis patients. DESIGN: Retrospective cohort analysis. SETTING: Hemodialysis unit of a 400-bed Department of Veterans' Affairs hospital. RESULTS: A cohort of 94 males (1,316 patient months) was studied. Fifty-one PAS infections in 31 patients were observed. Six patients had two PAS infections, four patients had three infections, and two patients had four infections. Twenty-nine of the 31 patients with PAS infections were bacteremic at least once. Univariate analysis identified seven factors significantly associated with PAS infection in this population: location of PAS other than forearm, type of vascular access (polytetrafluoroethylene [PTFE] versus endogenous arteriovenous [AV] fistula), limited ambulatory status, residence in a nursing home, bacterial infection at a distant site, number of access-site revisions, and number of hospitalizations. In a logistic regression analysis, only graft type and number of PTFE graft revisions were associated independently with PAS infection. The odds ratio for PAS infection in PTFE grafts compared to endogenous AV fistula was 7.8; the odds ratio for PAS infection with each PTFE graft revision was 1.5. CONCLUSIONS: PAS infections were associated independently with the type of graft and the number of PTFE graft surgical revisions.

Adult↗
PubMed1997

Pityriasis rubra pilaris: an unusual cutaneous complication of AIDS.

Pityriasis rubra pilaris is an uncommon hyperkeratotic, papulosquamous disorder that has been reported in patients infected by HIV. We recount a case of pityriasis rubra pilaris in an HIV-seropositive man. A 36-year-old man with a history of ulcerative colitis and recurrent otitis externa had diffuse psoriaform erythroderma. He was treated initially with methotrexate and isoretinoin without clinical improvement. Skin examination showed large, erythematous, orange, scaly patches on the upper extremities and thickening of the nail beds. The palms and soles were hyperkeratotic. Skin biopsy revealed changes that were consistent with pityriasis rubra pilaris. Six months before the onset of symptoms, results of an enzyme-linked immunosorbent assay (ELISA) and Western Blot assay for HIV were negative. Six months after symptoms, results of repeat enzyme-linked immunosorbent assay and Western blots for HIV were positive (CD4+ T-cell count = 200 cells/ mm3). Clinical course had been complicated by episodes of Staphylococcus aureus bacteremia, mucocutaneous candidiasis, and development of localized squamous cell carcinoma of the skin. The increased severity of pityriasis rubra pilaris should prompt clinicians to consider coinfection with HIV in patients who have disease that is refractory to treatment. Clinicians also should remain vigilant for the development of squamous cell carcinoma.

AIDS-Related Opportunistic Infections↗
PubMed1997

Construction and characterization of an OHIO-1 beta-lactamase bearing Met69Ile and Gly238Ser mutations.

Amino acid changes that influence activity and resistance to beta-lactams and beta-lactamase inhibitors were explored by constructing the Gly238Ser and Met69Ile-Gly238Ser mutants of the OHIO-1 beta-lactamase, a class A enzyme of the SHV family. The Km values of cefotaxime and ceftazidime for OHIO-1 and Met69Ile beta-lactamases were > or = 500 microM. The Km of cefotaxime for the Gly238Ser beta-lactamase was 26 microM, and that of ceftazidime was 105 microM. The Km of cefotaxime for the Met69Ile-Gly238Ser beta-lactamase was 292 microM, and that of ceftazidime was 392 microM. For the beta-lactamase inhibitors clavulanate and sulbactam, the apparent Ki values for the Met69Ile-Gly238Ser enzyme were 0.03 and 0.15 microM, respectively. Relative Vmax values indicate that the Met69Ile-Gly238Ser mutant of the OHIO-1 beta-lactamase possesses cephalosporinase activity similar to that of the Gly238Ser mutant but diminished penicillinase activity. In an Escherichia coli DH5alpha strain that possesses a Met69Ile beta-lactamase of the OHIO-1 family, the added Gly238Ser mutation resulted in a phenotype with qualities that confer resistance to expanded-spectrum cephalosporins and, to a lesser extent, beta-lactamase inhibitors.

Cephalosporin Resistance↗
PubMed1996

Molecular genetics of resistance to both ceftazidime and beta-lactam-beta-lactamase inhibitor combinations in Klebsiella pneumoniae and in vivo response to beta-lactam therapy.

The molecular basis of ceftazidime resistance in 2 isolates of Klebsiella pneumoniae was studied. The first (21300) expressed resistance to ceftazidime and piperacillin-tazobactam. The second (26139) expressed resistance to ceftazidime but remained susceptible to piperacillin-tazobactam. The 2 strains harbored similar large plasmids that hybridized to TEM- and SHV-related beta-lactamase genes. An Escherichia coli strain harboring the plasmid conferring resistance to both compounds (pLRM7) produced beta-lactamases of pI 5.9 (TEM-6) and pI 7.6 (SHV-1). E. coli harboring the other plasmid (pLRM8) expressed only the TEM enzyme because of insertion of IS15 within blaSHV-1. In vivo studies suggested that resistance to beta-lactam-beta-lactamase inhibitor combinations conferred by pLRM7 will be clinically important. Clinical resistance to both extended-spectrum cephalosporins and beta-lactam-beta-lactamase inhibitor combinations is achievable via the production of two enzymes, with only one possessing an extended spectrum of activity.

