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M J Rybak

Publications and source records attributed to M J Rybak.

At least 37 records · Page 2Linked to original sources
PubMed2000

Once-daily aminoglycoside in the treatment of Enterococcus faecalis endocarditis: case report and review.

Once-daily administration of aminoglycosides (ODA) is effective and safe for many indications. By optimizing pharmacodynamic principles, it enhances bactericidal activity and minimizes toxicity. Its use for the treatment of enterococcal infection is controversial, however, and results of in vitro studies and animal models of endocarditis are conflicting. To date, no case reports or clinical trials have examined its utility in human enterococcal endocarditis. A patient with right-sided endocarditis caused by Enterococcus faecalis was managed by once-daily gentamicin. Clinical and bacteriologic cures of this patient raise questions as to whether enterococcal endocarditis should be regarded as contraindication to ODA. The clinical utility of ODA in this disease deserves further investigation.

Adult↗
PubMed2000

Pharmacokinetics and pharmacodynamics of ceftizoxime in patients with dosages adjusted for renal function.

STUDY OBJECTIVE: Our institution developed dosing guidelines for patients with renal impairment based on pharmacokinetic data and class-specific pharmacodynamics. Ceftizoxime was chosen as a model agent to evaluate if the modified guidelines achieved similar minimal plasma concentration (Cp(min)) and time above the minimum inhibitory concentration of the infecting organism (T>MIC) in patients with renal impairment versus those with normal renal function. DESIGN: Prospective pharmacokinetic and pharmacodynamic evaluation of ceftizoxime dosages. SETTING: University-affiliated hospital. PATIENTS: Forty-three patients with suspected or documented infection were enrolled and classified into four groups based on creatinine clearance (Cl(cr); ml/min): group 1, above 100; group 2, 61-99; group 3, 31-60; and group 4, 15-30. INTERVENTIONS: Ceftizoxime serum concentrations were obtained at steady state. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic and pharmacodynamic parameters were calculated. As expected, clearance and elimination rate constant were reduced, and half-life tended to be greater in patients with renal impairment. The Cp(min) and area under the concentration-time curve over 24 hours were similar between groups (p=0.39, p=0.42). The T>MIC was 100% for all patient isolates, and 90% or more versus our clinical strain for all groups. Clinical outcomes were similar among all groups. CONCLUSION: Our dosing guidelines achieved similar Cp(min) among all groups of patients. Our results support that recommendations for dosing adjustments should be based on pharmacokinetic data and must also consider pharmacodynamic parameters.

Adult↗
PubMed1999

The effects of NorA inhibition on the activities of levofloxacin, ciprofloxacin and norfloxacin against two genetically related strains of Staphylococcus aureus in an in-vitro infection model.

NorA is a membrane-associated multidrug efflux protein that can decrease susceptibility to fluoroquinolones in Staphylococcus aureus. We have previously determined that NorA inhibition can increase fluoroquinolone killing activity and post-antibiotic effect. In the current investigation, we studied the killing activity and development of resistance for levofloxacin, ciprofloxacin and norfloxacin with or without the H+/K+ ATPase inhibitor omeprazole, in a wild-type strain of S. aureus (SA-1199) and its NorA hyperproducing mutant (SA-1199-3) in an in-vitro pharmacodynamic model with infected fibrin-platelet matrices. Each drug was administered every 12-24 h for 72 h and human pharmacokinetics were simulated. Levofloxacin was the most potent fluoroquinolone against both strains and its activity was not significantly affected by combination with omeprazole. The addition of omeprazole to ciprofloxacin significantly lowered colony counts at all time-points against both strains and decreased the time to 99.9% kill from 72.2 h to 33.8 h against SA-1199. The addition of omeprazole minimally increased norfloxacin activity against both strains. Omeprazole decreased the frequency of ciprofloxacin resistance nearly 100-fold at the 24 h time-point, but the frequency of resistance was not significantly different for any of the fluoroquinolone regimens after this time-point. No resistance was detected during levofloxacin regimens. The hydrophobic fluoroquinolones such as levofloxacin appear to circumvent NorA efflux, which may contribute to their better activity and decreased resistance rates against staphylococci. More durable and potent NorA inhibitor compounds are needed that can improve killing activity and prevent resistance.

Anti-Infective Agents↗
PubMed1999

Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus.

