|Year : 2015 | Volume
| Issue : 3 | Page : 393-400
Adverse drug reactions profile of antimicrobials: A 3-year experience, from a tertiary care teaching hospital of India
Richa1, VR Tandon2, S Sharma1, V Khajuria2, V Mahajan2, Z Gillani2
1 Department of Biotechnology, Arni University, Indora, Himachal Pradesh, India
2 Department of Pharmacology and Therapeutics, Government Medical College, Jammu, Jammu and Kashmir, India
|Date of Submission||24-Mar-2014|
|Date of Acceptance||12-Dec-2014|
|Date of Web Publication||12-Jun-2015|
Department of Biotechnology, Arni University, Indora, Himachal Pradesh
Source of Support: Indian Pharmacopeia Commision, Gaziabad New
Delhi India & WHO, Conflict of Interest: Declared Data is confidential
and only property of IPC under PvPI; reflect only suspected events and
the data is generated by spontaneous reporting system as proposed
by PvPI. There may be many other confounding factors which could
have affected the final outcome of the study which were beyond the
scope of current retrospective cross-sectional study.
Aim of Study: To evaluate adverse drug reaction (ADR) profile of antimicrobials over 3-year period. Material and Methods: A retrospective cross-sectional study was undertaken using suspected adverse drug data collection form available under Pharmacovigilance Programme of India (PvPI). Results: A total of 2,586 ADR events were recorded in 3 years, out of which 392 (15.15%) were because of antimicrobials. Male: female was 1.02:1. Medicine department contributed maximally (98.97%). The intravenous (IV) route of drug administration accounted maximum ADRs (53.32%), followed by oral route (45.41%). Monotherapy was responsible for 80.87%, whereas combination therapy for 19.13%. Combinations therapy was irrational in 79.67%. The most common antibiotic resulting in ADRs was injection ceftriaxone (35.71%), followed by tab. azithromycin (7.39%), tab. ofloxacin + ornidazol (5.35%), ofloxacin (3.57%), ciprofloxacin (2.29%), amoxicillin (2.55%), tab. cefixime (2.29%), inj. linezolid (2.04%). Rash remained the most common ADR, followed by diarrhoea and gastritis. Most common organ system involved was dermatological (47.44%), followed by gastrointestinal (GI) (39.28%), central nervous system (CNS) (5.35%), cardiovascular system (CVS) (3.57%) and renal and genitourinary (1.78%). While 47.96% ADR's were latent, 26.785% were acute and 25.26% were sub-acute. Moreover, 89.79% of ADRs were moderate in nature, whereas 26.88% were severe and 3.33% mild in nature. Furthermore, 92.86% were non-serious and 7.14% serious in nature. Also, 65.06% of antimicrobial caused ADRs were type A and 34.64% were type B reactions. As per World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) scale, 73.98% of ADRs were probable/likely and 26.02% as possible. However, 99.47% of ADRs required intervention. Conclusion: The current study suggest that ADRs due to antimicrobials is a significant health problem.
Keywords: Adverse drug reactions, antimicrobial, infectious diseases, pharmacovigillance
|How to cite this article:|
Richa, Tandon V R, Sharma S, Khajuria V, Mahajan V, Gillani Z. Adverse drug reactions profile of antimicrobials: A 3-year experience, from a tertiary care teaching hospital of India. Indian J Med Microbiol 2015;33:393-400
|How to cite this URL:|
Richa, Tandon V R, Sharma S, Khajuria V, Mahajan V, Gillani Z. Adverse drug reactions profile of antimicrobials: A 3-year experience, from a tertiary care teaching hospital of India. Indian J Med Microbiol [serial online] 2015 [cited 2020 May 30];33:393-400. Available from: http://www.ijmm.org/text.asp?2015/33/3/393/158564
| ~ Introduction|| |
Antibiotic remain the most commonly prescribed group of drugs by all the clinical specialties due to high prevalence of infectious diseases, particularly in developing countries. However, this group is also most widely misused in the form of self-medication, over-the-counter use and irrationally prescribed many a times. ,, Consequently, leading to worrisome increase in prevalence of resistant pathogen, which have a significant impact on the mortality and morbidity due to infectious diseases and can add unnecessary financial burden to the patient and community at large. 
Other less studied impact of overuse/misuse of antibiotics is increase prevalence of adverse drug events among users. Though the data on adverse drug reaction (ADR)'s related to antimicrobial exist in volumes. ,,,,,,,,,, But, no study exists from the Indian hospital exclusively analyzing the ADR's trends and patterns related to antibiotics.
Moreover, variations in ADRs are likely to exist worldwide because of varied patterns of prescribing practices and trends of hospitals, genetic and epidemiological variations of the population. Thus, undertaking such studies shall definitely prove useful in reframing hospital and national antibiotic policy in the interest of patient care and safety.
