EMERGENCE OF MULTI DRUG RESISTANT (MDR) ENTERIC FEVER: AN ALARMING THREAT TO HEALTH OF INDIAN CHILDREN
Dr. S.P. Srivastava*, Dr. Utpal Kant Singh**, Dr. B.P. Jaiswal***
MD, NDHA, FIAMS FIAP FIMSA. FAMS, MCH Fellow, Liverpool (U.K.) Ex-Professor & HOD of Pediatric's, PMCH, Patna.*, MD, PhD, FRCP FRCPCh (London), FIAP Professor, Department of Pediatrics, Nalanda Medical college, Patna.**, MD, Assistant professor of Pediatrics, Nalanda Medical College, Patna.***
Introduction
Enteric fever is one of the most important infectious disease caused by salmonella group of organism, which is a major public health problem, causing enormous morbidity and mortality in developing countries such LS India, where multidrug-resistant (MDR) salmonellosis causes enteric fever-with increased morbidity}' and mortality. An estimated 600,000 deaths from enteric fever occur annually throughout the world. Salmonella enterica serovar Typhi causes approximately 10 million cases of typhoid that result in 600,000 deaths each year, mostly in developing countries. Though typhoid fever is endemic in India but the disease occurs throughout the year, there is a definite increase in the incidence during the rainy season (June to September). Despite major advances in our understanding of the pathogenesis and risk factor for typhoid fever, the disorder is still widely prevalent throughout the developing world. It is estimated that typhoid fever, accounts for almost 16 million cases annually worldwide and over 600,000 deaths (WHO). Although difficult to estimate with any degree of accuracy, the population-based incidence of typhoid in developing countries ranges from 150-1000 cases per 100,000 population. Recent data from South Asia also indicate that contrary to earlier opinion, typhoid fever is widely prevalent among young children under five years of age with comparatively higher morbidity and hospitalization rates.

Although, typhoid fever is invariably treated with antibiotics. Effective therapy dramatically reduces suffering and loss of life. A favorable clinical response is usually seen within 1-2 days of starting treatment. The duration of the disease is shortened, the incidence of complications is reduced and mortality rates fall from more than 10% to less than 1%. The conventional antibiotics that form the mainstay of therapy in developing countries are chloramphenicol, ampicillin, and cotrimoxazole. Chloramphenicol was widely used throughout, the world from 1948 until the 1970s and is still the standard treatment in some developing countries. Unfortunately, many chloramphenicol-resistant strains of Salmonella typhi have developed. This, coupled with the fact the drug can have a number of undesirable side effects, including aplastic anemia, has meant that it has generally been superseded by other antibiotics. Amoxicillin and cotrimoxazole are as effective as chloramphenicol and are much safer for the treatment of children, but strains of salmonella typhi which are resistant to all of these drugs have been isolated in many parts of the world. Furzolidone 10 mg/kg has also been used with equal results even though the drug is poorly observed from intestines and thus has mainly a local effect and not a systemic effect. Hence, this drug alone is not recommenced for serious infection. MDR strains of S. Typhi (resistant to all the first line antimicrobial drugs) have caused outbreaks in the Indian subcontinent, Southeast Asia, and the Middle East since 1987). An outbreak of enteric fever called 'Dombivali Fever' was reported from Mumbai in 1990 and the causative organism was MDRST. Due to the development of multi drug resistance and atypical presentation of the disease, typhoid fever is becoming difficult to diagnose unless aided by blood culture studies.
Magnitude of MDR Enteric Fever Problem
Typhoid fever remains a serious public health problem in India due to the emergence of multidrug resistant Salmonella typhi, which has been reported since 1983. Recently, use of chloramphenicol has been associated with drug resistance, high relapse rate, high rate of continued and chronic carriage, bone marrow toxicity and high mortality. This has resulted in the decreasing trends of its usage. At the same time, number of the culture positive cause of typhoid fever resistant to multiple conventional anti-typhoid drugs are being reported with increasing frequency from all over the world. During the past few year in Delhi, salmonella cultures showed the MDR rate to be more than 45%. Recent data revealed that the MDR rate in enteric fever was as high as 70%, as compared with the overall reported incidence of 50%. This may be in part due to data from a tertiary care center and the patients being from a lower socioeconomic group. The S. typhi isolates used in the study were obtained from the blood of patients clinically suspected of enteric fever who attended- the Calcutta School of Tropical Medicine, India from January 1991 to December 2001. A total of 421 S. typhi isolates from blood samples of enteric fever patients were tested for antibiotic susceptibility pattern by the agar dilution method using Mueller- Hinton agar medium against A, C, Co, and tetracycline (T). The amount of antimicrobial agents (g/ml) were A.C, Co. and T. Escherichia coli ATCC 25922 strain was used as control. The antibiotic susceptibility patterns of 421 S. typhi isolates obtained from 1991 to 2001 are helped a lot in the understanding the MDR reasons behind the scene. In 1991, all 64 (100%) isolates showed a pattern of resistance to ACCoT. In following 4 years (1992-1995) various resistance patterns were found: ACCoT, ACT, CCoT, AcoT, and CoT along with the emergence of antibiotic sensitive isolates in an increasing manner (15-82%). From 1996 to 1998, the isolates showed 100% sensitivity to A, C, Co, and T. During last 3 years (1999- 2001) of the study period, a decrease in frequency of sensitive isolates (76-21%) and reemergence of resistant isolates showing patterns of resistance to ACCoT, ACoT, CCoT, CoT, and Co were noticed.

