The resistance to antibacterials therapy has been increasing in recent years.1,2 The rational use of anti-bacterials should include: (1) choosing the right drugs according to the scope of their antibacterials function and making sure they are suitable for treatment of the microorganisms that have induced the infection;3 (2) administering anti-bacterials by a rational method according to their pharmacodynamics;4 (3) paying attention to the systemic condition of the patients according to pharmacokinetics of the drugs.5,6
There are many pharmacodynamic/pharmacokinetic (PK/PD) parameters to be considered in order to use anti-bacterials rationally.7,8 For the purpose of giving consideration to these factors, maximally increasing the curative effect and decreasing the adverse effects, the antibacterial-application software called Laenne™ Clinical Pharmacodynamic Monitoring (Laenne™ CPM) was created by Pulmonary Department and Pharmacy Department of East Hospital, and was developed by the Boartland Health Technology Co., Ltd, China.
Case 1: Selection of the appropriate dosage of cefepime to avoid epileptic seizure
The first patient was a 41 years old female with postpartum hemorrhage, disseminated intravascular coagulation (DIC), hemorrhagic shock, hysterectomy, laparotomy and sepsis. On March 21, 2007, the patient had an epileptic seizure, right Babinski sign (+). MRI displayed multi-cerebral infarcts and a left hippocampus compressed by edema. Electroencephalogram exam showed eleptiform discharge. Sodium valproate and phenobarbital sodium were given to treat the epileptic seizure.
The result of a sputum culture showed an Enterobacter cloacae which was cefepime sensitive. According to the usual prescription, cefepime was given 2.0 g i.v, bid. However, cefepime may accumulate and induce an epileptic attack.9 A judicious dosage choice was needed for cefepime that has an effective therapeutic activity to infection of Enterobacter cloacae while avoiding its possibility of exacerbating epileptic seizure.
With the antibacterial-application software (2.0 version), we selected Enterobacter cloacae in the “Bacterium information” column, and selected sensitive in the “minimum inhibitory concentration” (MIC) column according to the results of the sensitivity test. In the “patient's information” column we input the demographic data, then added cefepime in the “Medication information” column, and then clicked “pharmacokinetic parameter selection”.
The recommended dosage of cefepime was 2000 mg, q12 h, time for intravenous injection was 0.5 hour, for 7 days. Cefepime is a time-dependent agent, so we selected T/MIC and clicked the “calculation” button; T/MIC was 100%, suggesting that the regimen might exacerbate epileptic seizure (Figure 1A).
Therefore we reduced the dosage to 1000 mg, i.v, q12 h, and the T/MIC was 86.13%, still over 50%. Considering the patient's infection was severe, the regimen was appropriate (Figure 1B).
According to this calculation analysis, cefepime was given 1000 mg i.v q12 h for 7 days, and the temperature returned to normal range. Moist rales in both lung disappeared. The patient had no epileptic seizure and the infection was well controlled until discharge.
Case 2: Over dose of levofloxacin induced renal dysfunction and hepatic damage
The second patient was an 82 years old male with hypertension, diabetes, coronary heart disease and primary hypothyroidism. With “right limbs debility and dysphrasia for 4 hours” he was admitted on May 8, 2005. Diagnosis was a cerebral infarction and pulmonary infection. On admission examination, serum creatinine was 149 mol/L (normal range 59–104 mol/L). Liver function was normal. The result of sputum culture was Klebsiella pneumoniae with sensitivity to levofloxacin (MIC=2 mg/L). On May 13, levofloxacin was given (0.3 g, i.v, bid). After 3 days, the serum creatinine was up to 235 mol/L, alanine transaminase (ALT) was 662 IU/L (normal range <64 IU/L). As a result, levofloxacin was immediately withdrawn.
Retrospective analysis of the software
According to the drug description (Beijing No. 1 Pharmaceuticals Company, China), the initial dose of levofloxacin should be 0.4 g, then 0.2 g per day afterwards. Administering levofloxacin (0.3 g, i.v, bid) was easier to start levofloxacin accumulation and kidney crystallization. All of these aggravated kidney inadequacy and damaged liver function.10 On May 15, the software showed further accumulation of levofloxacin in the body (Figure 2A).
On May 17 (3 days after withdrawing levofloxacin), the serum creatinine was 214 mol/L, ALT was 464 IU/L. On May 22, the serum creatinine was 187 mol/L, GPT was in normal range. According to the dispensatory, and as displayed by the software (Figure 2B), the initial dose of levofloxacin was 0.4 g, and then 0.2 g per day, the concentration of levofloxacin in this patient should be stable (AUC/MIC 104.12), which obtained anti-infection efficacy and avoided renal and liver function damage concurrently.
Case 3: Isepamicin and isosorbide mononitrate led to acute kidney function failure, imipenam led to severe liver function damage
The patient was a 74 years old female, with “repeated cough and wheezing more than 8 years, aggravated one day”, who was admitted on February 22, 2007, diagnosed as chronic bronchitis with infection, emphysema, respiratory failure, hypertension and basal ganglia cerebral infarction. On admission, liver and kidney functions were normal. Isepamicin was used (i.v.) for 3 days (February 26–28), imipenam 500 mg i.v q8 h for 7 days (February 28-March 6), isosorbide mononitrate orally and amiodarone for atrial premature intravenously were given concurrently. From March 1, the patient presented with hypotension. On March 5, the patient suffered from renal failure.
Retrospective analysis by the software
The patient had respiratory failure and hypertension, possibily followed by infectious shock that lead to hypovolemia; all can induce renal parenchyma damage. In addition, isepamicin can lead to acute renal tubular necrosis. After using isosorbide mononitrate, the patient had severe hypotension. There is report that imipenem can lead to more than 50% patients' ALT rise.10 Renal failure can lead to the accumulation of imipenam.
