Abstract
Abstract
Background:
Gram-negative bacterial resistance to antibiotics is of increasing concern. Carbapenem resistance among strains of Klebsiella pneumoniae is a relatively new phenomenon. Resistance attributable to production of carbapenemases is notoriously difficult to combat.
Methods:
Case report and review of the pertinent English-language literature.
Results:
A patient, hospitalized for aortic dissection complicated by intra-abdominal catastrophe and acute kidney injury, developed bacteremia exhibiting meropenem non-susceptibility secondary to expression of blaKPC-2. High-dose, continuous-infusion meropenem achieved serum drug concentrations above the minimum inhibitory concentration and eradicated the infection.
Conclusion:
This is the first report of a meropenem-non-susceptible carbapenamase-positive Klebsiella pneumoniae blood stream infection treated successfully with high-dose, continuous-infusion meropenem. Application of this regimen in certain patients, such as those with mild-to-moderate renal insufficiency, may be a reasonable option for multi-drug-resistant nosocomial infections.
Beta-lactam antibiotics eradicate bacteria when the drugs' free concentrations are above the minimum inhibitory concentration (MIC) for a sufficient time during the dosing interval (fT>MIC). For carbapenems, the effective fT>MIC has been 40% in in vivo and in vitro animal models [4]. Continuous infusion has been proposed as a mechanism for optimizing the attainment of pharmacodynamic targets in plasma. We present a case of bacteremia caused by a multi-drug-resistant strain of Klebsiella pneumoniae that was treated successfully with continuous infusion of high-dose meropenem.
Case Report
The patient, a 58-year old man with a history of hypertension, presented with a Type B aortic dissection with extension to the renal and superior mesenteric arteries, leading to infarction of the right kidney, gallbladder, right colon, and much of the small bowel. He required cholecystectomy, ileo-cecal resection with Brooke end-ileostomy, and an aorto-superior mesenteric bypass graft. His post-operative course was complicated by acute kidney injury, respiratory failure necessitating a tracheostomy, open-abdomen wound management, and total parenteral nutrition to manage multiple enteric fistulas draining into the open surgical site. He had a prolonged critical illness complicated by protein–calorie malnutrition and multiple infections, including ventilator-associated pneumonia, recurrent urinary tract infections, and multiple catheter-related blood stream infections. Five months into his hospitalization, he developed bacteremia with a strain of K. pneumoniae that produced a carbapenemase of type KPC-2, as confirmed by polymerase chain reaction. The source was most likely his urinary tract, as the same organism was cultured from a urine sample submitted concurrently. The antimicrobial susceptibility results are shown in Table 1.
The patient was treated initially with 24 h of piperacillin/tazobactam (3.375 g q 6 h) and four days of daptomycin (6 mg/kg q 24 h) dosed on the basis of a glomerular filtration rate (GFR) of 55 mL/min, but on receipt of antimicrobial susceptibility testing results indicating β-lactam resistance, his regimen was changed to polymyxin B (15,000 units/kg/day) and linezolid (600 mg q 12 h) for a total of two weeks. Clinical improvement was noted, and repeat blood and urine cultures showed no evidence of any organisms. However, this organism re-emerged two months later, with urine and blood cultures yielding the same organism with non-susceptibility to meropenem (Table 1). He was treated with polymyxin B (25,000 units/kg/day) and amikacin (7.5 mg/kg/day) on the basis of a GFR of 50 mL/min. Further renal deterioration over the next two weeks (nadir GFR 15 mL/min) necessitated revised dosing to 15,000 units/kg/day and 5 mg/kg/day, respectively. Repeat blood cultures over the next two weeks demonstrated persistent bacteremia. After this treatment failure, he was started on meropenem, 2 g IV q 8 h, administered as a continuous infusion. Because the stability of the compound is not sufficient to support the use of a single infusion bag over 24 h, the 2-g dose was prepared in 100 mL of 0.9% NaCl for infusion over 8 h. Additional bags were prepared for each subsequent 8 h period over a six-week course of therapy.