Abdominal Abscess↗
PubMed1995

Complementary roles of mutations at positions 69 and 242 in a class A beta-lactamase.

Analysis of the three-dimensional structure of class A beta-lactamases suggests that deformation of the substrate binding site can be produced by changes in the hydrophobicity of residue 69 behind the beta-sheet and by outward movement of the B3 beta-strand by introduction of a non-glycine residue at position 242 on the B4 beta-strand. By site-directed mutagenesis Met69-IleGly242-Cys, a double mutant, of the OHIO-1 beta-lactamase, was constructed. The minimum inhibitory concentrations (MICs) of the double mutant compared with the wild type and each single mutant revealed an increased susceptibility to beta-lactams. Met69-IleGly242Cys hydrolyzed cephaloridine (Km = 213 microM) but had Km > 500 microM for other beta-lactams tested including cefotaxime, and demonstrated a higher apparent Ki for inhibitors (clavulanate Ki = 500 microM sulbactam = 434 microM, and tazobactam = 70 microM). In a competition experiment with cephaloridine, the apparent Ki values for penicillin and cefotaxime remained low, 21 microM and 0.7 microM, respectively. Since Ile is twice as hydrophobic as Met, the Met69-Ile mutation may result in partial collapse of the oxyanion hole. This would also increase the distance between Arg-244 and the carboxyl of clavulanic acid. The Gly242-Cys mutation opens the lower portion of the active site to bulky R groups of cephalosporins. Although these two mutations result in a catalytically impaired enzyme, they can be used to model the complementary role of two distinct residues, neither of which interacts directly with beta-lactam substrates or inhibitors.

Anti-Bacterial Agents↗
PubMed1995

beta-Lactamase mutations far from the active site influence inhibitor binding.

Analysis of the three dimensional structure of the class A beta-lactamases shows that Arg-244, a spatially conserved residue important for inactivation by clavulanic acid, is held in place by a hydrogen (H) bond from the residue at 276. An Asn276-Gly mutant of OHIO-1, an SHV family class A enzyme, was constructed to investigate the importance of that interaction. Compared to a strain expressing the wild type enzyme, OHIO-1, the MIC of the Asn276-Gly mutant strain was more resistant to clavulanate (0.25 vs. 2.0 micrograms/ml) in the presence of ampicillin (16 micrograms/ml) but was as susceptible to sulbactam or tazobactam plus ampicillin as the OHIO-1 bearing strain. No difference in MICs was observed when other beta-lactams were tested. Consistent with the susceptibility test results, the apparent Ki of clavulanate for the Asn276-Gly enzyme (4.5 microM) was 10-fold greater than OHIO-1 (0.4 microM). For sulbactam and tazobactam the apparent Ki decreased for Asn276-Gly enzyme (1.0 and 0.1 micrograms/ml, respectively) compared to the wild-type parent (17 and 0.7 micrograms/ml, respectively). Comparing the Asn276-Gly heta-lactamase with OHIO-1, the Vmax for most substrates except cephaloridine did not change substantially. There was a 2-15 fold decreased affinity (Km) and catalytic efficiency (Vmax/Km) for beta-lactam substrates. These data support the observation and emphasize the role for this H bonding residue in orienting Arg-244 towards the active site.

Anti-Bacterial Agents↗
PubMed1993

Cytomegalovirus ventriculoencephalitis in AIDS. A syndrome with distinct clinical and pathologic features.

Cytomegalovirus ventriculoencephalitis is a late and terminal complication of AIDS. Cytomegalovirus retinitis was diagnosed before the onset of encephalitis in all but 1 of the 7 patients in this series. A distinct clinical presentation was observed, with encephalitis often associated with cranial nerve deficits and gaze-directed nystagmus. Examination of CSF demonstrated pleocytosis with elevated protein and hypoglycorrhachia. Increased signal of periventricular white matter was visualized by MRI soon after the development of encephalitis, and progressive ventriculomegaly was detected by serial CT scanning. Cytomegalovirus ventriculoencephalitis developed in some patients while receiving ganciclovir or foscarnet maintenance therapy, and the response to higher doses of these agents was limited in the 2 patients so treated. Death ensued a median of 4 weeks after the onset of neurologic symptoms. Pathologic examination showed extensive necrotizing periventriculitis involving ependymal and subependymal regions with spread to the meninges and adjacent cranial nerve roots. The infection was associated with characteristic CMV inclusion-bearing cells. This entity should be considered in AIDS patients with encephalitis, particularly in the presence of cranial nerve impairment or ascending muscle weakness. With the improvement in survival of patients with AIDS it is expected that this manifestation of CMV infection will become increasingly common.

AIDS-Related Opportunistic Infections↗