ANTIBIOTIC RESISTANCE ISSUES IN CLINICAL PATHOGENS: A REVIEW

ANTIBIOTIC RESISTANCE ISSUES IN CLINICAL PATHOGENS: A REVIEW

Sikandar Khan Sherwani*¹, Aisha Irshad ¹, Muhammad Ajmal Shah ², Munazza Ajaz ¹ and Haroon Ahmad ³

Department of Microbiology ¹, Department of Pharmacognosy ², Federal Urdu University of Arts, Science and Technology, Karachi, Pakistan

Department of Biotechnology, Qauid-e-Azam University ³, Islamabad, Pakistan

ABSTRACT: Antibiotic resistance in pathogens is on the increase but in the past few decades this problem raised a deepening concern among scientific community in terms of the clinical management of infectious diseases. In this review, the common gram negative clinically significant pathogenic bacteria who have acquired resistance with passage of time like Shigella dysenteriae, Sh. Boydii, Sh. Flexneri, Listeria monocytogenes, Acinetobacter baumannii, acinetobacter, A. baumannii, Morganella morganii, Enterobacteriaceae, Citrobacter freundii,  Citrobacter braakii, or Citrobacter amalonaticus, P. stuartii, Providencia rettgeri, P. alcalifaciens, P. rustigianii, E. coli, Salmonella. paratyphi, S. typhi, Salmonella enterica, have been compiled with their plausible ways of causing resistance. We conclude from our literature review that resistance in gram negative bacteria is on the rise and new and advanced antibiotics need to be designed   and introduced

Keywords:

Antibiotic resistance, pathogen, gram negative pathogen, clinical pathogens

INTRODUCTION: Antibiotics literally means “against life”; in this case, against microbes. There are many types of antibiotics such as antibacterials, antivirals, antifungals, and antiparasitics. Some drugs are effective against many organisms; these are called broad-spectrum antibiotics.

Others are effective against just a few organisms and are called narrow spectrum antibiotics. The most commonly used antibiotics are antibacterial in nature ¹. Ehrlich made the first antibiotic called Salvarsan, now known as Arsphenamine ^{2, 3, 4}.

Later, the science of antibiotics entered into an age of progress and at the time of penicillin discovery it was thought that soon we would have an upper hand over pathogenic microbes. However in recent past several studies have demonstrated authentically that now these disease causing agents are developed resistance to most of these antibiotics at an alarmingly faster rate and the race once we thought would soon be over after penicillin discovery in 1928 seems had just started ⁵.

Resistance Mechanisms: There are several mechanisms by which a microbe can get resistant to a particular antibiotic however among them the most studied and frequent one is the horizontal gene transfer between microbes ⁶. The antibiotic action against the pathogen can be seen as an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce. They will then pass this trait to their offspring, which will result in the evolution of a fully resistant colony.

Other four major type of resistance mechanism are; drug inactivation or modification, alteration of target site, alteration of metabolic pathway and reduced drug accumulation ^7-8.

Some gram negative bacteria involved in diahorreal infections: As in case of Shigella infection yet claims for a significant proportion of bacillary dysentery in many tropical and subtropical countries and review of research papers shows the global rise in the growing pattern of resistance of Shigella species particularly type-I strains that poses great problem not in antibacterial therapy but also in clinical management all over the world⁷. In Somalia, a studied conducted in which the resistance to conventional antibiotics of 240 Shigella strains (like ampicillin, chloramphenicol, streptomycin, tetra cycline, and sulfonamides) and particularly Shigella dysenteriae type-I were found to be resistant to more than one drug.

The study also suggested that polymyxin B or M sulfate could be used as they had found effective in in-vivo trails for which have proved to be effective for bacillary dysentery ¹⁰. A similar but a bit at large scale study conducted in London and Wales in which two thousand three hundred and seventy strains of Sh. dysenteriae, Sh. flexneri, and Sh. boydii were tested for resistance to a panel of a dozen of antimicrobial drugs and eighty per cent of strains were resistant to one or more drugs, with significantly sulphonamide resistance was observed, except in Sh. Soneii ⁹.

