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Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model

Mohamed AF, Kristoffersson AN, Karvanen M, Nielsen EI, Cars O, Friberg LE

J Antimicrob Chemother, 2016 May;71(5):1279-90.
PMID: 26850719 DOI: 10.1093/jac/dkv488

Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa.

Matched MeSH terms: Thienamycins
Fulltext Additivity vs Synergism: Investigation of the Additive Interaction of Cinnamon Bark Oil and Meropenem in Combinatory Therapy

Yang SK, Yusoff K, Mai CW, Lim WM, Yap WS, Lim SE, et al.

Molecules, 2017 Nov 04;22(11).
PMID: 29113046 DOI: 10.3390/molecules22111733

Combinatory therapies have been commonly applied in the clinical setting to tackle multi-drug resistant bacterial infections and these have frequently proven to be effective. Specifically, combinatory therapies resulting in synergistic interactions between antibiotics and adjuvant have been the main focus due to their effectiveness, sidelining the effects of additivity, which also lowers the minimal effective dosage of either antimicrobial agent. Thus, this study was undertaken to look at the effects of additivity between essential oils and antibiotic, via the use of cinnamon bark essential oil (CBO) and meropenem as a model for additivity. Comparisons between synergistic and additive interaction of CBO were performed in terms of the ability of CBO to disrupt bacterial membrane, via zeta potential measurement, outer membrane permeability assay and scanning electron microscopy. It has been found that the additivity interaction between CBO and meropenem showed similar membrane disruption ability when compared to those synergistic combinations which was previously reported. Hence, results based on our studies strongly suggest that additive interaction acts on a par with synergistic interaction. Therefore, further investigation in additive interaction between antibiotics and adjuvant should be performed for a more in depth understanding of the mechanism and the impacts of such interaction.

Matched MeSH terms: Thienamycins/pharmacology*; Thienamycins/chemistry; Thienamycins/agonists*
Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration

Jamal JA, Mat-Nor MB, Mohamad-Nor FS, Udy AA, Wallis SC, Lipman J, et al.

Int J Antimicrob Agents, 2015 Jan;45(1):41-5.
PMID: 25455853 DOI: 10.1016/j.ijantimicag.2014.09.009

The objective of this study was to describe the pharmacokinetics of meropenem, administered by continuous infusion (CI) or intermittent bolus (IB), in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and to evaluate the frequency of pharmacokinetic/pharmacodynamic target attainment with each dosing strategy. This was a prospective, randomised controlled trial in critically ill patients receiving CVVH and administered meropenem by CI or IB. Serial meropenem concentrations in plasma and ultrafiltrate were measured after administration of a standard total daily dose (4 g/day on Day 1, followed by 3g/day thereafter) on two occasions during antibiotic therapy. Meropenem pharmacokinetic parameters were calculated using a non-compartmental approach. Sixteen critically ill patients receiving CVVH concurrently treated with meropenem were randomised to CI (n = 8) or IB dosing (n = 8). IB administration resulted in higher maximum concentrations (C(max)) [64.7 (58.9-80.3) and 64.8 (48.5-81.8) mg/L, respectively] on both sampling occasions compared with CI (P < 0.01 and P = 0.04, respectively). CI resulted in a higher meropenem steady-state concentration (Css) on occasion 1 [26.0 (24.5-41.6) mg/L] compared with the minimum concentration (C(min)) observed for IB patients [17.0 (15.7-19.8)mg/L; P < 0.01]. CVVH contributed to ca. 50% of meropenem total clearance in these patients. The administered meropenem doses resulted in plasma drug concentrations that were >4× the targeted susceptibility breakpoint (2mg/L) for 100% of the dosing interval, for both groups, on both occasions. CI could be an alternative to IB for meropenem administration in critically ill patients receiving CVVH.

Matched MeSH terms: Thienamycins/administration & dosage*; Thienamycins/pharmacokinetics*
Imipenem for the treatment of melioidosis

Minassian MA, Gage A, Price E, Sefton AM

Int J Antimicrob Agents, 1999 Aug;12(3):263-5.
PMID: 10461846

Melioidosis is a protean disease caused by Burkholderia pseudomallei. It is rare in the UK and is generally only seen in patients with a travel history to endemic areas such as Thailand, Singapore and Malaysia. Cases may present with disseminated bacteraemic, non-disseminated bacteraemic, multi-focal bacteraemic or localized disease. Subclinical infections also occur. Following acquisition of the organism a patient may remain asymptomatic for several years before infection becomes clinically apparent. Factors such as diabetes, renal failure or other causes for a decrease in host immunity may precipitate the appearance of overt disease. The current treatment choice for severe melioidosis is parenteral ceftazidime followed by oral amoxycillin-clavulanic acid or a combination of co-trimoxazole, doxycycline and chloramphenicol. We report a case of melioidosis in a 59-year-old male diabetic from Bangladesh who initially responded to piperacillin-tazobactam but was changed to ceftazidime when a definitive diagnosis was made. His condition deteriorated on the latter antibiotic. He subsequently responded to imipenem. The patient's long-term outcome is still not known.

