Stephen H. Zinner

Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance.

An in vitro pharmacokinetic model was used to study the comparative antibacterial activities of multiple-dose regimens of enoxacin and netilmicin. Strains of Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus were exposed to changing drug concentrations, mimicking human two-compartment pharmacokinetics. Oral administration was simulated for the quinolone, and intravenous administration was simulated for the aminoglycoside. Similar ratios of peak concentration to MIC resulted in similar changes in bacterial concentrations over time with both compounds. Following the initial dose, a rapid bactericidal effect occurred, with a greater than 99% reduction of the bacterial counts within 4 h at peak concentrations more than three times the MIC. However, bacterial regrowth occurred within 24 h unless the peak concentration/MIC ratio exceeded 8:1 (P less than 0.01). For the regrowing bacteria, MICs were four- to eightfold higher, and little or no bactericidal effect occurred following the second and subsequent doses. These data demonstrate the equally potent bactericidal activity of orally administered enoxacin and intravenously administered netilmicin. Selection of resistant subpopulations was similar with each drug. The peak concentration/MIC ratio may be an important parameter in the clinical use of quinolone and aminoglycoside antibiotics.

Oral versus Intravenous Empirical Antimicrobial Therapy for Fever in Patients with Granulocytopenia Who Are Receiving Cancer Chemotherapy

BACKGROUND Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

Familial Aggregation of Blood Pressure in Childhood

Abstract The familial aggregation of blood pressure is well known in adults. To determine if this familial effect is detectable in childhood, blood pressures of 721 children two to 14 years of age were taken in the homes of 190 families. A portable, automated blood-pressure recorder was used, and scores adjusted for age and sex were expressed in standard-deviation units. For both systolic and diastolic pressures, variance of blood-pressure scores was significantly less within families than among all children in this age group (p less than 0.01). Sib-sib and mother-child regression coefficients were 0.34 and 0.16 for systolic pressure and 0.32 and 0.17 for diastolic pressure respectively. The clustering effect was measurable at all levels of blood pressure. Thus, a familial influence on blood pressure can be detected in children, and it is possible that factors responsible for essential hypertension are acquired in childhood.

Piperacillin-tazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.

Gram-positive bacteria have become the predominant infecting organisms in granulocytopenic cancer patients. Empiric antibiotic regimens used in febrile neutropenic patients often include an extended-spectrum cephalosporin, but the response to therapy in gram-positive coccal bacteremia has been unsatisfactory. Thus, new antibiotics with better activity against gram-positive bacteria should be tested. The objective of this prospective randomized controlled study was to evaluate and compare the efficacy and tolerance of piperacillintazobactam plus amikacin with that of ceftazidime plus amikacin, the standard regimen of the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer, in the empiric treatment of febrile granulocytopenic cancer patients. A total of 858 episodes were eligible for this study, and 706 episodes were assessable for efficacy. The antibiotic treatment was successful in 210 (61%) of 342 episodes in the piperacillin-tazobactam-amikacin group compared with 196 (54%) of 364 episodes treated with ceftazidime plus amikacin (P = 0.05). The time to defervescence was significantly shorter (P = 0.01) and the time to failure was significantly longer (P = 0.02) in the piperacillin-tazobactam-amikacin group. A significant difference in response to bacteremic infections between the two patient groups was found: piperacillin-tazobactam plus amikacin was successful in 40 of 80 episodes (50%), and ceftazidime plus amikacin was successful in 35 of 101 episodes (35%) (P = 0.05). A multivariate analysis showed that the probability of failure was significantly greater with ceftazidime plus amikacin than with piperacillin-tazobactam plus amikacin (P = 0.02). This trial suggests that piperacillin-tazobactam plus amikacin is more effective than ceftazidime plus amikacin for the empiric treatment of fever and bacteremia in granulocytopenic cancer patients. Although cutaneous reaction was more frequently associated with piperacillin-tazobactam plus amikacin than with ceftazidime-amikacin, this unwanted effect was relatively mild and its incidence was comparable to that of other penicillin compounds.