Another study in Central Isreal over a period of approximately 10 years difference indicated the significantly increased resistance to tetracycline from 23% to 87%, and high resistance to trimethoprim–sulfamethoxazole (94%) and ampicillin (85%) were also noted ⁹.In Nepal, a study was conducted with the same aim a couple of years and results indicated that resistance to cotrimoxazole was highest (80.7%), followed by tetracycline (74.7%), gentamicin (55.4%), ampicillin (53%). chloramphenicol (39.7%) and nalidixic acid (31.3%) ¹². In a vast study conducted in Pakistan, where, 79.3% S. typhi and 59.9% S. paratyphi A were isolated from patients under 15 years of age, with the MDR rate increased in S. typhi (34.2 to 48.5% p<0.001), but decreased in S. paratyphi A (44.5 to 8.6%) in the first line of drugs.

However, Quinolone resistance (MIC>1μg/ml) increased in both S. typhi (1.6 to 64.1%) and S. paratyphi A (0 to 47%) in older patients. Apart from endemic and sporadic cases, and MDR strains have been responsible for numerous outbreaks on the Asian continent. The Asian isolates, eighteen of 25 isolates of Salmonella enterica serovar Typhi were multidrug resistant and contained class 1 integrons with a single cassette, dfrVII or aadA1 on an IncHI1 plasmid. Salmonella serovar Typhi could become resistant to broad-spectrum cephalosporins by integrating cassettes, such as veb-1, a commntegron-Associated Antibiotic Resistance in Salmonella enterica Serovar Typhi from Asia ¹³.

In an extensive molecular study, seventy-eight Salmonella typhi strains isolated in 1994 and 1995 from patients living in Dhaka, Bangladesh, were subjected to phage typing, ribotyping, IS200 fingerprinting, and PCR fingerprinting. The data indicated a significant number of the S. typhi strains (67%) were demonstrated to be multiple drug resistant (MDR) strains were  resistant to chloramphenicol, ampicillin, trimethoprim, streptomycin, sulfamethoxazole, and tetracycline (R type CATmSSuT), that could be conjugated to Escherichia coli and resulted in the complete transfer of the MDR phenotype ¹⁴.

High resistance, most probably plasmid mediated a serious public health concern and could be responsible for this increased mortality ¹⁵. In a study conducted, L. monocytogenes was isolated in 4.5% of fish samples and 8.3% of seawater samples. Multi-resistant environmental strains as 6% of L. monocytogenes strains isolated showed multi-resistance to ampicillin, erythromycin, tetracycline, dicloxacillin, and trimethoprim-sulfamethoxazole, that a serious threat to human health ¹⁶.

Resistant Nosocomial Infection, A Potential Risk for Health Care Professionals:Acinetobacter baumannii, is a worldwide nosocomial pathogen associated with opportunistic infections, community and healthcare-associated infections (HAIs) like pneumonia, urinary tract, bloodstream, skin and soft tissue infections¹⁷.Thus, it constitutes a major public health problem due to its propensity to develop resistance to numerous drugs ¹⁸. A study was conducted to determine the possible resistant genes in case of MDR acinetobacter starins and found about eight resistance gene determinants the genes blaOXA-23 and ampC, resistance to carbapenems and cephalosporins, respectively. However, resistance to quinolones and fluoroquinolones was conferred by an S83L mutation in GyrA and blaTEM-1, which was found, associated to β-lactam resistance, and strB, which contributed to aminoglycoside resistance that give rise to the MDR phenotype both in sporadic and epidemic cases ¹⁹.

A similar research on a tertiary care 1000 bed hospital in Iran was carried out the results indicated that the A. baumannii strains showed high rate of resistance to ceftriaxone (90.9%), piperacillin (90.9%), ceftazidime (84.1%), amikacin (85.2%) and ciprofloxacin (90.9%) however, Imipenem was the most effective antibiotic against A. baumannii strains and the rate of resistance for imipenem was 4.5% ²⁰ among various uro-pathogens responsible for urinary infections.

The natural antibiotic susceptibility of 38 Providencia rettgeri, 35 P. stuartii, 23 P. alcalifaciens and 20 P. rustigianii strains was examined. MIC values were determined by a microdilution procedure and evaluated by a table calculation programme. P. stuartii was the least susceptible Providencia sp. and was naturally resistant to tetracyclines, some penicillins, older cephalosporins, sulphamethoxazole and fosfomycin and to antibiotics to which other species of Enterobacteriaceae are also resistant. It was naturally sensitive to modern penicillins and cephalosporins, carbapenems and aztreonam ²¹.