Matched MeSH terms: Thienamycins/therapeutic use*
Detection of blaoxa genes and identification of biofilm-producing capacity of Acinetobacter baumannii in a tertiary teaching hospital, Klaten, Indonesia

Nirwati H, Hakim MS, Darma S, Mustafa M, Nuryastuti T

Med J Malaysia, 2018 10;73(5):291-296.
PMID: 30350807

INTRODUCTION: Acinetobacter baumannii (A. baumannii) is commonly found as an agent of nosocomial infections and demonstrates a high antibiotic resistance due to its carbapenemase production. The objectives of this study were to explore the antibiotic resistance pattern, the presence of OXAs genes and the biofilm-producing capacity of A. baumannii isolated from clinical specimens.
METHODS: Antibiotics susceptibility testing, detection of OXAs genes and the biofilm-producing capacity were performed using the Kirby Bauer method, polymerase chain reaction (PCR) and adherence quantitative assays, respectively.
RESULTS: A total of 80 A. baumannii isolates were mainly obtained from sputum and most of them were resistant to antibiotics. All A. baumannii carried blaOXA-51 gene, yet no blaOXA-24 and blaOXA-58 genes were detected. Fourteen (82.4%) of the 17 meropenem resistant isolates carried blaOXA-23 gene, but it was not found in meropenem sensitive isolates. In addition, sixty (75.0%) of 80 isolates were biofilm producers with 2 (2.5%), 16 (20.0%), and 42 (52.5%) isolates were identified as strong, moderate and weak biofilm producers, respectively.
CONCLUSION: Most of A. baumannii isolates had a high level of antibiotic resistance and had a capacity to produce biofilm.

Matched MeSH terms: Thienamycins
Fulltext Antimicrobial susceptibility of clinical isolates of Pseudomonas aeruginosa from a Malaysian Hospital

Pathmanathan SG, Samat NA, Mohamed R

Malays J Med Sci, 2009 Apr;16(2):27-32.
PMID: 22589655 MyJurnal

Ongoing surveillance of Pseudomonas aeruginosa resistance against antimicrobial agents is fundamental to monitor trends in susceptibility patterns and to appropriately guide clinicians in choosing empirical or directed therapy. The in vitro activity level of eight antimicrobial drugs was assessed against 97 clinical isolates of P. aeruginosa collected consecutively for three months in 2007 from a Malaysian hospital. Antimicrobial susceptibility was determined using the E-test method in addition to the hospital's routine diagnostic testing by the disk diffusion method. Respiratory and wound swab isolates were the most frequently encountered isolates. The E-test and disk diffusion methods showed high concordance in determining the in vitro activity of the antimicrobial agents against the E isolates. Piperacillin-tazobactam was the most active antimicrobial agent with 91.8% susceptibility, followed by the aminoglycosides (amikacin, 86.6% and gentamicin, 84.5%), the quinolone (ciprofloxacin, 83.5%) and the beta-lactams (cefepime, 80.4%, ceftazidime, 80.4%, imipenem, 79.4% and meropenem, 77.3%). Incidence of multidrug resistance was 19.6% (19 out of 97 isolates). Periodic antibiotic resistance surveillance is fundamental to monitor changes in susceptibility patterns in a hospital setting.

Study site: Hospital Kuala Lumpur

Matched MeSH terms: Thienamycins
Burkholderia pseudomallei: in vitro susceptibility to some new and old antimicrobials

