Multidrug-Resistant Pseudomonas aeruginosa : A Case of Pyelonephritis and Herbal Therapy

Introduction

P seudomonas aeruginosa is a gram-negative, aerobic, rod-shaped bacterium that inhabits a wide range of environments. It is also an important cause of morbidity in high-risk patients, such as cancer, cystic fibrosis, burn, and immunosuppressed patients. ¹ Due to its potential for developing resistance against multiple antibiotic and antiseptic compounds, P. aeruginosa has emerged as a major, difficult-to-treat nosocomial pathogen. Extended-spectrum-β-lactamase (ESBL) is the transferable resistance determinant having the highest clinical impact on antimicrobial therapy. The detection of ESBL in the strain adds further complexity and concern to the resistance patterns of the organism. ²

P. aeruginosa has developed resistance not only to cephalosporins but also to carbapenems and quinolones. In 2003, the National Nosocomial Infections Surveillance System reported that resistance rates of P. aeruginosa to broad-spectrum cephalosporins, quinolone, and imipenem were 31.9, 29.5, and 21.1%, respectively. Compared to rates in the period between 1998 and 2002, these rates were increased by 20, 9, and 15%, respectively. ³ Therefore, new anti-P. aeruginosa agents that have no cross-resistance to currently marketed antibacterial agents need to be found.

Herbal medicine has been an integral part of Traditional Chinese Medicine for more than 2000 years. Many herbal formulations have been developed and are used in the treatment of urinary tract infection. Recently, a case of pyelonephritis caused by multidrug-resistant P. aeruginosa was successfully treated with the herbal decoction in the authors' clinic. No similar reports appear in the previous literature.

Case Report

A 65-year-old woman presented on May 22, 2012 at the authors' department with clinical signs of pyelonephritis. She had a past medical history of lung adenocarcinoma that required a resection and radiation therapy. She presented to our clinic with dysuria, frequency, suprapubic pain, urinary incontinence, and a white blood cell count of 11,200. Antibiotic treatment was started empirically with oral cefixime (400 mg every 24 hours). A urine sample was taken. After 48 hours, P. aeruginosa was grown (10⁶ colony-forming units [CFU]/mL) as a single organism from the urine. Bacterial identification was based on positive arginine dihydrolase and cytochrome oxidase tests, a nonfermentative Kligler, and growth at 42°C.

Antimicrobial susceptibility testing was performed by disc diffusion on Mueller-Hinton agar incubated for 24 hours at 35°C and was interpreted according to Clinical and Laboratory Standards Institute criteria. The organism was found to be susceptible to colistin but resistant to piperacillin–tazobactam, ceftazidime, cefixime, aztreonam, gentamicin, tobramycin, imipenem, meropenem, amikacin, and ciprofloxacin.

In accordance with documented cefixime in vitro activity, the patient returned 3 days later with worsening symptoms. Cefixime was discontinued, a second urine sample was taken, and a Chinese herbal decoction was started as follow: Tong Cao (Medulla tetrapanacis) 20 g, Hua Shi (talcum) 15 g, Chi Shao (Radix Paeoniae rubrae) 15 g, Xiao Hui Xiang (Fructus Foeniculi vulgaris) 15 g, Rou Gui (Cortex Cinnamomi) 15 g, Li Zhi He (Semen litchi) 15 g, Tian Kui Zi (Radix Semiaquilegiae) 15 g, Zi Hua Di ding (Herba cum Rd Violae yedoensitis) 20 g, Qu Mai (Herba Dianthi) 15 g, Ma Chi Xian (Herba Portulacae) 50 g, and Pu Gong Ying (Herba taraxaci) 30 g. The decoction was prepared by mixing the crude herbs in 800 mL water, obtaining 200 mL of liquor after the herbs were decocted in 800 mL of water (100°C for 30 minutes twice). The decoction was orally administered as 200 mL/day.

After 48 hours, P. aeruginosa was grown (10⁶ CFU/mL) as a single organism from the second urine sample as well. P. aeruginosa isolates were confirmed as class A ESBL-producing isolates by molecular testing. A bla _BEL allele was detected by multiplex polymerase chain reaction targeting bla _SHV, bla _TEM, bla _BEL, bla _PER, bla _VEB, and bla _GES alleles. ⁴ The isolates were identified as ST235, serotype O11 by methods described previously ⁵ or according to the manufacturer's instructions (Bio-Rad, Marnes-La-Coquette, France).

The patient returned 8 days later with relief of symptoms. Two urine samples were taken after 1 week and 2 weeks from the end of herbal therapy, respectively. However, it was not possible to isolate P. aeruginosa again.

Discussion

Urinary tract infections are one of the most common types of bacterial infections occurring in humans. P. aeruginosa has been implicated in urinary tract infections. ⁶ As an opportunistic infectious pathogen, P. aeruginosa can lead to life-threatening diseases. For example, P. aeruginosa is the main cause of mortality in cases of polymicrobial bacteremia. ⁷

In a study by D'Costa et al., ⁸ the soil was demonstrated to be a reservoir of resistance genes. The close relationship of P. aeruginosa to the soil has made it possible for the organism to acquire highly effective resistance determinants in response to multiple challenges. In this case, the strains of P. aeruginosa were isolated from urine of a patient suffering from cancer, which was particularly problematic because the organism was resistant to many antimicrobial drug classes. ⁹ The P. aeruginosa strain was found to produce ESBL. A bla _BEL allele was detected. This multidrug-resistant, ESBL-producing, ST235, serotype O11 P. aeruginosa clone, which first detected in the authors' hospital, was multiresistant to β-lactams, aminoglycosides, and ciprofloxacin, but remained susceptible to colistin. There were perilously few antibiotic choices.

In our previous studies, the Chinese formulation used in this case was proved to have antibacterial effects both in vitro and in vivo. ^{10 –12} The therapeutic results of Chinese herbs were expected to be poor in patients with multidrug-resistant infections previously. Yet these Chinese herbs eradicated isolates from the urine successfully.

In Traditional Chinese Medicine, drug resistance is believed to be caused by antimicrobial exposure and the patient's weak internal environment. In high-risk groups, while selective pressure is a factor leading to the emergence of resistant strains, the stability of the internal environment is a determining factor. This is in line with the concept of Traditional Chinese Medicine described in “The Medical Classic of Yellow Emperor”: while vital Qi exists, pathogenic factors cannot invade. ¹³

Herbal resistance is not easily generated. Herbal formulations have multiple and complicated active ingredients, which can act on a number of different positions, targets, and different stages of the reproduction process of bacteria. They can act on many metabolic processes of bacteria and often have a broad bacteriostatic spectrum. They can recover the micro-ecological balance, alleviate the select pressure, and modulate the immune system. These mechanisms might lead to successful eradication of the organism.

Bacteria resistance to multiple classes of antibiotics seriously compromises the ability to treat patients who are infected with these pathogens. In many instances, there are perilously few antibiotic choices. Hence, for the host, timely institution of effective therapy is a matter of survival. The case presented here provides further evidence for the pathogenic potential of P. aeruginosa. The case supports the notion that these Chinese herbs are useful in treating pyelonephritis caused by multidrug-resistant P. aeruginosa. Chinese herbal medicine has allowed physicians another choice of treatment.