In vitro pharmacodynamic evaluation of the mutant selection window hypothesis using four fluoroquinolones against Staphylococcus aureus.

ABSTRACT To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant Staphylococcus aureus exposed to moxifloxacin (MOX), gatifloxacin (GAT), levofloxacin (LEV), and ciprofloxacin (CIP) was tested daily by using an in vitro dynamic model that simulates human pharmacokinetics. A series of monoexponential pharmacokinetic profiles that mimic once-daily administration of MOX (half-life, 12 h), GAT (half-life, 7 h), and LEV (half-life, 6.8 h) and twice-daily administration of CIP (half-life, 4 h) provided peak concentrations (Cmax) that either equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC) (i.e., within or “inside” the MSW), or exceeded the MPC. The respective ratios of the area under the curve (AUC) over a 24-h dosing interval (AUC24) to the MIC varied from 13 to 244 h, and the starting inoculum was 108 CFU/ml (6 × 109 CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC24/MIC values (from 24 to 62 h) that corresponded to quinolone concentrations within the MSW over most of the dosing interval (>20%). Less-pronounced increases in MIC were associated with the smallest simulated AUC24/MIC values (15 to 16 h) of GAT and CIP, whose Cmax exceeded the MICs. No such increases were observed with the smallest AUC24/MIC values (13 to 17 h) of MOX and LEV, whose Cmax were close to the MICs. Also, less pronounced but significant increases in MIC occurred at AUC24/MIC values (107 to 123 h) that correspond to quinolone concentrations partly overlapping the MIC-to-MPC range. With all four drugs, no change in MIC was seen at the highest AUC24/MIC values (201 to 244 h), where quinolone concentrations exceeded the MPC over most of the dosing interval. These “protective” AUC24/MIC ratios correspond to 66% of the usual clinical dose of MOX (400 mg), 190% of a 400-mg dose of GAT, 220% of a 500-mg dose of LEV, and 420% of two 500-mg doses of CIP. Thus, MOX may protect against resistance development at subtherapeutic doses, whereas GAT, LEV, and CIP provide similar effects only at doses that exceed their usual clinical doses. These data support the concept that resistant mutants are selectively enriched when antibiotic concentrations fall inside the MSW and suggest that in vitro dynamic models can be used to predict the relative abilities of quinolones to prevent mutant selection.

Risk of Local and Systemic Infection with Polyethylene Intravenous Catheters

Abstract Risk of local and systemic infection associated with polyethylene intravenous catheters was determined in a prospective study of 213 catheterizations in 176 general medical and surgical patients. Catheters were used in approximately 80 per cent of all patients receiving fluids. Phlebitis occurred in 39 per cent of catheterizations but was not a reliable sign of local infection; cultures of less than half the catheters removed from phlebitic patients were positive at the time of removal. One third of all catheters were positive by culture at removal. Risk of local infection with pathogenic organisms increased with duration of use. Risk of catheter-induced bacteremia was 2 per cent in the study group, and such bacteremia was a major contributing cause of death in 1 per cent. Further studies to curtail or modify the use of intravenous catheters are indicated.

Stability of blood pressure rank and urinary kallikrein concentration in childhood: an eight-year follow-up.

