Treatment Options for Carbapenem- Resistant Gram-Negative Infections.

BACKGROUND: Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. RESULTS: Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. CONCLUSION: The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.

Application of statistical process control for spotting compliance to good pharmaceutical practice

ABSTRACT For the release of pharmaceutical products into the drug market; most of the pharmaceutical companies depend on acceptance criteria - that are set internally, regulatory and/or pharmacopeially. However, statistical process control monitoring is underestimated in most quality control in cases; although it is important not only for process stability and efficiency assessment but also for compliance with all appropriate pharmaceutical practices such as good manufacturing practice and good laboratory practice, known collectively as GXP. The current work aims to investigate two tablet inspection characteristics monitored during in-process control viz. tablet average weight and hardness. Both properties were assessed during the compression phase of the tablet and before the coating stage. Data gathering was performed by the Quality Assurance Team and processed by Commercial Statistical Software packages. Screening of collected results of 31 batches of an antibacterial tablet - based on Fluoroquinolone -showed that all the tested lots met the release specifications, although the process mean has been unstable which could be strongly evident in the variable control chart. Accordingly, the two inspected processes were not in the state of control and require strong actions to correct for the non-compliance to GXP. What is not controlled cannot be predicted in the future and thus the capability analysis would be of no value except to show the process capability retrospectively only. Setting the rules for the application of Statistical Process Control (SPC) should be mandated by Regulatory Agencies.

Development of certified reference materials for accurate determination of fluoroquinolone antibiotics in chicken meat.

Certified reference materials (CRMs; KRISS CRM 108-03-003, 108-03-004) were developed for the accurate determination of fluoroquinolones (enrofloxacin and ciprofloxacin, respectively) in chicken meat. Two groups of chickens were cured with feeds containing enrofloxacin and ciprofloxacin, respectively. After slaughter, the thigh and breast meats were combined for the respective groups and the meat was freeze-dried, pulverized, sieved, and V-mixed. The final bulk material was bottled in 10g portions. For certification of the CRMs, isotope dilution-liquid chromatography/tandem mass spectrometry was used. The certified values of the CRMs were (19.06±0.86)mg/kg for enrofloxacin and (1.095±0.038)mg/kg for ciprofloxacin. The stabilities of the CRMs were monitored at -70°C for 12months, at -20°C for 2months, and at room temperature for 1month. Both CRM candidates were stable during the monitoring period for each temperature.

Spectrofluorimetric methods for the determination of gemifloxacin in tablets and spiked plasma samples.

Two new, sensitive and selective spectrofluorimetric methods have been developed for the determination of gemifloxacin (GFX) in tablets and spiked plasma samples. Gemifloxacin, as a primary amine compound, reacts with 7-chloro-4-nitrobenzofurazon (NBD-Cl) (for method A) and fluorescamine (for method B) which are a highly sensitive fluorogenic reagents used in many investigations. For method A, the reaction product was measured spectrofluorimetrically at 516 nm with excitation at 451 nm. The reaction proceeded quantitatively at pH 8.5, 80 °C in 7 min. For method B, the method was based on the reaction between GFX and fluorescamine in borate buffer solution of pH 8.5 to give highly fluorescent derivatives that were measured at 481 nm using an excitation wavelength of 351 nm. The fluorescence intensity was directly proportional to the concentration over the range 40-200 ng mL(-1) and 100-1,200 ng mL(-1) for method A and B, respectively. Successful applications of the developed methods, for the drug determination in pharmaceutical preparations and spiked plasma samples, were performed.

Socially responsible antibiotic choices in primary care: a qualitative study of GPs' decisions to prescribe broad-spectrum and fluroquinolone antibiotics.