Karunakaran R, Puthucheary SD

Scand. J. Infect. Dis., 2007;39(10):858-61.
PMID: 17852912

The treatment of melioidosis currently involves the use of antimicrobials such as ceftazidime, trimethoprim-sulfamethoxazole, amoxicillin-clavulanate and doxycycline. Evaluation of other antimicrobials with activity against the organism continues to be pursued, however, as the causative organism, B. pseudomallei, may not always be susceptible to the above antimicrobials. This study aimed to test the susceptibility of Malaysian isolates of B. pseudomallei against imipenem, meropenem, ertapenem, moxifloxacin and azithromycin. 80 previously stocked clinical isolates collected between 1978 and 2003 from the UMMC, Kuala Lumpur were tested for in vitro susceptibility to these antimicrobials using the E-test minimum inhibitory concentration method. 100% of isolates were sensitive to imipenem and meropenem, 97.5% were sensitive to trimethoprim-sulfamethozaxole, 37.5% to moxifloxacin, and only a minority was sensitive to ertapenem (7.5%). Using breakpoints for Staphylococcus and Haemophilus, 5.0%-6.3% of isolates were sensitive to azithromycin. In conclusion, our findings support the in vitro efficacy of imipenem, meropenem and trimethoprim-sulfamethoxazole against B. pseudomallei. Moxifloxacin, ertapenem and azithromycin cannot be recommended for the treatment of melioidosis; however, further studies are needed to test the efficacy of azithromycin in combination with quinolones.

Matched MeSH terms: Thienamycins/pharmacology*
Fulltext An imported case of acute melioidosis caused by ST881 Burkholderia pseudomallei

Zong Z, Wang X, Deng Y

Southeast Asian J. Trop. Med. Public Health, 2016 Mar;47(2):219-22.
PMID: 27244959

A previously healthy Chinese male working in Malaysia returned to China with high fever. A blood culture showed Burkholderia pseudomallei strain WCBP1. This isolate was sequenced, showing type, ST881, which appears to be present in Malaysia. WCP1 had unusual susceptibility to aminoglycosides and habored the Yersinia-like fimbrial gene cluster for virulence. The patient's condition deteriorated rapidly but he recovered after receiving meropenem and intensive care support. Melioidosis is a potential problem among Chinese imigrant workers with strains new to China being identified.

Matched MeSH terms: Thienamycins/therapeutic use
Carbapenem-resistant Pseudomonas aeruginosa in malaysia producing IMP-7 beta-lactamase

Ho SE, Subramaniam G, Palasubramaniam S, Navaratnam P

Antimicrob Agents Chemother, 2002 Oct;46(10):3286-7.
PMID: 12234862

We have isolated and identified a carbapenem-resistant Pseudomonas aeruginosa strain from Malaysia that produces an IMP-7 metallo-beta-lactamase. This isolate showed high-level resistance to meropenem and imipenem, the MICs of which were 256 and 128 micro g/ml, respectively. Isoelectric focusing analyses revealed pI values of >9.0, 8.2, and 7.8, which indicated the possible presence of IMP and OXA. DNA sequencing confirmed the identity of the IMP-7 determinant.

Matched MeSH terms: Thienamycins/pharmacology
Fulltext Antimicrobial susceptibility and genetic characterisation of Burkholderia pseudomallei isolated from Malaysian patients

Khosravi Y, Vellasamy KM, Mariappan V, Ng SL, Vadivelu J

ScientificWorldJournal, 2014;2014:132971.
PMID: 25379514 DOI: 10.1155/2014/132971

Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to many antibiotics. Ceftazidime (CAZ), the synthetic β-lactam, is normally used as the first-line antibiotic therapy for treatment of melioidosis. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, leading to mortality if therapy is not switched to a different antibiotic(s) in a timely manner. In this study, susceptibilities of 81 B. pseudomallei isolates to nine different antimicrobial agents were determined using the disk diffusion method, broth microdilution test and Etest. Highest percentage of susceptibility was demonstrated to CAZ, amoxicillin/clavulanic acid, meropenem, imipenem, and trimethoprim/sulfamethoxazole. Although these drugs demonstrated the highest percentage of susceptibility in B. pseudomallei, the overall results underline the importance of the emergence of resistance in this organism. PCR results showed that, of the 81 B. pseudomallei, six multidrug resistant (MDR) isolates carried bpeB, amrB, and BPSS1119 and penA genes. Genotyping of the isolates using random amplified polymorphic DNA analysis showed six different PCR fingerprinting patterns generated from the six MDR isolates clusters (A) and eight PCR fingerprinting patterns generated for the remaining 75 non-MDR isolates clusters (B).