Imipenam is a time-dependent antibiotic. According to software analysis, if the dose of imipenam was 500 mg, i.v, q8 h, T/MIC was 100% representing an overdose (Figure 3A). When reducing the dose to 250 mg, i.v, q8 h, T/MIC was 90.17%, this regimen might be appropriate (Figure 3B).
The clinicians didn't decrease the dose of imipenam when the patient suffered from renal failure, so it resulted in an over dose accumulation that led to liver function damage. Other reasons that caused liver function damage might be amiodarone, isosorbide mononitrate and the severe infection or hypoxia.
The main factor that influences the effect of the antibacterials is the interaction between the parameters of the pharmacodynamics and the antimicrobial susceptibility.11–13 (1) Aminoglycosides and quinolones are the concentration-dependent agents. For quinolones, if the ratio of serum area under the curve to MIC in 24 hours (AUC/MIC) >125, it has therapeutic efficacy. For aminoglycosides, if Cmax/MIC >12, it can be anticipated as having efficacy.14,15 (2) Time-dependence agents include β-lactam, macrolides, clindamycin, and glycopeptides. When T >MIC is 50%-70%, the dosage and regimen of the agents are considered suitable.
The software system collects the information that comes from the American National Clinical Laboratory Standard Commission (NCCLS).16 The function of this software includes: (1) Establishing mathematical models according to the pharmodynamics and pharmacokinetics equations; (2) For time-dependent anti-bacterials, displaying the ratio of the antibacterials concentration beyond MIC; (3) For concentration-dependent anti-bacterials, displaying serum Cmax/MIC and the AUC/MIC; (4) realizing the cure of the infectious disease by computer technology.
The software can reflect the dynamic blood curve of antibacterials, offer a quick reference to adjust the regimen, and give more effective and more economical therapy. We can adjust the accuracy of the dosage of the antibacterials and offer a referenced therapeutic regimen by the software. We have completed analysis of about 200 infectious cases with this software, and have proved that it can analyze the clinical data quickly and to satisfy the demand of the clinic.
The software is based on the theories of the pharmacodynamics and pharmacokinetics, reflecting the dynamic serum curve of antibacterials. It can give quick reference to devise or adjust dosage and regimen for a rational application of antibacterials and more economical therapy to the infectious patients while avoiding adverse effects. To our knowledge this software is the first tool to establish a direct relationship between the theory of PK/PD and clinical practice in China. This software has already obtained a patent from China National Copyright Bureau (No. 2007SR00479).
1. Van Belkum A. 40 years of methicillin resistant Staphylococcus aureus,
MRSA is here to stay-but it can be controlled. BMJ 2001; 323: 644–645.
2. Bratu S, Landman D, Haag R, Recco R, Eramo A, Alam M, et al. Rapid spread of Carbapenem-resistant Klebsiella pneumoniae
in New York city: A new threat to our antibiotic armamentarium. Arch Intern Med 2005; 165: 1430–1435.
3. Franklin DL. Antimicrobial resistance: the example of Staphylococcus aureus.
J Clin Invest 2003; 111: 1265–1273.
4. Rybak MJ. Pharmacodynamics: relation to antimicrobial resistance. Am J Infect Control 2006; 4(5 Suppl 1):S38-S45; discussion S64–S73.
5. Regoes RR, Wiuff C, Zappala RM, Garner KN, Baquero F, Levin BR. Pharmacodynamic functions: a multiparameter approach to the design of antibiotic treatment regimens. Antimicrob Agents Chemother 2004; 48: 3670–3676.
6. Nightingale CH, Murakawa T, Ambrose PG. Antimicrobial pharmacodynamics in theory and clinical practice. Marcel Dekker, Inc., 2002: 16–17.
7. Scheetz MH, Hurt KM, Noskin GA, Oliphant CM. Applying antimicrobial pharmacodynamics to resistant Gram-negative pathogens. Am J Health Syst Pharm 2006; 63: 1346–1360.
8. Jean SS, Teng LJ, Hsueh PR, Ho SW, Luh KT. Antimicrobial susceptibilities among clinical isolates of extended-spectrum cephalosporin-resistant Gram-negative bacteria in a Taiwanese University Hospital. J Antimicrob Chemother 2002; 49: 69–76.
9. Zou L. Cefepime leads to paroxysmal epileptic seizure. J Drug Adverse Reaction 2004; 4: 257–258.
10. Jia GP, Xie HP. Prevention and cure for drug adverse. Beijing: The People's Publishing House; 2002: 496-500; 504–506.
11. Conly J. Antimicrobial resistance in Canada. CMAJ 2002; 167: 885–891.
12. Hickev E. Tools to define the relevance of PK/PD parameters to the efficacy, toxicity and emergence of resistance of antimicrobials. Curr Opin Drug Discov Devel 2007; 10: 49–52.
13. Pharmacodynamics: relation to antimicrobial resistance. Am J Med 2006; 119 (6 Suppl 1): S37-44; discussion S62–70.
14. Tod MM, Padoin C, Petitjean O. Individualising aminoglycoside dosage regimens after therapeutic drug monitoring: simple or complex pharmacokinetic methods? Clin Pharmacokinet 2001, 40: 803–814.
15. Wright DH, Broum GH, Peterson ML, Rotschafer JC. Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother 2000, 46: 669–683.
16. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163: 1730–1754.
Keywords:© 2008 Chinese Medical Association
antibacterial-application software; antibacterial; pharmacodynamic/; pharmacokinetic parameters