NorA is a membrane-associated multidrug efflux protein that can decrease susceptibility to fluoroquinolones in Staphylococcus aureus. To determine the effect of NorA inhibition on the pharmacodynamics of fluoroquinolones, we evaluated the activities of levofloxacin, ciprofloxacin, and norfloxacin with and without various NorA inhibitors against three genetically related strains of S. aureus (SA 1199, the wild-type; SA 1199B, a NorA hyperproducer with a grlA mutation; and SA 1199-3, a strain that inducibly hyperproduces NorA) using susceptibility testing, time-kill curves, and postantibiotic effect (PAE) methods. Levofloxacin had the most potent activity against all three strains and was minimally affected by addition of NorA inhibitors. In contrast, reserpine, omeprazole, and lansoprazole produced 4-fold decreases in ciprofloxacin and norfloxacin MICs and MBCs for SA 1199 and 4- to 16-fold decreases for both SA 1199B and SA 1199-3. In time-kill experiments reserpine, omeprazole, or lansoprazole increased levofloxacin activity against SA 1199-3 alone by 2 log10 CFU/ml and increased norfloxacin and ciprofloxacin activities against all three strains by 0.5 to 4 log10 CFU/ml. Reserpine and omeprazole increased norfloxacin PAEs on SA 1199, SA 1199B, and SA 1199-3 from 0.9, 0.6, and 0.2 h to 2.5 to 4.5, 1.1 to 1.3, and 0.4 to 1.1 h, respectively; similar effects were observed with ciprofloxacin. Reserpine and omeprazole increased the levofloxacin PAE only on SA 1199B (from 1.6 to 5.0 and 3.1 h, respectively). In conclusion, the NorA inhibitors dramatically improved the activities of the more hydrophilic fluoroquinolones (norfloxacin and ciprofloxacin). These compounds may restore the activities of these fluoroquinolones against resistant strains of S. aureus or may potentially enhance their activities against sensitive strains.

Anti-Infective Agents↗
PubMed1999

Evaluation of bactericidal activities of LY333328, vancomycin, teicoplanin, ampicillin-sulbactam, trovafloxacin, and RP59500 alone or in combination with rifampin or gentamicin against different strains of vancomycin-intermediate Staphylococcus aureus by time-kill curve methods.

This in vitro study evaluated the activities of vancomycin, LY333328, and teicoplanin alone and in combination with gentamicin, rifampin, and RP59500 against Staphylococcus aureus isolates with intermediate susceptibilities to vancomycin. Ampicillin-sulbactam and trovafloxacin were also evaluated. LY333328 and ampicillin-sulbactam resulted in bactericidal activity against all isolates. The combination of gentamicin with glycopeptides showed synergistic activity, while rifampin had no added benefit.

Ampicillin↗
PubMed1999

Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity.

The nephrotoxicity and ototoxicity associated with once-daily versus twice-daily administration of aminoglycosides was assessed in patients with suspected or proven gram-negative bacterial infections in a randomized, double-blind clinical trial. Patients who received therapy for >/=72 h were evaluated for toxicity. Patients also received concomitant antibiotics as deemed necessary for treatment of their infection. Plasma aminoglycoside concentrations, prospective aminoglycoside dosage adjustment, and serial audiologic and renal status evaluations were performed. The probability of occurrence of a nephrotoxic event and its relationship to doses and daily aminoglycoside exposure served as the main outcome measurement. One hundred twenty-three patients were enrolled in the study, with 83 patients receiving therapy for at least 72 h. For 74 patients plasma aminoglycoside concentrations were available for analysis, and the patients formed the group evaluable for toxicity. The primary infectious diagnosis for the patients who were enrolled in the study were bacteremia or sepsis, respiratory infections, skin and soft tissue infections, or urosepsis or pyelonephritis. Of the 74 patients evaluable for toxicity, 39 received doses twice daily and 35 received doses once daily and a placebo 12 h later. Nephrotoxicity occurred in 6 of 39 (15.4%) patients who received aminoglycosides twice daily and 0 of 35 patients who received aminoglycosides once daily. The schedule of aminoglycoside administration, concomitant use of vancomycin, and daily area under the plasma concentration-time curve (AUC) for the aminoglycosides were found to be significant predictors of nephrotoxicity by multivariate logistic regression analysis (P </= 0.001). The time to a nephrotoxic event was significantly influenced by vancomycin use and the schedule of administration, as assessed by Cox proportional hazards modeling (P </= 0.002). The results of the multivariate logistic regression analysis and the Cox proportional hazards modeling demonstrate that both the probability of occurrence and the time to occurrence of aminoglycoside nephrotoxicity are influenced by the schedule on which the aminoglycoside is administered as well as by the concomitant use of vancomycin. Furthermore, this risk of occurrence is modulated by the daily AUC for aminoglycoside exposure. These data suggest that once-daily administration of aminoglycosides has a predictably lower probability of causing nephrotoxicity than twice-daily administration.