Matched MeSH terms: Thienamycins/pharmacology
Fulltext The Development of Drugs against Acanthamoeba Infections

Siddiqui R, Aqeel Y, Khan NA

Antimicrob Agents Chemother, 2016 11;60(11):6441-6450.
PMID: 27600042 DOI: 10.1128/AAC.00686-16

For the past several decades, there has been little improvement in the morbidity and mortality associated with Acanthamoeba keratitis and Acanthamoeba encephalitis, respectively. The discovery of a plethora of antiacanthamoebic compounds has not yielded effective marketed chemotherapeutics. The rate of development of novel antiacanthamoebic chemotherapies of translational value and the lack of interest of the pharmaceutical industry in developing such chemotherapies have been disappointing. On the other hand, the market for contact lenses/contact lens disinfectants is a multi-billion-dollar industry and has been successful and profitable. A better understanding of drugs, their targets, and mechanisms of action will facilitate the development of more-effective chemotherapies. Here, we review the progress toward phenotypic drug discovery, emphasizing the shortcomings of useable therapies.

Matched MeSH terms: Thienamycins/pharmacology
Fulltext Disruption of adeB gene has a greater effect on resistance to meropenems than adeA gene in Acinetobacter spp. isolated from University Malaya Medical Centre

Wong EW, Yusof MY, Mansor MB, Anbazhagan D, Ong SY, Sekaran SD

Singapore Med J, 2009 Aug;50(8):822-6.
PMID: 19710984

The AdeABC pump of Acinetobacter spp. confers resistance to various antibiotic classes. This pump is composed of the AdeA, AdeB, and AdeC proteins where AdeB is a member of the resistance-nodulation-division efflux pump superfamily. The adeA, adeB, and adeC genes are contiguous and adjacent to adeS and adeR, which are transcribed in the opposite direction and which specify proteins homologous to sensors and regulators of two-component systems, respectively. In this study, an attempt is made to elucidate the role of the AdeABC efflux pump in carbapenem resistance in Acinetobacter spp.

Matched MeSH terms: Thienamycins/pharmacology*
Fulltext The relationship between bacterial sources and genotype to the antimicrobial resistance pattern of Burkholderia pseudomallei

Sadiq MA, Hassan L, Aziz SA, Zakaria Z, Musa HI, Amin MM

Vet World, 2018 Nov;11(10):1404-1408.
PMID: 30532493 DOI: 10.14202/vetworld.2018.1404-1408

Background: Melioidosis is a fatal emerging infectious disease of both man and animal caused by bacteria Burkholderia pseudomallei. Variations were suggested to have existed among the different B. pseudomallei clinical strains/genotypes which may implicate bacterial susceptibility and resistance toward antibiotics.
Aim: This study was designed to determine whether the phenotypic antibiotic resistance pattern of B. pseudomallei is associated with the source of isolates and the genotype.
Materials and Methods: A collection of 111 B. pseudomallei isolates from veterinary cases of melioidosis and the environments (soil and water) were obtained from stock cultures of previous studies and were phylogenetically characterized by multilocus sequence typing (ST). The susceptibility to five antibiotics, namely meropenem (MEM), imipenem, ceftazidime (CAZ), cotrimoxazole (SXT), and co-amoxiclav (AMC), recommended in both acute and eradication phases of melioidosis treatment were tested using minimum inhibitory concentration antibiotics susceptibility test.
Results: Majority of isolates were susceptible to all antibiotics tested while few resistant strains to MEM, SXT, CAZ, and AMC were observed. Statistically significant association was found between resistance to MEM and the veterinary clinical isolates (p<0.05). The likelihood of resistance to MEM was significantly higher among the novel ST 1130 isolates found in veterinary cases as compared to others.
Conclusion: The resistance to MEM and SXT appeared to be higher among veterinary isolates, and the novel ST 1130 was more likely to be resistant to MEM as compared to others.

Matched MeSH terms: Thienamycins
Fulltext Fatal melioidosis in a captive elephant trunk snake (Acrochordus javanicus) in Kuala Lumpur, Malaysia

Sadiq, M.A., Zakaria, Z., Saharee, A.A., Abba, Y., Hassan, L.

Jurnal Veterinar Malaysia, 2016;28(1):20-26.
MyJurnal

An adult female Elephant Trunk Snake (Acrochordus javanicus) was reported to have been weak and inappetent for five days. The following morning the snake found dead, while in the process of shedding its skin. On post mortem examination, there were multiple circumscribed caseous nodules of various sizes distributed all over the liver, along the respiratory tract and on the lungs. Bacteriological analysis of the lungs and liver swab samples yielded Burkholderia pseudomallei, which was confirmed by PCR amplification of specific 16S rRNA. The condition was diagnosed as melioidosis and the organism was genotypically characterized as sequence type 51, a genotype that has been previously characterized in humans in Malaysia. Antibiotic susceptibility by both Disc diffusion or Kirby Bauer and E-test minimum inhibitory concentration (MIC) showed that the organism exhibited susceptibility to meropenem, imipenem, ceftazidime, cotrimoxazole and co-amoxyclav; the antibiotics recommended in the treatment of melioidosis.

