Blood cultures positive for coagulase-negative staphylococci: antisepsis, pseudobacteremia, and therapy of patients.

A blood culture cohort study investigating issues related to isolation of coagulase-negative staphylococci (CoNS) and other skin microflora is reported. Data were collected over 12 weeks to determine the incidence of significant CoNS bacteremia versus that of pseudobacteremia (contaminants) and to evaluate drug therapy in patients with cultures positive for CoNS. In addition, the effectiveness of 0.2% chlorine peroxide as a bactericidal disinfectant was compared to that of 10% providone iodine. A total of 3,276 cultures of blood from 1,433 patients were evaluated in the study. Eighty-nine cultures were positive for skin flora, with 81 of 89 (91%) involving CoNS. The incidence of significant CoNS bacteremia was 20 of 81 (24.7%), that of indeterminate bacteremia was 10 of 81 (12.3%), and that of contamination was 59 of 81 (72.8%). The incidence of significant bacteremia involving CoNS was double the 10 to 12% rate based on previous estimations at our institutions. In tests with the two bactericidal disinfectants, 22 of 1,639 cultures (1.3%) in the chlorine peroxide group versus 37 of 1,637 (2.3%) in the providone iodine group were considered contaminated (P = 0.065). Rates of contamination for venipuncture versus catheter collection were not significantly different (P = 0.46). The overall contamination rate was 59 of 3,276 (1.8%), which is consistent with the lower end of published quality assurance benchmark standards. The low rate was believed to be due to the professional phlebotomy staff in our institutions. There was excellent agreement between retrospective analysis by reviewers, when formal criteria were used, and the attending physicians' intuitive clinical impressions in the classification of significant bloodstream infections (100% agreement) or contamination (95% agreement). However, physicians still used antimicrobial agents to treat nearly one-half of the patients with contaminated blood cultures, with vancomycin being misused in 34% of patients. In addition, 10% of patients with significant bacteremia were treated with inappropriate agents. There were no significant adverse events or prolonged hospital stays due to the unnecessary use of vancomycin; however, the additional costs of treating patients whose cultures contained CoNS contaminants was estimated to be $1,000 per patient. Measures to limit the unnecessary use of vancomycin (and other agents) are important.

Levofloxacin: a therapeutic review.

This therapeutic review discusses the pharmacology, pharmacokinetics, in vitro activity, drug interactions, and adverse effects of levofloxacin, a fluoroquinolone antibiotic. Particular emphasis is placed on the clinical efficacy of levofloxacin and its place in therapy. Compared with ciprofloxacin and the earlier quinolone agents, levofloxacin has an improved pharmacokinetic profile that allows convenient once-daily dosing in either an oral or parenteral formulation. Levofloxacin has enhanced activity against gram-positive aerobic organisms, including penicillin-resistant pneumococci. In published comparative trials involving commonly used treatment regimens, levofloxacin had equivalent if not greater activity in the treatment of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, acute pyelonephritis, and complicated urinary tract infection. Levofloxacin is well tolerated and induces minimal adverse drug reactions. Based on the above attributes, it may be reasonable to include levofloxacin on the hospital formulary in place of older quinolones. More recently released quinolones such as trovafloxacin exhibit similar advantages; however, until direct comparative trials between levofloxacin and these newer agents are conducted, it is difficult to advocate one agent over another. Regardless of which quinolone is the primary agent on the formulary, it is imperative that this class of antimicrobial drugs be used with discretion to minimize the development of resistance.

Comparison of various in vitro susceptibility methods for testing Stenotrophomonas maltophilia.