In one of the study on  multidrug-resistant Enterobacteriaceae (MDRE) in solid-organ transplant patients, as often in compromised hosts, resistant to cephalosporins due to overexpression of their chromosomal β-lactamase found that almost half of patients colonized with MDRE carried one or more cefpodoxime-resistant. Citrobacter species are infrequent nosocomial pathogens, and can cause a number of infections due to impairment of immune system ²² and include urinary tract infections, neonatal sepsis, brain abscess, meningitis, bloodstream infections ²³. Citrobacter freundii, Citrobacter braakii, or Citrobacter amalonaticus strains ²⁴.

Our study shows that qnr gene has occurred in Citrobacter freundii isolates from Anhui Province, China. qnr gene was therefore present in both quinolone-resistant and -susceptible isolates and some of them could be transferred by conjugation experiments. qnr positive isolates strains showed multi-resistance and no clone was spread found in these SHV- and TEM-derived extended-spectrum β-lactamases (ESBLs) have also been described for Citrobacter species in the context of outbreaks of clonal strains and plasmids ²⁵.

Resistance Cases with some recent clinical importance:Morganella morganii is also involved in a number of clinical cases. The different strains of this species are usually resistant to ampicillin, to the amoxicillin-clavulanic acid combination, and to cephalothin, and usually they are susceptible to other antibiotics active against gram-negative bacilli²⁶. In some studies, the potential reason behind the resistance his contribution M. morganii is the production of extended-spectrum β-lactamases (ESBL) to drug resistance was examined in Morganella  morganii ²⁷a high-molecular-weight (49,000) class I cephalosporinase, which contributes in the resistance with ampicillin, carbenicillin, and and broad-spectrum cephalosporins ²⁸.

In the same way, in the hospital of Portugal, a strain of M. morganii (FFLM15), isolated from the urine of a neonate, showed resistance to ceftazidime and aztreonam and reduced susceptibility to cefotaxime by the disk diffusion method, however the synergistic results between expanded-spectrum cephalosporins and clavulanic acid was performed, and the positive result indicated the presence of an ESBL producer ²⁹.  Another pathogen, Citrobacter species also are infrequent nosocomial pathogens, and can cause a number of infections due to impairment of immune system and cause urinary tract infections, neonatal sepsis, brain abscess, meningitis, bloodstream infections.

In one of the study on multidrug-resistant Enterobacteriaceae (MDRE) in solid-organ transplant patients, resistant to cephalosporins due to overexpression of their chromosomal β-lactamase have been noticed and almost half of patients were also resistant with one or more cefpodoxime-resistant Citrobacter freundii, Citrobacter braakii, or Citrobacter amalonaticus strains ^{22, 23}. Through research, qnr gene found in Citrobacter freundii isolates from Anhui Province, China associated with quinolone-resistance and some of them could be transferred by conjugation trials.

Upon screening, plasmid association with resistance, SHV- and TEM-derived extended-spectrum β-lactamases (ESBLs) have also been noted for Citrobacter species in case of the outbreaks of clonal strains and plasmids. The susceptibility profile of 38 clinical isolates of Providencia rettgeri, 35 P. stuartii, 23 P. alcalifaciens and 20 P. rustigianii strains was examined by a microdilution procedure. P. stuartii was the least susceptible among Providencia sp. and was naturally resistant to tetracyclines ²³. A total of 238 isolates of Providencia stuartii obtained from infected patients in six Dublin hospitals. Both chromosome-encoded and plasmid-coded resistance mechanisms were important and most of the clinical isolates were resistant to several of these antibacterial agents including tetracycline, resistance to penicillin, moreover resistance to polymyxin was also noticed ²³.