Matched MeSH terms: Thienamycins
Fulltext Sputum bacteriology and in-vitro antibiotic susceptibility in hospitalized patients with community acquired pneumonia in a state tertiary-referral hospital – a retrospective study

Chin, Yow-Wen, Loh, Li-Cher, Wong, Thim-Fatt, Abdul Razak Muttalif

International e-Journal of Science, Medicine & Education, 2007;1(2):74-79.
MyJurnal

Introduction: To review the sputum bacteriology and its in-vitro antibiotic susceptibility in patients hospitalized with community-acquired pneumonia (CAP) in a state tertiary-referral Hospital (Penang hospital, Malaysia) in order to determine the most appropriate empiric antibiotics.
Methods: From September 2006 to May 2007, 68 immunocompetent adult patients [mean age: 52 years (range 16-89); 69% male] admitted to respiratory wards for CAP with positive sputum isolates within 48 hours of admission were retrospectively identified and reviewed.
Results: 62 isolates were Gram(-) bacilli (91%) & 6 were Gram(+) cocci (9%). The two commonest pathogens isolated were Pseudomonas aeruginosa (n=20) and Klebsiella pneumoniae (n=19) together constituted 57% of all positive isolates. Among the Pseudomonas isolates, 84.2% were fully sensitive to cefoperazone and cefoperazon/sulbactam; 95% to ceftazidime, cefepime, piperacillin/tazobactam, ciprofloxacin and amikacin, and 100% to gentamycin, netilmycin, imipenem and meropenem. Among the Klebsiella isolates, 5.3% were fully sensitive to ampicillin; 84.2% to amoxicillin, ampicllin/sulbactam, cefuroxime and ceftriazone; 89.5% to piperacillin/ tazobactam; 93.3% to cefoperazon/sulbactam and 100% sensitive to ceftazidime, cefepime, ciprofloxacin, all aminoglycosides and carbopenems.
Conclusion: In view of the high prevalence of respiratory Pseudomonas aeruginosa, ampicillin/ sulbactam, currently the most prescribed antibiotic to treat CAP in our respiratory wards, may not be the most appropriate empiric choice. Higher generation cephalosporins with or without beta-lactamase inhibitors, ciprofloxacin or carbapenem may be the more appropriate choices. The lack of information on patients’ premorbidities such as recent hospitalization and prior antibiotic exposure, limits the interpretation of our findings and may have biased our results towards higher rates of Gram negative organisms.

Matched MeSH terms: Thienamycins
Fulltext Antimicrobial resistance of Listeria monocytogenes and Salmonella Enteritidis isolated from vegetable farms and retail markets in Malaysia

Kuan, C.H., Rukayadi, Y., Ahmad, S. H., Wan Mohamed Radzi, C.W.J., Kuan, C.S., Yeo, S.K., et al.

International Food Research Journal, 2017;24(4):1831-1839.
MyJurnal

Listeriosis and salmonellosis are the major foodborne illnesses worldwide. Over the last decade,
increasing reports about the antibiotic resistance of Listeria monocytogenes and Salmonella from diverse sources have prompted public health concerns, especially in developing countries with over reliance or misuse of antibiotic drugs in the treatment of humans and animals. In this study, antibiotic susceptibility profiles of 58 L. monocytogenes and 12 Salmonella Enteritidis strains from vegetable farms and retail markets in Malaysia were testedby the standard disk diffusion method. Listeria monocytogenes isolates were found to exhibit 100% resistance to penicillin G. Also, high resistance patterns were observed for meropenem (70.7%) and rifampicin (41.4%). The multiple antibiotic resistance (MAR) index of L. monocytogenes isolates ranged from 0.11 to 0.56. Besides, the antibiogram results revealed that multidrugresistant (MDR) S. Enteritidis were detected and all the S. Enteritidis isolates demonstrated resistance to at least four antibiotics. Ampicillin, amoxicillin, and trimethoprim failed to inhibit all the S. Enteritidis strains. Salmonella Enteritidis isolates also displayed high resistance to nalidixic acid (75.0%), trimethoprim-sulfamethoxazole (75.0%), and chloramphenicol (66.7%). Findings in this study indicated that vegetables could be potential sources of multidrug resistance of L. monocytogenes and S. Enteritidis, which can be a serious issue and a major concern for public health. Thus, there is a great need for surveillance programs in Malaysia to continuously monitor the antibiotic resistance profiles of important pathogens.

Matched MeSH terms: Thienamycins

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