Adult↗
PubMed1999

Analysis of vancomycin population susceptibility profiles, killing activity, and postantibiotic effect against vancomycin-intermediate Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus strains with decreased vancomycin susceptibility have been isolated from patients in the United States and Japan. The impact of decreased vancomycin susceptibility on the drug's pharmacodynamic parameters has not been addressed. We studied the activity of vancomycin against three clinical strains of vancomycin intermediate-susceptible Staphylococcus aureus (VISA) under high- and low-inoculum conditions, with stationary- and logarithmic-growth-phase kill curves, and in postantibiotic effect (PAE) experiments. We also investigated the stability of the decreased vancomycin susceptibility by using population susceptibility profiles. The respective vancomycin microdilution MICs and MBCs for VISA strains HIP5836, 14379, and Mu50 were 8 and 8, 8 and 8, and 8 and 16 microg/ml. HIP5836 had the most homogeneous elevation of vancomycin MICs, because the MIC for nearly all bacteria in the inoculum was 8 microg/ml. The population MICs (defined as the lowest vancomycin concentration inhibiting 99. 9% of growth) for the first serial passages of HIP5836, Mu50, and 14379 were 8, 4, and 2 microg/ml, respectively. After 10 passages, they decreased to 4, 2, and 1 microg/ml, respectively. The Mu50 population MIC increased to 12 microg/ml after five serial passages on vancomycin agar. In the low- and high-inoculum kill curves, time to 99.9% killing was significantly (P < 0.05) longer for both Mu50 and HIP5836 than that for 14379 and a control strain. However, colony counts at 24 h were similar to those of the vancomycin-sensitive strain for all VISA strains. The PAE (at 4x MIC) ranged from 1.3 h for 14379 to 2.0 h for HIP5836 and was similar to or greater than the PAE against the vancomycin-sensitive strain. In conclusion, we found that the decreased vancomycin susceptibility increased during persistent exposures to the drug and decreased upon removal of the selective pressure. The decreased vancomycin susceptibility decreased the rate of vancomycin killing, but did not affect the extent of killing or the PAE.

Anti-Bacterial Agents↗
PubMed1999

Evaluation of Acinetobacter baumannii infection and colonization, and antimicrobial treatment patterns in an urban teaching hospital.

In 1990 there was a sudden increase in the incidence of colonization and infection due to Acinetobacter baumannii (AB) in our intensive care units (ICUs). The isolates were multiply resistant to beta-lactam and aminoglycoside antibiotics, but remained susceptible to imipenem, amikacin, and ampicillin-sulbactam. We examined the frequency of infection and colonization with AB and the effects of increased imipenem and amikacin therapy on Pseudomonas aeruginosa. We also used disease-matched controls to determine the clinical and financial impacts of treating colonization. All patients with at least one AB isolate from January-December 1992 were identified retrospectively and classified as infected or colonized based on published Centers for Disease Control criteria; the control group was selected from a computerized medical records data base matching primary diagnostic codes (102 patients both groups). The 102 patients yielded 140 isolates, 124 resistant AB and 16 sensitive AB. Thirty three patients were infected, 69 colonized. Mortality correlated with APACHE II scores. Patients acquired the organism approximately 2 weeks after admission; they had a mean ICU stay of 27.35 days, compared with 5.53 days for controls. Patients with positive AB cultures required significantly more use of ventilators than those with negative AB cultures. They also had significantly longer hospital stay, more bed transfers, greater duration and number of antibiotics, and higher hospital and pharmacy charges. Unnecessary treatment for colonization with either imipenem or amikacin resulted in a substantial decrease of P. aeruginosa susceptibility to each agent. The financial impact of treating colonization was significant and is a potential area for cost avoidance. Our results emphasize the need to extubate and move patients to non-ICU beds as soon as possible to decrease the risk of nosocomial infection. It also highlights the need to avoid treating colonization, thus avoiding unnecessary antibiotic therapy.