A total of 238 isolates of Providencia stuartii obtained from infected patients in six Dublin hospitals were grouped by using serological and bacteriocin typing methods and tested for sensitivity to a number of antimicrobial agents. Most isolates were resistant to several of these agents. Resistance to tetracycline, resistance to penicillin, resistance to polymyxin, and probably resistance to nitrofurantoin was intrinsic. Plasmid screening coupled with resistance transfer studies showed that both chromosome-encoded and plasmid-coded resistance mechanisms were clinically important. Ampicillin resistance was both chromosomally and plasmid encoded, whereas resistance to kanamycin and resistance to carbenicillin were exclusively plasmid encoded ³⁰.

CONCLUSION: Therefore to encounter these defense mechanisms of resistance, from the pathogens, we need to keep discovering new antibiotics against them so as to cure the diseases. However at the moment perhaps, the biggest problem with antibiotic resistance at the moment is the fact that it’s inevitable i.e. no matter how exquisite a new drug is, microbes are going to develop resistance to it in one way or another and yet this matter does not get the kind of attention that other health treats like dengue and bird flu did. Perhaps the biggest obstacle in tackling resistance is the fact that too many people accept it as inevitable.

As Weber explained, “even if drugs were used exquisitely perfectly, the emergence of drug resistance is likely.” Also, this problem does not receive much attention compared with other health issues-recent scares, such as severe acute respiratory syndrome (SARS), avian flu and bioterrorism, have clearly overshadowed the distant possibility of bacterial resistance with the short-term fear of imminent danger. However, Levy, who highlighted the dangers of antibiotic resistance more than a decade ago in his book The Antibiotic Paradox, feels that public awareness, is slowly increasing. “The message is out there,” he said. The next step is overcoming resistance to change.

REFERENCES:

1. Immunizations & Infectious Diseases: An Informed Parent's Guide (Copyright © 2006 American Academy of Pediatrics)
2. Limbird LE: The receptor concept: a continuing evolution. Molecular Intervention 2004; 4 (6): 326–36.
3. Bosch F, Rosich L: The contributions of Paul Ehrlich to pharmacology: a tribute on the occasion of the centenary of his Nobel Prize. Pharmacology 2008; 82 (3): 17-19.
4. Calderon CB, Sabundayo BP: Antimicrobial Classifications: Drugs for Bugs. In Schwalbe R, Steele-Moore L, Goodwin AC. Antimicrobial Susceptibility Testing Protocols. CRC Press. Taylor & Frances group 2007; ISBN 978-0-8247-4100-6.
5. Leimane V. Clinical outcome of individualized treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study. Lancet 2005; 365: 318-326.
6. Ochiai K, Yamanaka T, Kimura K, Sawada O: Inheritance of drug resistance (and its transfer) between Shigella strains and Between Shigella and E.coli strains (in Japanese). Hihon Iji Shimpor 1959; 34: 1861.
7. Li X, Nikadio H: Efflux-Mediated Drug Resistance in Bacteria: an Update. Drug 2009; 69 (12): 1555–623.
8. Morita Y, Kodama K, Shiota S, Mine T, Kataoka A, Mizushima T, Tsuchiya T: NorM, a Putative Multidrug Efflux Protein, of Vibrio parahaemolyticus and Its Homolog in Escherichia coli. Antimicrobial Agents Chemotherapy 1998; 42 (7): 1778–82.
9. Shai A, Itzhak L, Vered K and Zmira S: Growing antimicrobial resistance of Shigella isolates. Journal of Antimicrobial Chemotherapy 2003; 51(2): 427-429.
10. E. Mero: Resistance to antibiotics of Shigella strains isolated in Somalia. Bulletin World

Health Organization 1976; 54(4): 473–474.