A total of 57 clinical isolates were screened by disk diffusion for a related pharmacodynamic study. Testing was performed using National Committee for Clinical Laboratory Standards guidelines, except that results were interpreted at 16 to 18 h and 48 h. Of the 57 isolates, 19 were randomly chosen for additional comparative susceptibility testing of five methods (disk diffusion, Etest, Alamar colorimetric broth microdilution, Vitek, and MicroScan) and an in-house broth microdilution method. The two diffusion methods (disk and Etest) had the closest correlation. The commercial broth microdilution methods and the in-house microdilution method generated inconsistent results for all agents except trimethoprim-sulfamethoxazole. Vitek compared poorly with both diffusion and microbroth dilution methods. The most significant discrepancies were evident with all methods when the incubation period was extended to 48 h. When results were interpreted at 48 h, the incidence of resistance for all bactericidal agents was approximately double the resistance observed at 16 to 18 h. The bacteriostatic agents, trimethoprim-sulfamethoxazole and doxycycline, demonstrated the greatest in vitro activity and were least influenced by extended incubation with diffusion methods. Because correlative in vivo and in vitro studies have not revealed an effective therapeutic regimen for serious S. maltophilia infections, susceptibility results with all testing methods should be interpreted with caution when choosing therapy for patients with life-threatening infections. Susceptibility testing for this heterogeneous group remains controversial and routine testing, with the possible exception of doxycycline (or minocycline) and trimethoprim-sulfamethoxazole, should be avoided. Our data support that if testing is done with bactericidal agents, consideration should be given to interpretation after 48-h incubation.

Agranulocytosis induced by vancomycin or ticarcillin/clavulanate.

OBJECTIVE: To reacquaint clinicians with a reportedly rare adverse event of agranulocytosis occurring after long-term administration of vancomycin and ticarcillin/clavulanate, with a subsequent review of other reported cases in the literature. CASE SUMMARY: A 45-year-old white woman with spina bifida developed agranulocytosis (2.7 x 10(3)/mm3 white blood cells with only 3% polymorphonuclear leukocytes and no reported eosinophils or basophils) after long-term administration of vancomycin and ticarcillin/clavulanate for decubitus ulcers and chronic osteomyelitis. Consequently, the cell counts rebounded rapidly on discontinuation of both medications and returned to normal within 1 week. DISCUSSION: The incidence of vancomycin-associated neutropenia is presumably rare, but the increased use of vancomycin may disclose a more frequent occurrence. It is suggested that the mechanism for the reaction is immunologically mediated, yet this remains unclear. Although it is difficult to determine the causative agent in this case, vancomycin was most suspect clinically. Ticarcillin/clavulanate is less likely because our patient has since been readmitted and treated with oxacillin, imipenem/cilastatin, and amoxicillin/clavulanate without affecting the white blood cell count. In that regard, it could be reasoned that an immunologic reaction to ticarcillin would have resulted in a similar outcome with other penicillins. CONCLUSIONS: This case serves as a reminder to clinicians that patients receiving long-term treatment with vancomycin should have their white blood cell count monitored at least weekly.

Influence of pH on the antimicrobial activity of clarithromycin and 14-hydroxyclarithromycin against Haemophilus influenzae using an in vitro pharmacodynamic model.

Clarithromycin activity can be influenced by the pH of the surrounding environment. Evidence supports a reduced pH of middle ear fluid (MEF) and lung tissues in patients with otitis media and pneumonia, respectively. To evaluate the influence of pH on clarithromycin activity, an in vitro pharmacodynamic chamber model (PDCM) was used to generate bacterial time-kill curves for clarithromycin and a 2:1 ratio of clarithromycin and 14-hydroxyclarithromycin (HC) against Haemophilus influenzae at three different pH values: 7.2, 6.8, 6.4. Concentrations observed in MEF and lung tissues were simulated for clarithromycin alone and clarithromycin plus HC. Differences in activity at each pH were identified by comparing initial kill curve slopes and total log reduction. Experiments with amoxicillin-clavulanate were conducted as a reference. In simulated MEF regimens at pH 7.2, activity of clarithromycin alone improved by adding HC (additional 2 log10 reduction at 8 h); however, at pH values of 6.8 and 6.4, kill curves resembled growth controls. In simulated lung regimens, differences between clarithromycin alone and clarithromycin plus HC were insignificant; both produced a 2 log10 reduction at pH 7.2, and activity dramatically dropped to < 0.4 log10 as pH declined. In contrast, amoxicillin-clavulanate consistently produced a 3 log10 reduction over each pH value with more rapid initial kill relative to all clarithromycin regimens. These findings suggest the activity of clarithromycin against H. influenzae may be significantly compromised in respiratory tract infections involving a reduced pH. Trials with emphasis on clinical outcomes analysis will assist further in determining the significance of these experimental findings.