Acinetobacter↗
PubMed1999

Pharmacologic and bacteriologic properties of SCH-27899 (Ziracin), an investigational antibiotic from the everninomicin family.

SCH-27899 is an investigational antibiotic from the everninomicin family, a group of oligosaccharide antibiotics produced by Micromonospora carbonacea. Information regarding the pharmacology, pharmacodynamics, pharmacokinetics, efficacy, and toxicity of this agent was obtained from a MEDLINE search and a review of abstracts presented at recent scientific meetings. SCH-27899 has in vitro bacteriostatic activity against a wide variety of gram-positive organisms, including highly resistant organisms such as methicillin-resistant Staphylococcus aureus, vancomycin-intermediate-sensitivity S. aureus, Streptococcus pneumoniae (both penicillin-susceptible and -nonsusceptible), and vancomycin-resistant enterococci. In vitro data, animal studies, and preliminary human studies indicate that it is effective and fairly well tolerated. Its place in therapy remains to be determined, and clinical trials continue.

Aminoglycosides↗
PubMed1999

Pharmacodynamic characterization of nephrotoxicity associated with once-daily aminoglycoside.

STUDY OBJECTIVE: To characterize nephrotoxicity associated with an individualized serum concentration target-specific, once-daily aminoglycoside (ODA) program. DESIGN: Concurrent and retrospective study. SETTING: University-affiliated trauma hospital. PATIENTS: Two hundred patients treated with ODA and 100 treated with individualized traditional dosing (TDA). INTERVENTIONS: Empiric dosing for both groups was based on patient-specific pharmacokinetics and severity of infection. Regimens were modified according to predetermined target maximum and minimum serum concentrations for both groups. MEASUREMENTS AND MAIN RESULTS: Nephrotoxicity occurred in 7.5% patients treated with ODA and 14.7% receiving TDA (p=0.05). Minimum serum concentrations, length of aminoglycoside therapy, and cumulative area under the curve (AUC) were all dependently related to nephrotoxicity, and concomitant vancomycin and other nephrotoxic drugs were independently related to the disorder. The cumulative AUC was greatest in patients receiving TDA (p=0.03), and the modeled probability of becoming toxic at any given cumulative AUC was significantly greater with TDA than with ODA (p<0.01). Clinical and microbiologic outcomes were similar between groups. Maximum concentration:minimum inhibitory concentration ratios were higher (p<0.01) and number of days to organism eradication was shorter in the ODA group (p=0.04). CONCLUSION: The trend was toward decreased nephrotoxicity in patients treated with ODA compared with TDA, and at any given cumulative AUC, the risk of toxicity was lower for ODA.

Aminoglycosides↗
PubMed1999

Outcome assessment of minimizing vancomycin monitoring and dosing adjustments.

An approach to minimize monitoring of vancomycin therapy was evaluated in 120 patients, and results were compared with data from 120 patients in whom vancomycin therapy was monitored and adjusted based on serum peak and trough concentrations and traditional pharmacokinetic methods. Patients dosed by the nomogram (NM) had regimens adjusted based on actual body weight, estimated creatinine clearance, and a targeted trough concentration of 5-20 microg/ml. A single trough serum concentration was drawn only after 5 or more days of therapy. Overall, the average length of therapy was similar between groups (9.9 +/- 9.4 days NM and 8.6 +/- 7.2 days pharmacokinetic). The most common regimen for both groups was 1 g every 12 hours, although NM patients received significantly fewer grams/day (1.9 +/- 0.7 g/day) than the pharmacokinetic group (2.2 +/- 1.0 g/day, p<0.04). Patients dosed by NM also had significantly fewer regimen changes (0.63 +/- 0.96 vs pharmacokinetic 0.92 +/- 0.97, p=0.02) as well as significantly fewer serum concentrations measured/patient (1.08 +/- 1.9 vs 1.96 +/- 2.0, p=0.001). In addition, serum concentrations for NM patients were drawn later in therapy (5.4 +/- 2.5 vs 3.8 +/- 3.4 days, p=0.004). Of patients dosed by NM guidelines, 77 had trough concentrations drawn; these data were used to validate the nomogram. Seventy-two patients (94%) had trough concentrations in the target range of 5-20 microg/ml. No differences were found between groups with respect to cure, improvement, failure, or days to eradication, or with respect to nephrotoxicity. Finally, total drug cost/patient was not different between groups. A considerable cost savings to our institution was noted for patients dosed by NM compared with pharmacokinetics ($232.5 +/- 50.74 vs $403.75 +/- 70.97/mo, p=0.009) based on levels saved. Caution should be applied when generalizing our results to other patient populations.