Thus, an attempt was made to analyze a regional data existing in a tertiary care teaching hospital retrospectively to study profile of ADRs due to antimicrobials.
| ~ Materials and Methods|| |
A retrospective observational cross-sectional analysis was carried out for the data collected w.e.f November 2010 to November 2013 to evaluate the profile of adverse drug events related to antimicrobials in Adverse Drug Reaction Monitoring (ADRM) Centre, working under Pharmacovigilance Programme of India (PvPI) in a tertiary care teaching hospital from north India using suspected drug reactions monitoring data collection form used under PvPI.
Institute Ethics Committee (IEC) permission vide no. S (R)/2012/2741 dated 1.11.12 was taken prior to commencement of the study. Verbal consent was obtained from all the participants as the study involved minimal risk and felled in Category-C as per Indian Council of Medical Research (ICMR) guidelines.
Information about patient, suspected ADR, suspected medication, reporter, date of reaction, date of recovery and presentation of problem were recorded. Under suspected medication, name of drug, brand of manufacturer, generic name of manufacturer (if known), expiry date, dose used, route, frequency and therapy dates as well as reason for prescribing suspected drug were also assessed. The information about de-challenge and re-challenge, concomitant medical treatment record, the relevant laboratory biochemical abnormality were recorded separately. Other relevant history including pre-existing medical conditions like allergy, pregnancy, smoking and alcohol used and any organ dysfunction was noted. The ADRs were defined and categorized as per the definition of Edwards and Arsonson, 2000.  The severity and seriousness of reaction, mode of onset, nature of ADRs, type of reaction, the outcome of reaction and onset time was recorded for every suspected ADR. Severity of reaction was classified as mild (bothersome but requires no change in therapy); moderate (requires change in therapy, additional treatment, hospitalization); severe (disabling or life-threatening). Serious reactions were defined as any event leading to (death, life-threatening, prolonged hospitalization, disability, required intervention to prevent permanent impairment/damage, congenital anomaly). Onset of event was categorized as acute (within 60 minutes); sub-acute (1 to 24 hours) and latent (> 2 days). Whereas nature and type of reaction was classified as type A (Augmented); type B (Bizarre); type C (Continues Use); type D (Delayed) and type E (End of Use). Outcome was described as fatal, recovering, recovered, unknown, continuing or other) as per recommended standard operative procedure (SOP) of PvPI.
The suspected ADRs were classified in term of causality using World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) scale and  Naranjo scale.  Detail sub-group analysis of ADRs detected and various socio-epidemiological, drug-related parameters like combination antibiotics, route of drug administration, rational/irrational antibiotics and other risk factors were also analyzed in the current study.
The details were collected by an independent observer with consultation of doctors which was finally validated and confirmed by the in-charge ADRM Centre, as an expert. The identity of reporter was kept confidential.
Any ADR from outpatient department (OPD) or inpatient of any severity, duration and any type of reaction were included pertaining to antimicrobials.
Whereas, any case of poisoning, medication error, over dosage, over/non-compliance, natural products/alternate medicines and unidentified drugs, anti tubercular, antileprotic and antimalarial were excluded.
Analysis was carried out with the help of computer software statistical package of social sciences (SPSS) Version 15 for windows. The data was expressed in n (%). Chi-square test was applied to prove their statistical significance P value < 0.05 was considered significant.
| ~ Results|| |
A total of 2,586 ADR events were recorded during the study period of 3 years. And, 392 (15.15%) of them were as a result of antimicrobials and antibiotics. Male patients contributed 64.55% and females 35.45%. The mean age of the male patients was 37.52, whereas of female was 36.6. The male: Female in the current study was 1.02:1. The adult population accounted for 63.1%, followed by geriatric (20.4%) and paediatric population (16.5%) of the total ADRs. 76% were from the rural population while 24% urban. Middle pass (65%), lower qualification (25%) and higher qualification accounted for 10% of the total ADRS. Moreover, 60.9% were reported by active surveillance and 39.1% were by spontaneous reporting. Regarding the personal habits of the subjects, 70% were non-smokers as well as non-alcoholics, whereas 30% were smokers and/or alcoholics. The intravenous (IV) route of drug administration accounted 209 (53.32%) of the total ADRs, followed by oral route 178 (45.41%) and intramuscular route 5 (1.27%). The distribution of the total ADRs as per the specialty depicted that the medicine department contributed maximally 388 (98.97%), followed by paediatrics and gynaecology 2 (0.52%) each [Table 1].
