Khalid H. Ibrahim

Synergistic Activity of Colistin and Ceftazidime against Multiantibiotic-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

ABSTRACT Despite the marketing of a series of new antibiotics for antibiotic-resistant gram-positive bacteria, no new agents for multiple-antibiotic-resistant gram-negative infections will be available for quite some time. Clinicians will need to find more effective ways to utilize available agents. Colistin is an older but novel antibiotic that fell into disfavor with clinicians some time ago yet still retains a very favorable antibacterial spectrum, especially for Pseudomonas and Acinetobacter spp. Time-kill curves for two strains of multiantibiotic-resistant Pseudomonas aeruginosa were generated after exposure to colistin alone or in combination with ceftazidime or ciprofloxacin in an in vitro pharmacodynamic model. MICs of colistin, ceftazidime, ciprofloxacin, piperacillin-tazobactam, imipenem, and tobramycin were 0.125, ≥32, >4, >128/4, 16, and >16 mg/liter, respectively. Colistin showed rapid, apparently concentration-dependent bactericidal activity at concentrations between 3 and 200 mg/liter. We were unable to detect increased colistin activity at concentrations above 18 mg/liter due to extremely rapid killing. The combination of colistin and ceftazidime was synergistic (defined as at least a 2-log10 drop in CFU per milliliter from the count obtained with the more active agent) at 24 h. Adding ciprofloxacin to colistin did not enhance antibiotic activity. These data suggest that the antibacterial effect of colistin combined with ceftazidime can be maximized at a peak concentration of ≤18 mg/liter.

Compartmental Pharmacokinetics and Tissue Distribution of the Antifungal Echinocandin Lipopeptide Micafungin (FK463) in Rabbits

ABSTRACT The plasma pharmacokinetics and tissue distribution of the novel antifungal echinocandin-like lipopeptide micafungin (FK463) were investigated in healthy rabbits. Cohorts of three animals each received micafungin at 0.5, 1, and 2 mg/kg of body weight intravenously once daily for a total of 8 days. Serial plasma samples were collected on days 1 and 7, and tissue samples were obtained 30 min after the eighth dose. Drug concentrations were determined by validated high-performance liquid chromatographic methods. Plasma drug concentration data were fit to a two-compartment pharmacokinetic model, and pharmacokinetic parameters were estimated using weighted nonlinear least-square regression analysis. Micafungin demonstrated linear plasma pharmacokinetics without changes in total clearance and dose-normalized area under the concentration-time curve from 0 h to infinity. After administration of single doses to the rabbits, mean peak plasma drug concentrations ranged from 7.62 μg/ml at 0.5 mg/kg to 16.8 μg/ml at 2 mg/kg, the area under the concentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 μg · h/ml, the apparent volume of distribution at steady state ranged from 0.296 to 0.343 liter/kg, and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in pharmacokinetic parameters and no accumulation was noted after multiple dosing. Mean tissue micafungin concentrations 30 min after the last of eight daily doses were highest in the lung (2.26 to 11.76 μg/g), liver (2.05 to 8.82 μg/g), spleen (1.87 to 9.05 μg/g), and kidney (1.40 to 6.12 μg/g). While micafungin was not detectable in cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 μg/g. These findings indicate linear disposition of micafungin at dosages of 0.5 to 2 mg/kg and achievement of potentially therapeutic drug concentrations in plasma and tissues that are common sites of invasive fungal infections.