Protease inhibitors: a therapeutic breakthrough for the treatment of patients with human immunodeficiency virus.

As one of the largest growing classes of antiretroviral drugs, protease inhibitors are promising agents for the management of patients infected with the human immunodeficiency virus (HIV). We reviewed the literature and compared efficacy, dosing, side effects, and drug-interaction profiles of the protease inhibitors saquinavir, ritonavir, indinavir, and nelfinavir. We addressed the use of these antiprotease agents as monotherapy versus use in combination therapy with other antiretroviral medications, and the potential for HIV to develop resistance to this drug class. We also discussed therapy with dual protease inhibitors and the use of protease inhibitors in pregnant or lactating women and in pediatric patients. Finally, we examined case reports of the addition of protease inhibitors to an antiretroviral regimen that ultimately decreases or reverses opportunistic infections.

Stenotrophomonas maltophilia: emergence of multidrug-resistant strains during therapy and in an in vitro pharmacodynamic chamber model.

Emergence of Stenotrophomonas maltophilia as a nosocomial pathogen is becoming increasingly apparent. Pleiotropic resistance characterizes S. maltophilia. Furthermore, a slow growth rate and an increased mutation rate generate discordance between in vitro susceptibility testing and clinical outcome. Despite original susceptibility, drug-resistant strains of S. maltophilia are often recovered from patients receiving beta-lactams, quinolones, or aminoglycosides. Given the disparity among various in vitro susceptibility methods, this study incorporated a unique pharmacodynamic model to more accurately characterize the bacterial time-kill curves and mutation rates of four clinical isolates of S. maltophilia following exposure to simulated multidose regimens of ceftazidime, ciprofloxacin, gentamicin, and ticarcillin-clavulanate. Time-kill data demonstrated regrowth of S. maltophilia with all four agents. With the exception of ticarcillin-clavulanate, viable bacterial counts at the end of 24 h exceeded the starting inoculum. Ciprofloxacin only reduced bacterial counts by less than 1.0 log prior to rapid bacterial regrowth. Resistant mutant strains, identical to their parent strain by pulsed-field gel electrophoresis, were observed following exposure to each class of antibiotic. Mutant strains also had distinct susceptibility patterns. These data are consistent with previous reports which suggest that S. maltophilia, despite susceptibility data that imply that the organism is sensitive, develops multiple forms of resistance quickly and against several classes of antimicrobial agents. Standard in vitro susceptibility methods are not completely reliable for detecting resistant S. maltophilia strains; and therefore, interpretation of these results should be done with caution. In vivo studies are needed to determine optimal therapy against S. maltophilia infections.

Activity of once-daily cefpodoxime regimens against Haemophilus influenzae and Streptococcus pneumoniae with an in vitro pharmacodynamic chamber model.

To characterize the in vitro effectiveness of once-daily dosing with cefpodoxime against Haemophilus influenzae and Streptococcus pneumoniae infections, an in vitro pharmacodynamic chamber model was used to compare the bacterial killing activities of three cefpodoxime regimens: 100 mg twice daily (BID), 200 mg once daily (QD), and 400 mg QD. At the end of 24 h, the regrowth of H. influenzae isolates in the QD regimens was of concern, and the total logarithmic reduction was greatest in the BID regimen (3.1 log). Against S. pneumoniae isolates, the largest reductions in bacterial counts were observed in the 100-mg BID (5.5 log) and 400-mg QD (4.0 log) regimens. These data suggest that 400 mg of cefpodoxime given QD may have a role in the therapy of infections involving S. pneumoniae isolates.

Identifying and treating common and uncommon infections in the patient with diabetes.