Changing patterns of antibiotic resistance of S. typhi have been reported earlier. Thus these data suggest that constant surveillance for antibiotic susceptibility patterns of current S. typhi isolates is imperative for determining effective treatment policies. MDR in Salmonella typhi i.e. resistance to 3 or more antibiotics was observed in 60.8% strains. Sanghavi et al (1999) from Pune have reported 60% MDRST and in their study 9.3% strains were resistant to ciprofloxacin. Nadgir et al (1998) have reported 3 isolates (5.3%) resistant to ciprofloxacin. Though, none of the S.typhi strains showed resistance to ciprofloxacin in sensitivity pattern, 66% strains were resistant to nalidixic acid (NA) and it was observed that for these strains MIC for ciprofloxacin was increased. Several reports indicate MDR S. typhi with plasmid mediated block resistance to chloramphenicol, ampicillin and cotrimoxazole thriving in Mumbai. It is also evident now, that there is a gradual increase in the incidence of resistance to newer drugs like quinolones. Thus, when the sensitivity pattern indicates resistance to nalidixic acid which is a marker for delayed clinical response to fluoroquinolones, it is necessary to increase the oral dose of ciprofloxacin or treat the patient with third generation cephalosporin like ceftriaxone.

Since the introduction of Chloramphenicol in the treatment of Typhoid fever, defervescence of fever was usually achieved within one week as compared to natural course of illness spanning over 3-4 weeks. But it must be continued for 10-14 days. Relapse may occur more frequently inspite of proper treatment and it does not prevent disease effectively. Major toxic effect is aplastic anemia which is not dose-related and occurs rarely. Chloramphenicol was the drug of choice for the treatment of typhoid fever till recently. Resistance to this drug was first observed in England in 1950 and later on reported from Mexico, Vietnam and Kerala, India.