BACKGROUND: There is considerable variation within and between countries in general medical practitioners' (GPs') prescribing of broad-spectrum antibiotics such as fluroquinolones, and resistance to these agents is increasing worldwide. Urgently promoting cautious fluroquinolone prescribing in primary care may limit increase in resistance. OBJECTIVE: We therefore interviewed 40 GPs in order to explore the reasons for their choice of prescribed antibiotic, in particular their decision to prescribe fluroquinolones. METHODS: We used a grounded theory approach to data collection and analysis, incorporating purposive and theoretical sampling, based on high and average fluroquinolone prescribing. Interviews were conducted with 26 GPs from practices known to be high prescribers of fluroquinolone antibiotics and 14 from average fluroquinolone prescribing practices. RESULTS: Chosing to prescribe a broad-spectrum antibiotic such as a fluroquinolone, rather than a narrow-spectrum antibiotic, related to a number of clinical considerations, perceptions of patient expectations and organizational influences. GPs from high fluroquinolone prescribing practices were more likely to prioritize patients' immediate needs, whereas GPs from average prescribing practices were more likely to consider longer term issues. GPs from both high and average fluroquinolone prescribing practices justified their antibiotic choices on the basis of a desire to do their best for their patients and society. CONCLUSION: Choosing to prescribe powerful, broad-spectrum antibiotics such as fluroquinolones, as well as choosing to keep these agents in reserve, was justified on the basis of social responsibility. Strategies to change fluroquinolone and broad-spectrum antibiotic prescribing will need to take into account clinicians' perceptions of social responsibility.

Determination of lomefloxacin in tablet preparations by liquid chromatography.

A sensitive, precise, and specific high-performance liquid chromatography (HPLC) method was developed for the assay of lomefloxacin (LFLX) in raw material and tablet preparations. The method validation parameters yielded good results and included the range, linearity, precision, accuracy, specificity, and recovery. It was also found that the excipients in the commercial tablet preparation did not interfere with the assay. The HPLC separation was performed on a reversed-phase Phenomenex C18 column (150 x 4.6 mm id, 5 microm particle size) with a mobile phase composed of 1% acetic acid-acetonitrile-methanol (70 + 15 + 15, v/v/v), pumped isocratically at a flow rate of 1.0 mL/min. The effluent was monitored at 280 nm. The calibration graph for LFLX was linear from 2.0 to 7.0 mg/mL. The interday and intraday precisions (relative standard deviation) were less than 1.0%. The method was applied for the quality control of commercial LFLX tablets to quantitate the drug.

Determination of gatifloxacin and ornidazole in tablet dosage forms by high-performance thin-layer chromatography.

A simple and sensitive high-performance thin-layer chromatography (HPTLC) method has been developed for the quantitative estimation of gatifloxacin and ornidazole in its combined dosage forms. Gatifloxacin and ornidazole were chromatographed on silica Gel 60 F(254) TLC plate using n-butanol:methanol:ammonia (6 M) (8:1:1.5 v/v) as the mobile phase and scanned at 302 nm using a Camag TLC Scanner 3. The R(f) value of gatifloxacin and ornidazole was found to be 0.21 +/- 0.02 and 0.76 +/- 0.04, respectively. The linearity of gatifloxacin and ornidazole were in the range of 100 - 500 ng/spot and 250 - 1250 ng/spot, respectively. The limit of detection was found to be 40 ng/spot for gatifloxacin and 100 ng/spot for ornidazole. The proposed method was applied for the determination of gatifloxacin and ornidazole in combined dosage forms.

Microbiological assay for enrofloxacin injection.

A simple, sensitive and specific agar diffusion bioassay for the antibacterial enrofloxacin was developed. Using a strain of Staphylococcus aureus ATCC 6538P as the test organism, enrofloxacin at concentrations ranging from 3.2 to 12.8 microg ml(-1) could be measured in injection. A prospective validation of the method showed that method was linear (r = 0.99998), precise (R.S.D. = 0.27) and accurate (it measured the added quantities). The method shows results that confirm its precision, not differing significantly the other method described in the literature. We conclude that microbiological assay is satisfactory for quantitation of in vitro antibacterial activity of enrofloxacin.