|Table 1: Demographical profile of adverse drug reactions (ADRs) due to antimicrobials |
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Monotherapy was responsible for 317 (80.87%), whereas combination therapy was responsible for 75 (19.13%) of the total ADRs as a result of antibiotics. Out of 75, combination therapy which resulted into ADRs were 21.33% were rational and 79.67% were irrational combination as per the recent WHO Essential Drug Model list 2012 [Table 2].
|Table 2: Parameters of adverse drug reactions (ADRs) due to antimicrobials |
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The most common antibiotic/antimicrobials resulting ADRs was injection ceftriaxone (35.71%), followed by tab. azithromycin (7.39%), tab. ofloxacin + ornidazol (5.35%), followed by ofloxacin (3.57%), ciprofloxacin (2.29%), amoxicillin (2.55%), tab. cefixime (2.29%), inj. linezolid (2.04%) and others. Among the total reported cases as a result of inj. ceftriaxone, the rash (24.28%) was the maximum presentation followed by diarrhoea (12.14%), gastritis (12.85%), pain epigastric (7.85%), hypotension/anaphylaxis (7.85%), nausea and vomiting (5%) and thrombophlebetis at the injection site (3.57%), whereas diarrhoea (44.82%) followed by gastritis (17.24%), epigastric pain (10.34%), rash and urticaria (6.89%) each were the common presentations with tab. azithromycin. Similarly, rash (66.66%) followed by fixed drug eruptions (14.28%), vertigo, urticaria and anaphylaxis (4.76%) each were the common presentations with tab. ofloxacin + ornidazole. Allergic reactions (50%), diarrhoea (44.44%), rash (55.55%) and constipation (25%) were the leading symptoms with tab. ofloxacin, inj. ciprofloxacin, tab. amoxicillin, tab. cefixime and inj. Linezolid, respectively [Table 3] and [Table 4].
|Table 3: Detail of adverse drug reactions (ADRs) due to antimicrobials by injectable route |
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|Table 4: Detail of adverse drug reactions (ADRs) due to antimicrobials by oral route |
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Rash remained the most common ADR, followed by diarrhoea and gastritis in the current study. Most common organ system involved as a result of ADRs due to antibiotics remained dermatological (47.44%), followed by gastrointestinal (39.28%), CNS (5.35%), cardiovascular system (3.57%), renal and genitourinary (1.78%) each and metabolic (0.76%), respiratory and hepatobillary (0.51%) each [Table 5]. Whereas, one ADR presented as toothache as a result of inj. ceftriaxone could not be specified and hence kept as under non-specific ADR. Whereas, one ADR, i.e. Disulfiram like reaction with tab. ofloxacin + nitazoxanide drug had multisystem manifestation in the form of cardiovascular manifestation and CNS manifestation, respectively.
Total 16 cases of altered biochemistry were recorded as a result of antimicrobials/antibiotics. And five cases were reported with RFT dysfunction and five were recorded as both renal and liver dysfunction followed by four cases of decreased blood sugar with drugs ceftriaxone and one case with decreased platelets count of 60,000/mm 3 with inj. benzathine penicillin was reported in the current study.
As per the mode of onset, 188 (47.96%) ADR's were latent in nature and accounted maximum in the current study, followed by acute 105 (26.78%) and sub-acute 99 (25.26%). Also, 352 (89.79%) of the total ADRs were moderate in nature, whereas 27 (6.88%) were severe and 13 (3.33%) mild in nature. Moreover, 364 (92.86%) were non-serious and 28 (7.14%) serious in nature. Analysis according to ABC type classification suggested 255 (65.06%) as type A and 136 (34.64%) type B reactions, whereas one reaction could not be classified in the current study. The present study while evaluating the causal relationship of ADRs according to WHO-UMC scale reported 290 (73.98%) to be probable/likely and 102 (26.02%) as possible. The further validation of causality assessment by Naranjo scale classified 281 (71.69%) as probable and 111 (28.31%) possible. No case accounted as doubtful and definite. As per the management of ADR in the current study 361 (92.09%) the drug was replaced and substituted by new drug and in 29 (7.4%) cases offending medicine had to be stopped and only 2 (0.51%) cases required no change to be carried since the ADR were too mild in nature. Furthermore, 235 (59.94%) ADR recovered, whereas 153 (39.03%) were recovering, (0.26%) was continuing and in 3 (0.77%) of the cases, outcomes were unknown at the time of report [Table 2].
| ~ Discussion|| |
In the current study, male patient dominated females. Adult and rural population accounted maximum number of ADR maximum population was middle pass and 60% of the contributed ADRs were by active surveillance, whereas only 30% of the population were smokers and/or alcoholics. The maximum number of ADRs was contributed by medicine department, followed by dermatology. In the current study, antimicrobials monotherapy accounted 80.87%, whereas combination therapy resulted 19.13% of the total ADRs. Among the combination therapy, majority of the combinations were irrational and not from WHO essential model list 2012. The study thus warrants the drug regulatory authorities to follow highest standards of regulation before any permission to manufacture and market antibiotic combinations is granted.