Of late, there has been an emergence of multi-drug resistant S. typhi (MDRST) strains throughout the world. Chloramphenicol has been the mainstay of treatment for enteric fever, with amoxicillin or cotrimoxazole (trimethoprim and sulfamethoxazole) as other cost- effective and well-tried primary drugs of choice. Drug resistance, however, has been reported since 1972 with increasing worldwide frequency. Mortality also came down from 105 to almost 1-2% and rate of complications also reduced significantly. Emergence of multidrug resistant typhoid fever has necessitated use of newer antibiotics like Cephalosporins and Quinolones. Oral cefuroxime or parenteral third generation Cephalosporin such as ceftriaxone or Cefotaxime are effective. Quinolones have an advantage of efficacious, cost-effective, and convenient dosage forms but the probable toxic effect on the growing cartilage is considered against is routines use in children. However, it may be used in cases where no better drug is available. Costly parenteral therapy and lack of an established safety profile for the use of quinolones in children necessitate evaluation of an oral treatment option. The efficacy, safety and cost effectiveness of oral third- generation cephalosporin (cefixime) in the treatment of MDR enteric fever has been documented by many researchers. The recent epidemic of multidrug resistant Typhoid fever has forced clinicians to use a short course of oral ciprofloxacin with good results. In otherwise normal patients, drug has an extra advantage of preventing relapse and carrier state also. However in the last few decade, with emergence of multidrug resistant strains of S. typhi the course of ill is altered. Inspite of use of newer antibiotics, clinical course is often prolonged to more than a week, though mortality has remained low.

Despite resistance to these conventional antityphoid drugs, S. typhi is susceptible to ciprofloxacin, which has replaced these drugs in the empirical treatment of typhoid fever and thus has resulted in the reemergence of S. typhi isolates sensitive to A, C, and Co. due to the withdrawal of selection pressure. But unrestricted use of the conventional antibiotics has led to the emergence of multidrug resistant S. typhi isolates again in very recent years. In children with MDR Salmonella typhi infection, 3rd generation Cephalosporins including ceftriaxone and cefoperazone are the initial drug of choice. Fluoroquinolones such a ciprofloxacin are effective but their frequent use* in children in not yet cleared officially expect when the benefits far exceed the possible risk to the growing cartilage. First and second generation Cephalosporins and aminoglycosides should not be employed for treating typhoid fever. A relative recent problem in the management of typhoid fever has been the emergence of multi-drug resistance (MDR) strains of Salmonella typhi (i.e. resistant to oral ampicillin, chloramphenicol and trimethoprim-sulfa or cotrimoxazole (Co), the conventional antityphoid antibiotics), the disorder has achieved global epidemic proportions. The emergence of quinolone resistance among Salmonella typhi isolates has further complicated the scenario; as such infections have been documented to be associated with significantly higher case fatality rates, at times approaching the 4-10% figure from the "pre- antibiotic era". Typhoid fever has thus once again assumed the status of a public health emergency and a need recognized for concerted efforts in understanding the pathogenesis, epidemiology and public health aspects of this disorder.
REASONS OF EMERGENCE OF MDR PROBLEM IN INDIA
Unfortunately these MDR problems associated with antibiotics in the treatment of typhoid fever are because:
  1. The early use of effective antibiotics is associated with a relatively high rate of relapse. Relapse rates of 20% can be expected compared to rates of 5-12% in untreated patients. This is presumably because prompt therapy inhibits the development of an adequate immune response.
  2. More significantly, many strains of Salmonella typhi which are resistant to commonly used antibiotics have emerged and spread throughout the world. MDR enteric fever has shown a recent upsurge in frequency and is a major therapeutic concern for physicians in developing countries. Others contributing factors may be overuse, misuse, and inappropriate prescribing practices of physicians, along with the intrinsic microbiologic plasmid-mediated factors. Genetic studies have shown that resistance is encoded on an HI1 incompatibility plasmid and is transferable.