SUMMARY Previous studies in a population of 721 children aged 2-14 years demonstrated the familial aggregation of blood pressure in children, and a significant regression coefficient (b = 0.25) of follow-up on initial blood pressures over a four-year period. Urinary kallikrein concentration (UKal) also aggregated in families, was lower in black than in white children and was inversely related to blood pressure.Further studies in the same cohort have been conducted. These variables were again measured in 484 children in 129 families seven to eight years after the initial blood pressure and three to four years after the original UKal measurements were made.Familial aggregation again was found for blood pressure and urinary kallikrein. Blood pressure tracking was demonstrated by the finding that blood pressure scores at the third survey were related significantly to those at both previous surveys.Kallikrein concentrations in casual urines at Survey 3 were related to those obtained at Survey 2 (r = 0.499), and were again significantly lower in black than in white children (log = 3.84 ± 0.8 vs 4.37 ± 0.7; P < 0.001). There were significant inverse relations between UKal/creatinine concentration and blood pressure in both white and black children.Thus, familial aggregation of blood pressure, blood pressure rank and concentration of kallikrein in casual urine specimens are relatively stable in children over an eight-year period of observation. This study demonstrates in a free living population of normal children, a stable relation between blood pressure and an enzyme which is involved in the production of potent vasodilator peptides and is related to hypertension in adults.

Prospective Randomized Comparison of Three Antibiotic Regimens for Empirical Therapy of Suspected Bacteremic Infection in Febrile Granulocytopenic Patients

The standard regimen used by members of the European Organization for Research on Treatment of Cancer Antimicrobial Therapy Cooperative Group for empiric therapy of febrile neutropenic cancer patients has been treatment with ticarcillin plus amikacin. A three-arm prospective randomized controlled trial was performed to determine whether the extended-spectrum antipseudomonal penicillin azlocillin or the extended-spectrum cephalosporin cefotaxime had more or less efficacy than the beta-lactam in the ticarcillin-plus-amikacin regimen. A total of 742 patients from 22 institutions were evaluated. Single gram-negative rod bacteremias accounted for 83 episodes, and it was among these patients that the prognosis was least satisfactory, leading to a more intensive evaluation of this patient group. In these patients the azlocillin-plus-amikacin regimen resulted in a 66% response rate, compared with a 37% response rate for patients who received cefotaxime plus amikacin (P = 0.080) and a 47% response rate for patients who received ticarcillin plus amikacin (P = 0.207). The patients with gram-negative rod bacteremias and persistently profound granulocytopenia had substantially poorer response rates (37%) than the patients with rising granulocyte counts (73%; P = 0.004). A logistic regression analysis indicated that the following factors also affected infection resolution: beta-lactam utilization in the regimen (azlocillin was better than ticarcillin or cefotaxime), resolution of profound granulocytopenia (less than 100 cells per microliter) during therapy, and susceptibility to the beta-lactam antibiotic.

Vancomycin versus Placebo for Treating Persistent Fever in Patients with Neutropenic Cancer Receiving Piperacillin-Tazobactam Monotherapy

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

Sexual Behavior of College Women in 1975, 1986, and 1989

To compare sexual practices in college women before and after the start of the current epidemics of Chlamydia trachomatis, genital herpesvirus, and human immunodeficiency virus type 1 infection, we surveyed 486 college women who consulted gynecologists at a student health service in 1975, 161 in 1986, and 132 in 1989 at the same university. There were no statistically significant differences in age, age at menarche, or reason for visiting the gynecologist. The percentages of women in this population who were sexually experienced were the same in all three years (88 percent in 1975, 87 percent in 1986, and 87 percent in 1989). Oral contraceptives were used by 55 percent of the women in 1975, 34 percent in 1986, and 42 percent in 1989; the use of condoms as the usual method of birth control increased (6 percent in 1975, 14 percent in 1986, and 25 percent in 1989; P less than 0.001). In 1975, only 12 percent reported the regular use of condoms during sexual intercourse, in some cases in conjunction with other methods of contraception, as compared with 21 percent in 1986 and 41 percent in 1989 (P = 0.0014). No significant differences were found in the three surveys in the number of male sexual partners or the frequency of fellatio, cunnilingus, or anal intercourse. An additional sample of 189 college women who did not consult the health service was surveyed in 1989, and similar sexual behavior was reported by those who were sexually experienced (65 percent). We conclude that in this population there has been little change in sexual practices in response to new and serious epidemics of sexually transmitted diseases, with the exception of an increase in the use of condoms (which still does not reach 50 percent).