Patients with diabetes represent a unique group of individuals who appear more prone than others to developing infections. Several mechanisms have been proposed to explain the association between diabetes and infections. However, few conclusive studies exist and considerable debate continues regarding evidence for this predisposition. Despite this lack of documented proof, many health care practitioners acknowledge that a number of infections are overrepresented in patients with diabetes. Some of these infections appear to occur exclusively in patients with diabetes, especially patients who are poorly controlled. The presenting clinical features, causative organisms, and preferred treatment approaches will be discussed in this article for a variety of common and uncommon infections observed in patients with diabetes. In addition, the proposed predisposing factors will be addressed briefly.

An in vitro pharmacodynamic model to simulate antibiotic behavior of acute otitis media with effusion.

The purpose of this investigation was to develop an in vitro pharmacodynamic model (IVPM) that would simultaneously simulate in vivo serum and middle ear amoxicillin pharmacokinetic characteristics of acute (purulent) otitis media and then utilize the IVPM to assess amoxicillin-mediated killing of a type 7F Streptococcus pneumoniae (MIC = 0.002 mg/L). The IVPM consisted of a sterile central compartment and a membrane-bound "infected" peripheral compartment. Peak peripheral compartment amoxicillin concentrations occurred within 2 hr after its introduction into the central compartment and were approximately 30% of peak central compartment concentrations. Amoxicillin elimination from the central compartment was designed to provide a 1-hr t 1/2. Amoxicillin elimination from the peripheral compartment was slower than from the central compartment, with an average half-life of 2.3 hr. Significant concentration-related differences in maximal bacterial kill rates were not detected over the range of amoxicillin concentrations studied (0.26 to 14.6 mg/L). However, at peak central compartment amoxicillin concentrations of less than or equal to 2 mg/L, a lag phase in killing was observed. In general, the in vitro pharmacokinetic data derived from this model compare well with published in vivo data.

Therapeutic advances in the prevention of hepatitis B: yeast-derived recombinant hepatitis B vaccines.

Viral hepatitis is second to gonorrhea as the most commonly reported infectious disease in the US. Hepatitis B accounts for the majority of viral hepatitis cases. Fortunately, the disease is self-limiting and frequently resolves completely with minimal complications; however, a significant number of individuals may experience long-term sequelae. Research utilizing genetic engineering has led to the development of yeast-derived recombinant DNA (YDR) hepatitis vaccines--a significant advancement in the control and prevention of hepatitis B. The recombinant process allows production of unlimited quantities of vaccine at considerably lower cost and without the potential threat of blood-borne illness. Clinical trials in various high-risk populations have demonstrated the effectiveness and safety of YDR vaccines. However, questions regarding optimal regimen and the need for periodic revaccination remain unanswered. Persons at risk should be adequately vaccinated against hepatitis B.

Assessment of effects of protein binding on daptomycin and vancomycin killing of Staphylococcus aureus by using an in vitro pharmacodynamic model.

Initial clinical trials with daptomycin (2 mg/kg per day) were prematurely suspended because of unexplained treatment failures in patients with bacteremia who were treated with daptomycin, despite in vitro data indicating that the gram-positive cocci causing the infection were susceptible to daptomycin. One explanation for these clinical failures may relate to the relatively high degree of daptomycin protein binding (94%). To evaluate the impact of protein on daptomycin activity, a two-chamber in vitro pharmacodynamic model was used to study and compare the interaction between Staphylococcus aureus (clinical isolate) and either daptomycin or vancomycin, each in the presence and absence of physiologic human albumin concentrations. Low-dose (2 mg/kg) daptomycin, high-dose (6 mg/kg) daptomycin, and 10 mg of vancomycin per kg beta-phase elimination serum-concentration-versus-time curves were simulated by using this in vitro pharmacodynamic model. The bacterial kill rates by all three regimens were decreased in the presence of albumin (P less than 0.0002). The average times required for a 99% kill of the initial S. aureus inocula (approximately 5 x 10(7) CFU/ml) without albumin were 0.81 (low-dose daptomycin), 0.33 (high-dose daptomycin), and 6.18 (vancomycin) h. The average times required for a 99% kill of S. aureus with albumin were 7.66 (low-dose daptomycin), 0.95 (high-dose daptomycin), and 10.52 (vancomycin) h. These data demonstrate that, depending on the concentration of daptomycin, the presence of albumin can profoundly diminish the bactericidal activity of daptomycin.