Adult↗
PubMed1998

Treatment of vancomycin-resistant Enterococcus faecium with RP 59500 (quinupristin-dalfopristin) administered by intermittent or continuous infusion, alone or in combination with doxycycline, in an in vitro pharmacodynamic infection model with simulated endocardial vegetations.

Quinupristin-dalfopristin is a streptogramin antibiotic combination with activity against vancomycin-resistant Enterococcus faecium (VREF), but emergence of resistance has been recently reported. We studied the activity of quinupristin-dalfopristin against two clinical strains of VREF (12311 and 12366) in an in vitro pharmacodynamic model with simulated endocardial vegetations (SEVs) to determine the potential for resistance selection and possible strategies for prevention. Baseline MICs/minimal bactericidal concentrations (microg/ml) for quinupristin-dalfopristin, quinupristin, dalfopristin, and doxycycline were 0.25/2, 64/>512, 4/512, and 0.125/8 for VREF 12311 and 0.25/32, 128/>512, 2/128, and 0.25/16 for VREF 12366, respectively. Quinupristin-dalfopristin regimens had significantly less activity against VREF 12366 than VREF 12311. An 8-microg/ml simulated continuous infusion was the only bactericidal regimen with time to 99.9% killing = 90 hours. The combination of quinupristin-dalfopristin every 8 h with doxycycline resulted in more killing compared to either drug alone. Quinupristin-dalfopristin-resistant mutants (MICs, 4 microg/ml; resistance proportion, approximately 4 x 10(-4)) emerged during the quinupristin-dalfopristin monotherapies for both VREF strains. Resistance was unstable in VREF 12311 and stable in VREF 12366. The 8-microg/ml continuous infusion or addition of doxycycline to quinupristin-dalfopristin prevented the emergence of resistance for both strains over the 96-h test period. These findings replicated the development of resistance reported in humans and emphasized bacterial factors (drug susceptibility, high inoculum, organism growth phase) and infectious conditions (penetration barriers) which could increase chances for clinical resistance. The combination of quinupristin-dalfopristin with doxycycline and the administration of quinupristin-dalfopristin as a high-dose continuous infusion warrant further study to determine their potential clinical utility.

Anti-Bacterial Agents↗
PubMed1998

Efficacy of trovafloxacin against experimental Staphylococcus aureus endocarditis.

Trovafloxacin is a new fluoronaphthyridone chemically and functionally related to members of the fluoroquinolone class of antimicrobial agents. The in vivo efficacy of the drug was compared with that of vancomycin by using the rabbit model of left-sided endocarditis. Rabbits infected with either a nafcillin-susceptible or -resistant test strain were treated with trovafloxacin (13.3 mg/kg of body weight every 12 h) or vancomycin (25 mg/kg of body weight every 8 h) for 4 days. In comparison with untreated controls, both antimicrobial agents effectively cleared bacteremia and significantly reduced bacterial counts in vegetations and tissues of animals infected with either test strain. No resistance to trovafloxacin emerged in test strains during therapy. We conclude that in this model trovafloxacin is as efficacious as vancomycin is and may serve as a viable alternative to vancomycin for use in humans with similar infections.

Animals↗
PubMed1998

Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium.

The activities of the oxazolidinone antibacterial agents eperezolid (PNU-100592) and linezolid (PNU-100766) were compared with that of vancomycin against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (n = 200), coagulase-negative staphylococci (n = 100), and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium (n = 50). Eperezolid and linezolid demonstrated good in vitro inhibitory activity, regardless of methicillin susceptibility for staphylococci (MIC at which 90% of the isolates are inhibited [MIC90] range, 1 to 4 microg/ml) or vancomycin susceptibility for enterococci (MIC90 range, 1 to 4 microg/ml). In time-kill studies, eperezolid and linezolid were bacteriostatic in action. A postantibiotic effect of 0.8+/-0.5 h was demonstrated for both eperezolid and linezolid against S. aureus, S. epidermidis, E. faecalis, and E. faecium.

Acetamides↗
PubMed1998

Efficacy of LY333328 against experimental methicillin-resistant Staphylococcus aureus endocarditis.