Four blood samples were taken at random to measure the serum concentrations of meropenem. After being allowed to clot, blood samples were centrifuged at 3,200 rpm for 10 min to separate the serum and were stored immediately at −80°C until analysis. All samples were assayed using a validated high-performance liquid chromatography method (coefficient of variation <5%) at the Center for Anti-Infective Research and Development (Hartford, CT) [5]. Serum meropenem concentrations averaged 22.45 micrograms/mL (range 19.63–28.53 micrograms/mL). Using a plasma protein binding of meropenem of 2% [6], the free (unbound) concentration in the samples ranged from 19.24–27.86 micrograms/mL, well exceeding the meropenem susceptibility testing MIC for this organism of 8 micrograms/mL. The patient's mean (±standard error [SE]) serum creatinine concentration at the four time points was 1.75±0.05 mg/dL (range 1.6–1.8 mg/dL). Using the Modification of Diet in Renal Disease (MDRD) equation for GFR estimation and the patient's dry weight, the mean GFR was calculated to be 40–45 mL/min [7]. Prior to initiating treatment, he had 12- and 24-h creatinine clearances ranging from 24–40 mL/min (mean 32 mL/min).
After clearance of the infection, the patient's hospital course was notable for takedown of his ostomy and enteric fistulae with abdominal wall reconstruction using a biological mesh prosthesis. The patient received six weeks of intravenous therapy with meropenem and was discharged off antibiotics. He did not require nephrectomy. He remains well and free of infection at 21 months' followup.
Discussion
Klebsiella pneumoniae is a gram-negative bacillus that is a common pathogen in healthcare-associated infections. Klebsiella pneumoniae can display multi-drug-resistant phenotypes, as well as the ability to transfer these antibiotic resistance determinants to other pathogens [8]. More recently, the organism has displayed resistance to carbapenems via the production of carbapenemases that hydrolyze this class of compounds rapidly. Klebsiella pneumoniae carbapenemase production is particularly concerning, as is its rapid worldwide dissemination. Carbapenemase-producing K. pneumoniae has been responsible for outbreaks of infection in New York, Israel, and South America, as well as sporadic cases in several other geographic areas [9].
Meropenem is a carbapenem antibiotic prescribed frequently for the treatment of nosocomial infections because of its broad spectrum of activity against gram-negative and gram-positive organisms. Meropenem exerts its antimicrobial activity in a time-dependent manner, and the efficacy is related to the time for which the free concentration is above the MIC during a dosing interval (fT>MIC). Time-dependent antibiotics optimize the attainment of pharmacodynamic targets in plasma, and a recent Monte Carlo simulation showed that continuous infusion of meropenem maintains higher concentrations in plasma than intermittent bolus dosing, leading to potential benefit in critically ill patients with sepsis [10]. This simulation suggested that the probability of target attainment of at least 40% fT>MIC with a continuous infusion of 6 g/day would produce sufficient exposures for organisms with meropenem MICs of >16 micrograms/mL, but would be insufficient for MICs exceeding 32 micrograms/mL. The measured meropenem concentrations obtained during the administration of 6 g/day in our patient with reduced renal function provides pharmacologic evidence for the effectiveness of this continuously infused regimen against this KPC-producing organism with an MIC of 8 micrograms/mL.
The benefit of continuous infusion of β-lactam antibiotics has been debated in the literature. Proponents cite higher serum trough concentrations and longer fT>MIC than is achieved with standard bolus dosing. One retrospective cohort examining 89 patients with gram-negative ventilator-associated pneumonia treated with meropenem showed a greater clinical cure rate in the continuous- than in the intermittent-dosing group [11]. A recent meta-analysis of continuous dosing of β-lactam antibiotics found no additional benefits [12]. However, continuous dosing may be an effective means of treatment in selected critically ill patients or for specific pathogens with higher MICs.
This case is unique because it is the first report of a meropenem-non-susceptible KPC-producing Klebsiella pneumoniae blood stream infection that was treated successfully with high-dose, continuous-infusion meropenem. Application of this treatment regimen in selected patients, including those with mild-to-moderate renal insufficiency, may be a reasonable option for multi-drug-resistant nosocomial infections.
Footnotes
Author Disclosure Statement
VPH was, in part, supported by the Surgical Infection Society Foundation/Wyeth Fellowship in Clinical Evaluative Sciences. SGJ, CIA, HKT, and DPN have no conflicts. PSB is a consultant to and has received honoraria from AstraZeneca and Cubist.