What do we really know about antibiotic pharmacodynamics

Antibiotic pharmacodynamics is an evolving science that focuses on the relationship between drug concentration and pharmacologic effect, which is an antibiotic‐induced bacterial death that also can manifest as an adverse drug reaction. The pharmacologic action of antibiotics usually can be described as concentration dependent or independent, although such classifications are highly reliant on the specific antibiotic and bacterial pathogen being studied. Quantitative pharmacodynamic parameters, such as ratio of the area under the concentration‐time curve during a 24‐hour dosing period to minimum inhibitory concentration (AUC0–24:MIC), ratio of maximum serum antibiotic concentration to MIC (Cmax:MIC), and duration of time that antibiotic concentrations exceed MIC (T>MIC), have been proposed as likely predictors of clinical and microbiologic success or failure for different pairings of antibiotic and bacteria. Thus far, most pharmacodynamic data reported have focused on fluoroquinolones, but work has been conducted on vancomycin, β‐lactams, macrolides, aminoglycosides, and other antibiotics. Despite the development of a number of different pharmacodynamic modeling systems, remarkable agreement exists between in vitro, animal, and limited human data. Although still somewhat premature and requiring additional clinical validation, antibiotic pharmacodynamics will likely advance on four fronts: the science should prove to be extremely useful and represent a cost‐effective and efficient method to help develop new antibiotics; formulary committees will likely use pharmacodynamic parameters to assist in differentiating antibiotics of the same chemical class in making antibiotic formulary selections; pharmacodynamic principles will likely be used to design optimal antibiotic strategies for patients with severe infections; and limited data to date suggest that the application of pharmacodynamic concepts may limit or prevent the development of antibiotic resistance. The study of antibiotic pharmacodynamics appears to hold great promise and will likely become a routine part of our daily clinical practices.

Intensive care unit antimicrobial resistance and the role of the pharmacist

Over the past 20 yrs, pharmacists have successfully integrated their services and expertise to gain acceptance as full members of pediatric, surgical, medical, and intensive care unit (ICU) patient care teams. The pharmacists’ training in pharmacology, pharmacokinetics, pharmacodynamics, and pharmacoeconomics complements the expertise of other members of the patient care team. Generally, a strong background in infectious diseases and critical care also provides a focal point for clinical pharmacy service intervention. Although practitioners often focus on issues exclusively related to their specific hospital or ICU, the issues surrounding antibiotic resistance are more global and societal in nature. Medical, surgical, and pharmaceutical practices inside the hospital and ICU extend their influence into the community. Customs and practices of daily living in our society coupled with use of agents capable of altering microbial flora impact our hospital and ICU when patients from the community are admitted. The misuse of antibiotics and the lack of effective infection control programs are often identified as key components in the perpetuation of these phenomena. The focus for the pharmacist and the ICU team must be on the optimization of antibiotic use and infection control guidelines. This review will address the many issues that surround the appropriate use of antibiotics and what role the pharmacist can play in ensuring the optimal use of infection control measures in the ICU and hospital.

Comparative Pharmacodynamics of Three Newer Fluoroquinolones versus Six Strains of Staphylococci in an In Vitro Model under Aerobic and Anaerobic Conditions

ABSTRACT Six strains of staphylococci were exposed to levofloxacin, moxifloxacin, or trovafloxacin in an in vitro pharmacodynamic model under both aerobic and anaerobic conditions. Each agent demonstrated a rapid 3-log10 kill versus susceptible isolates regardless of condition. Against clinical isolates with reduced susceptibility, regrowth occurred by 24 h and was frequently associated with further increases in MICs.

Microbiologic effectiveness of time- or concentration-based dosing strategies in Streptococcus pneumoniae

This in vitro study evaluated the pharmacodynamic performance of levofloxacin using different dosing strategies against both a levofloxacin-sensitive (MIC = 1 mg/liter) and -resistant (MIC = 16 mg/liter) strain of Streptococcus pneumoniae. The strain was genotypically characterized by a mutation in gyrA and two mutations in parE; resistance was shown not to be efflux-mediated. The purpose of this study was to determine if simulated levofloxacin dosing strategies focused either on time or concentration would affect microbiologic outcome. Differing peak concentration/MIC ratios (1,2, and 10), T>MIC (3.6,9.6,15.6, and 24 h corresponding to 15, 40, 65, and 100% of the 24-h dosing interval), and AUC/MIC ratios (13-180) were generated by varying dosing strategies. Initial bacterial inocula were decreased by 99.9% in each experiment conducted. Despite the wide variation in exposure levels, in terms of AUC/MIC, Cp-max/MIC, and T>MIC, the kill portions of the bacterial density curves were super-imposable between all permutations of antibiotic exposure. However, there appeared to be an AUC/MIC breakpoint (35-40) defining bacterial regrowth. Over a 10-fold concentration range, levofloxacin appeared to kill S. pneumoniae in a concentration-independent fashion. When given in concentrations suitable to achieve specified pharmacodynamic endpoints (AUC/MIC >/=35), levofloxacin demonstrated the ability to eradicate both a levofloxacin-resistant and levofloxacin-sensitive strain of S. pneumoniae in the in vitro model.