The in vivo efficacy of LY333328, a new glycopeptide antibiotic, was compared with that of vancomycin by using the rabbit model of left-sided methicillin-resistant Staphylococcus aureus endocarditis. Animals received LY333328 or vancomycin (25 mg/kg of body weight every 24 or 8 h, respectively) for 4 days. These drugs were equally effective in clearing bacteremia and in reducing bacterial counts in vegetations and tissues. We conclude that in this model, LY333328 was microbiologically effective and may be a therapeutic alternative to vancomycin.

Animals↗
PubMed1998

Pharmacodynamic analysis of the activity of quinupristin-dalfopristin against vancomycin-resistant Enterococcus faecium with differing MBCs via time-kill-curve and postantibiotic effect methods.

Quinupristin-dalfopristin (Q-D) is a new water-soluble, semisynthetic antibiotic that is derived from natural streptogramins and that is combined in a 30:70 ratio. A number of studies have described the pharmacodynamic properties of this drug, but most have investigated only staphylococci or streptococci. We evaluated the relationship between Q-D, quinupristin (Q), and/or dalfopristin (D) susceptibility parameters and antibacterial activities against 22 clinical isolates of vancomycin-resistant Enterococcus faecium (VREF) by using the concentration-time-kill-curve method and by measuring postantibiotic effects. Q-D, Q, and D MICs and minimum bactericidal concentrations (MBCs) ranged from 0.125 to 1 and 0.25 to 64, 8 to 512 and >512, and 2 to 8 and 8 to 512 microgram/ml, respectively. There were no significant relationships between susceptibilities to the individual components and the susceptibilities to the Q-D combination product. In the time-kill-curves studies, Q-D at a concentration of 6 microgram/ml was at least bacteriostatic against all VREF tested. There was increased activity against more susceptible isolates when the isolates were grouped either by Q-D MBCs or by Q MICs. By multivariate regression analyses, the percent change in the inoculum from that at the baseline was significantly correlated with the Q MIC (R = 0.74; P = 0.008) and the Q-D concentration-to-MBC ratio (R = 0.58; P = 0.02) and was inversely correlated with the Q-D MBC-to-MIC ratio (R = 0.68; P = 0.003). A strong correlation existed between the killing rate and the Q-D concentration-to-MBC ratio (R = 0.99; P < 0.0001). Time to 99.9% killing was best correlated with the Q-D MBC (R = 0.96; P < 0.0001). The postantibiotic effect ranged from 0.2 to 3.2 h and was highly correlated with the Q-D concentration-to-MBC ratio (R = 0.96; P < 0.0001) and was less highly correlated with the Q MIC (R = 0.42; P = 0.04). Further study of these relationships with in vitro or in vivo infection models that simulate Q-D pharmacokinetics should further define the utility of these pharmacodynamic parameters in the prediction of Q-D activity for the treatment of VREF infections in humans.

Drug Resistance, Microbial↗
PubMed1998

Trimethoprim/sulfamethoxazole-induced tremor in a patient with AIDS.

OBJECTIVE: To report a case of trimethoprim/sulfamethoxazole (TMP/SMX)-induced tremor responsive to a reduction in dosage. CASE SUMMARY: A 55-year-old white man with AIDS and Pneumocystis carinii pneumonia (PCP) developed a tremor after receiving 5 days of therapy with TMP/SMX 19.4 mg/kg/d (TMP). The tremor resolved completely 3 days after a dosage reduction to TMP/SMX 15.1 mg/kg/d. DISCUSSION: Central nervous system adverse reactions to TMP/SMX have been reported in both the AIDS and non-AIDS populations. To our knowledge, this is the first reported case of TMP/SMX-induced tremor responsive to a reduction in dosage. Pharmacokinetic and clinical data suggest a concentration-dependent etiology for various adverse effects, including tremor. The mechanism of the tremor is unknown; however, toxic metabolites of SMX and disruptions of biogenic amine neurotransmission by TMP have been hypothesized. CONCLUSIONS: TMP/SMX remains the drug of first choice for treating PCP, but it is clearly not well tolerated by patients with AIDS. Concentration-dependent toxicities such as tremor may lead to premature discontinuation of proven, effective TMP/SMX therapy. Using the lower end of the recommended dosing range for TMP/SMX (TMP 15 mg/kg/d) may reduce the incidence of these toxicities while still achieving acceptable TMP concentrations and antimicrobial efficacy.

AIDS-Related Opportunistic Infections↗