The emergence of an MDR S. typhi strain in Kenya is of concern because resistance to first-line antibiotics that are also commonly used for treatment of other bacterial infections in hospitals may pose a major challenge to health care. Although these newly emerged MDR S. Typhi are sensitive to nalidixic acid and ciprofloxacin, their MICs are five and ten times higher, respectively, than those of the sensitive S. Typhi from 1988-1993. Although fluoroquinolones are not widely available in Kenya, they may be needed to treat MDR S. Typhi, and resistance will lead to problems with treatment, as in Asia, MDR S. Typhi isolates from Kenya produced an indistinguishable PFGE pattern that was related to those of sensitive strains but unrelated to those of MDR S. Typhi from Asia. This finding implies that the Kenyan MDR S.Typhi are most likely to have arisen from sensitive isolates by acquisition of resistance plasmids from antibiotic group HII are those most frequently found in S.Typhi, but we did not detect them in any of our nontyphoidal salmonellae with the same plasmid-encoded resistance.
DIAGNOSIS OF MDR ENTERIC FEVER IN CHILDREN
Most of the laboratories in India use conventional blood culture techniques for detecting bacteraemia. However, semi-automated machines like BACTEC system, which are designed for rapid detection of bacteria in blood and sterile body fluids, are now available. With this system, identification of blood stream pathogen and results of antimicrobial susceptibility test can be available to the clinicians in 48 hours.

Whenever the emergence of S. Typhi resistant to all first-line drugs used for treatment of typhoid in India and in many other Asian countries causes major threat to health is suspected, then laboratories in India should perform surveillance by routinely testing S. Typhi for susceptibility to first-line treatment drugs and to nalidixic acid to detect quinolone resistance, Effective surveillance for this newly emerged MDR. S. Typhi in Asia and other developing regions of the world where MDR S. Typhi has not yet emerged would ensure prompt diagnosis, susceptibility testing and appropriate antimicrobial chemotherapy.
Management of MDR Enteric Fever in Children
Emergence of MDR has also been documented in India since 1980 and has rapidly attained alarming proportions. These resistant cases have a higher morbidity and require expensive parenteral antibiotics such as ceftriaxone cefotaxime or aztreonam. Lately, the use of quinolones in children has been prevalent but without any established safety profile studies. Therefore, the availability of an orally administered alternative that is effective, safe, and less expensive is desirable in areas with a high prevalence of MDR enteric fever. Cefixime, a third -generation orally administrated cephalosporin active against salmonellae with some reports of successful use. The safety, efficacy, and cost effectiveness make them superior than chloramphenicol in the treatment of enteric fever in children . Longterm public health measures with vaccination and health education will be helpful in combating this problem, but identification of safe, effective, and cheaper treatment alternatives is essential. Fluoroquinolones have offered an effective, affordable oral treatment option for adult patients. The safety of these agents in children, however, has yet to be established.

s Recent reports of salmonellae resistant to ciprofloxacin further reinforce the need, for alternate therapy. Parenteral alternatives available for MDR enteric fever in children, such as ceftriaxone or aztreonam, are too expensive for use in Third World countries. Oral third-generation cephalosporins administered alone or after parenteral antibiotics offer an option in many clinical setting. In pediatrics, cefixime has been used successfully for a variety of pathogens and clinical conditions, such as otitis media, severe pneumonia, and cystic fibrosis. Girgis et al (1996) also studied cefixime as therapy for MDR enteric fever. Quinolones, such as ciprofloxacin, and third-generation Cephalosporins, such as ceftriaxone, are now recommended as firstline treatment for multidrug-resistant typhoid fever. However, these drugs are expensive and impose a substantial load on the health budgets of developing countries. There are also signs that their effectiveness is likely to be challenged by the emergence of further drug-resistant Salmonella typhi strains. It is difficult to eradicate the chronic carrier state with antibiotics. The conventional treatment has been a six-week course of ampicillin or amoxycillin. Recent studies suggest that a shorter course of treatment with ciprofloxacin is probably more effective.
Control Measure for MDR Enteric Fever Problems
The recent emergence and spread of MDR strains of Salmonella typhi has made effective treatment of typhoid fever increasingly difficult and expensive. Emphasis must therefore be placed on preventing the disease occurring in the first place the provision of safe drinking water and proper sanitation along with the practice of simple public health education are the best long-term preventive measures, but they require planning and large budgetary allocations. Newer vaccines for enteric fever do hold promise for endemic area, but their efficacy and safety need to be established in the group less than 5 years of age. Specific antimicrobial therapy for enteric fever became available in 1948 with the introduction of chloramphenicol which is remains drug of choice till recently.
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