Aminoglycosides: another perspective.

Despite the introduction of several new classes of antimicrobial agents, aminoglycosides are still recognized as first-line therapeutic agents in the management of severe gram-negative sepsis. The major obstacle limiting the use of aminoglycoside antibiotics has been, and continues to be, the possibility of drug-induced ototoxicity and nephrotoxicity. This review critically examines the definitions used to establish the diagnosis of aminoglycoside-induced nephrotoxicity and ototoxicity and the clinical significance of these adverse reactions. The review also focuses on the practical and economic issues surrounding therapeutic drug monitoring practices. We conclude that aminoglycoside antibiotics remain an effective and economical form of therapy for severe infections and that if careful criteria are used in the selection of these agents, the benefits of therapy outweigh the risk of toxicity.

Suboptimal effect of daptomycin in the treatment of bacteremias.

We have reported two cases involving bacteremic patients who failed to respond adequately to the investigational agent daptomycin. Despite apparent sensitivity of the organisms, therapy was unsuccessful in both patients using the recommended dosage. The sponsor of daptomycin is currently reevaluating the recommendation and may be revising their dosage guidelines in the future.

Current immunization practices. 1. Polio, diphtheria, tetanus, pertussis, measles, mumps, rubella, and influenza.

When used appropriately, immunization can effectively prevent many infections and diseases. Some vaccines, such as that for polio, are believed to produce lifelong immunity. Others, such as those for tetanus and diphtheria, may require that a booster injection be given upon exposure to assure full immunity. Still others, such as that for influenza, confer immunity for only a limited time. Inoculation is not without risk, particularly in immunosuppressed, allergic, febrile, or pregnant patients. However, in otherwise healthy patients, serious sequelae are so rare that they are far overshadowed by the enormous benefits of immunization.

Clinical assessment of a published model to predict aminoglycoside-induced nephrotoxicity.

During the past decade, several patient risk factors have been identified as contributing to the development of aminoglycoside nephrotoxicity. Sawyers et al. recently published a method for estimating the probability of aminoglycoside nephrotoxicity on an individual patient basis. The present work represents a refinement of previous publications and has not been tested with the common variations used in aminoglycoside dosing. The purpose of this study was to determine both the qualitative and quantitative value of this method in predicting aminoglycoside induced nephrotoxicity. Eighty-three patients (47 male, 36 female) meeting the inclusion criteria of Sawyers et al. were entered into the study. Patient risk factors (age, sex, initial 1-h postinfusion aminoglycoside serum level, initial calculated creatinine clearance, duration of therapy, and presence of liver disease) were entered into a logistic regression analysis to determine the individual patient's risk of developing nephrotoxicity. These calculated probability scores were then compared with the observed nephrotoxicity in specific groups within our patient sample to see how effectively the model quantitatively performed. Twelve patients (14.5%) developed nephrotoxicity. The model predicted only 5 of the 12 patients developing nephrotoxicity (sensitivity or true positive = 42%). In the nonnephrotoxic group, the model accurately predicted only 38 of 71 patients (specificity or true negative = 54%). These data suggest that the model may accurately quantitate the number of patients likely to develop nephrotoxicity from a specific group but is unable to discriminate specific patients at risk of developing aminoglycoside-induced nephrotoxicity.

Therapeutic update on glycopeptide and lipopeptide antibiotics.

Glycopeptide antibiotics in the form of vancomycin have been available for almost 30 years. In the past, vancomycin usually was reserved as an alternative agent to treat staphylococcal and streptococcal infection in patients with a penicillin allergy or hemodialysis shunt infection. With the increasing frequency of both methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, now it is often used as a first-line agent. Over a 10-year period, vancomycin sales have increased by almost $1 hundred million. Several new glycopeptide and lipopeptide antibiotics are in various stages of evaluation. While vancomycin resistance to date is a rare phenomenon, these drugs represent a potentially more potent and safer antibiotic alternative to vancomycin. Teicoplanin and daptomycin are two of these investigational agents.