1. Gross RJ, Rowe B, Cheasty T, Thomas LV: Increase in drug resistance among Shigella dysenteriae, Sh flexneri, and Sh.boydii. British Medical Journal (Clinical Research Ed) 1981; 283(6291):575-6.
2. Godwin W, Joshy ME, Chiranjoy M and Shivananda PG: Isolation & antimicrobial susceptibility of Shigella from patients with acute gastroenteritis in western Nepal. Indian Journal of Medical Research 2006; 123:145-150.
3. Hasan R, Zafar A, Abbas Z,  Mahraj V, Malik F, Zaidi A: Antibiotic resistance among Salmonella enterica serovars Typhi and Paratyphi A in Pakistan (2001-2006). Journal of Infection in Developing Countries 2008; 2(4): 289-294.
4. Threlfall EJ: Antimicrobial drug resistance in Salmonella: problems and perspectives in food- and water-borne infections. FEMS Microbiology Review 2002; 26:141-148.
5. Charpentier E and Courvalin P:Antibiotic resistance in Listeria spp. Antimicrobial Agents and Chemotherapy 1999; 43:2103-2108.
6. Rodas-Suárez OR,  Flores-Pedroche JF, Betancourt-Rule  JM, Quiñones-Ramírez EI and  Vázquez-SalinasC: Occurrence and Antibiotic Sensitivity of Listeria monocytogenes Strains Isolated from Oysters, Fish, and Estuarine Water. Applied and Environmental Microbiology2006; 72(11): 7410-7412.
7. Perez F: Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrobial Agents Chemotherapy 2007; 51:3471-3484
8. Fournier PE, Richet H: The epidemiology and control of Acinetobacter baumannii in health care facilities. Clinical Infectious Diseases 2006; 42:692-9.
9. Jennifer KM, Kim M, Pham J, Tapsall J, White PA: Antibiotic resistance determinants in nosocomial strains of multidrug-resistant Acinetobacter baumannii. Journal of Antimicrobial and Chemotherapy 2009; 63(1): 47-54.
10. Rahbar M, Mehrgan H, Aliakbari NH: Prevalence of antibiotic-resistant Acinetobacter baumannii in a 1000-bed tertiary care hospital in Tehran, Iran. Indian Journal of Pathology and Microbiology 2010; 53(2)290-293.
11. Stock I, Wiedemann B: Natural antibiotic susceptibility of Providencia stuartii, P. rettgeri, P. alcalifaciens and P. rustigianii strains. Journal of Medical Microbiology1998; 47(7):629-42.
12. Lu CH, Chang WN, Chuang YC and Chang HW: Gram-negative bacillary meningitis in adult post-neurosurgical patients. Surgical Neurology 1999; 52:438-444.
13. Tellez I, Chrysant GS, Omer I and Dismukes WE:Citrobacter diversus endocarditis. American Journal of Medical Sciences 2000; 320:408-410.
14. Champs DC, Sirot D, Chanal C, Poupart MC, Dumas MP, and Sirot J: Concomitant dissemination of three extended-spectrum beta-lactamases among different Enterobacteriaceae isolated in a French hospital. Journal of Antimicrobial Chemotherapy 1991; 27:441-457.
15. Neuwirth C, Siebor E, Lopez J, Pechinot A and Kazmierczak A: Outbreak of TEM-24-producing Enterobacter aerogenes in an intensive care unit and dissemination of the extended-spectrum beta-lactamase to other members of the family Enterobacteriaceae. Journal of Clinical Microbiology 1996; 34:76-79.
16. Monnet D and Richard C: Autres Enterobacteriaceae. in Manuel de bacteriologie clinique, eds Freney J, Renaud F, Hansen W, Bollet C. (E. S. Elsevier, Paris, France), Edition 2, 1994, 1053–1128.
17. Yang YJ and Livermore DM: Chromosomal beta-lactamase expression and resistance to beta-lactam antibiotics in Proteus vulgaris and Morganella morganii. Antimicrobial Agents and Chemotherapy 1988; 32(9):1385–1391.
18. Coudron PE, Moland ES, Sanders CC: Occurrence and detection of extended-spectrum beta-lactamases in members of the family Enterobacteriaceae at a Veterans medical center: seek and you may find. Journal of Clinical Microbiology 1997; 35:2593–2597.
19. Barroso H, Freitas-Vieira A, and Duarte A:  Molecular Characterization of a Ceftazidime-Resistant Morganella morganii Isolate Producing a TEM-10 β-Lactamase. Antimicrobial Agents and Chemotherapy 1999; 43(2): 434–435.
20. McHale PJ, Keane CT, and Dougan G: Antibiotic resistance in Providencia stuartii isolated in hospitals. Journal of Clinical Microbiology1981; 13(6):1099-104.
    

    ---

    How to cite this article:

    Sherwani SK, Irshad A, Shah MA, Ajaz M and Ahmad H: Antibiotic resistance issues in Clinical Pathogens: A Review. Int J Pharm Sci Res 2013; 4(5); 1725-1729.

    ---