Comparison of Linezolid Activities under Aerobic and Anaerobic Conditions against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus faecium

ABSTRACT Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium were exposed to linezolid (MIC of 2 mg/liter) under aerobic or anaerobic conditions in an in vitro pharmacodynamic model. Drug concentration and half-life were adjusted to simulate clinical dosing (600 mg twice daily) of linezolid. Linezolid produced a 2-log10 killing at 24 h, and rates of killing against each of these facultative organisms as measured by mean survival time appeared similar under aerobic and anaerobic conditions.

Bacillus anthracis: Medical Issues of Biologic Warfare

Recent world events refocused attention on the possibility of nations engaging in biologic warfare, including an attack with Bacillus anthracis. The single available anthrax vaccine in the United States for human use, formerly known as MDPH‐PA, has decreased ability to protect laboratory animals against virulent B. anthracis strains, especially compared with new vaccines being developed. Studies with these vaccines, however, have several shortcomings. The pathogenesis, diagnosis, treatment, and prophylaxis of anthrax are discussed, as well as the implications that an attack with B. anthracis would place on the health care system.

Pharmacodynamics of Pulse Dosing versus Standard Dosing: In Vitro Metronidazole Activity against Bacteroides fragilis and Bacteroides thetaiotaomicron

ABSTRACT Pulse dosing is a novel approach to dosing that produces escalating antibiotic levels early in the dosing interval followed by a prolonged dose-free period. Antibiotic is frontloaded by means of four sequential bolus injections, after which antibiotic levels are allowed to diminish until the next dose. This study compares standard thrice-daily dosing and pulse dosing of metronidazole against Bacteroides spp. in an in vitro model. Two American Type Culture Collection Bacteroides fragilis isolates (metronidazole MIC for each organism = 1 mg/liter) were exposed to metronidazole for 48 or 96 h. Human pharmacokinetics were simulated for an oral 500-mg dose given every 8 h (maximum concentration of drug [Cmax] = 12 mg/liter; half-life = 8 h; area under the curve [AUC] = 294 mg · h/liter) and for pulse dosing. Pulses, each producing an increase in metronidazole concentration of 9 mg/liter, were administered at times 0, 2, 4, and 6 h of each 24-h cycle, with a targeted half-life of 8 h (AUC = 347 mg · h/liter). A metronidazole-resistant B. fragilis strain (metronidazole MIC = 32 mg/liter) was exposed to both dosing regimens and, additionally, to a regimen of 1,500 mg administered once daily (Cmax = 36 mg/liter; AUC = 364 mg · h/liter). Furthermore, regimens against one B. fragilis isolate and one B. thetaiotaomicron isolate corresponding to one-fourth and one-eighth of the thrice-daily and pulse dosing regimens, mimicking peak metronidazole concentrations achieved in abscesses, were simulated in 48-h experiments (metronidazole MIC = 1 mg/liter). Time-kill curves were generated for each experiment and analyzed for bactericidal activity, defined as a bacterial burden reduction ≥ 3 log10 CFU/ml. The results of paired (Wilcoxon matched-pair signed-rank test) and nonpaired (Mann-Whitney test) statistical analyses conducted on time to 3 log10 kill data and area under the kill curve data from each of the thrice-daily dosing experiments versus each of the pulse dosing experiments were considered not significant for a given isolate-dosing regimen combination. The thrice-daily dosing, pulse dosing, and once-daily dosing regimens all exhibited bactericidal activity. Metronidazole administered in standard or pulse dosing fashion was highly active against both susceptible and resistant strains of Bacteroides spp.

Mutation prevention concentration of ceftriaxone, meropenem, imipenem, and ertapenem against three strains of Streptococcus pneumoniae

This investigation tested the mutation prevention concentration (MPC) concept using imipenem, meropenem, ceftriaxone, and ertapenem against three strains of Streptococcus pneumoniae (PCN MIC = 0.012, 1, 8 mg/L, respectively). MIC, MBC, and MPC values for each of the beta-lactams did not differ by more than one tube dilution. While an interesting concept, MPC may not apply to antimicrobials that do not utilize a dual targeting system, such as beta-lactams, or to bacteria that exhibit multiple mechanisms of resistance and/or mutate at a rate where the frequency would likely be captured by the standard inoculum size used in routine MIC testing.