The previous studies have shown advancing age, paediatric age, female gender, multiple drug usage, smoking, alcohol usage and irrational drug combination as important risk factors for ADRs. (Carbonin P et al., 1991; Field TS et al., 2001; Onder G et al., 2002 and Fialova D et al., 2005). ,,,
The results of the current study has pointed towards some of the risk factors like multiple drug usage, irrational drug combinations, advancing age, poly pharmacy as some of the risk factors likely to increase ADR events with antibiotic use. However, no attempt was made to establish any statistical correlation with these risk factors.
The reasons for predominance of male and adult patients may be due to the fact that this population is a working class and more exposed to communicable diseases; hence, more likely to be prescribed antibiotics which can increase their risk towards ADRs.
The most common antibiotics/antimicrobials resulting ADRs in our study was inj. Ceftriaxone, followed by tab. azithromycin and tab. ofloxacin + ornidazole. The maximum ADRs were in the form of allergic reactions, GI, CNS, followed by CVS and renal/genitourinary.
These results are in accordance to the study of Dharnidharkar VR et al. (1993)  who reported antimicrobials to be maximally responsible for ADRs and skin rash to be the dominant symptom in their study.
In another study by Arulmani et al. (2007)  , like our study, reported antibiotics to be responsible for one-third of the ADRs (33.5%) and among these ciprofloxacin was the drug resulting maximum ADRs in their study. Rash and diarrhoea were the two most frequent manifestations as ADR in their study. However, the results of the current study reported inj. ceftriaxone to be maximally contributing for the ADR unlike ciprofloxacin reported in their study. The possible reasons maybe that the current study is carried in tertiary care teaching hospitals with inclusion of inward patients.
Similarly, antimicrobials have been suggested the largest contributing to ADRs in the study of Palalian et al. (2010)  and Singh H et al. (2010)  and skin manifestation similar to our study remained the most affected organ system in these studies.
The study of Shrivastava MP et al. (2011)  reported antimicrobials, followed by Nonsteroidal anti-inflammatory drugs (NSAIDs) as the most common drugs responsible for ADRs and among antimicrobials unlike our study cotrimoxazole, ampicillin, rifampcin and azithromycin shared the maximum number in their study. The possible reason for such variations may be due to changing variable trends of antimicrobials/antibiotics used.
In the study of Palanisamy S et al. (2011)  , gastrointestinal system was the most affected organ system (37%) which is very much comparable with our study (39.28%). However, the GI manifestation remained the second most common manifestation after allergic rash.
Vora MB et al. (2011)  reported 3.2% and 2.1% as potentially serious and life threatening reactions due to antimicrobials. However, the results are unlike our study as only (1.08%) and (14.07%) as serious and non-serious ADRs due to antimicrobials were recorded in our study.
The results of another recent study by Jha N et al. (2012)  recorded antimicrobials, followed by antihypersensitive and NSAID's like our study to cause ADRs maximally in the form of rash followed by diarrhoea.
Very negligible contributions by biochemical abnormalities (n = 12) were recorded into the total pool of ADRs. This possibly explained by the physicians' tendency not to keep an eye on the biochemical abnormalities and their inability to correlate with ADRs.
Among the total antibiotics resulted into ADRs 89.79%, 6.88% and 3.33% were moderate, severe and mild in severity, whereas 92.86% and 7.14% were non-serious and serious, respectively, in nature, thereby warranting strict vigilance on ADRs due to antibiotics and rational and judicious use of these agents in clinical practice.
Maximum ADRs were of type A and 34.64% were of type B suggesting that large number of ADRs could have been preventable, if anticipated. Furthermore, it is highly recommended to prepare the detailed list of antibiotics contributing as type B reactions and carry subgroup analysis to find out the common offending agents and various factors resulting into unpredictable ADRs.
Maximum ADRs were probable and possible as per WHO-UMC and Naranjo causality assessment scale in the current study. Maximum patients required substitution of treatment and 7.4% required stoppage of medication and maximum recovered from the ADR at the time of study.
The result of the current study strongly points towards an urgent need for a hospital based team constituting of pharmacologists, dermatologists, treating physicians and treating consultant from emergency medicine to diagnose, correlate and manage ADRs promptly in the interest of patient safety. It further stress need to improvise antibiotic prescription practices and reframing hospital antibiotic policy to minimize ADRs events related to antibiotics.
There are some limitations in the current study that it does not represent the true prevalence of the problem due to voluntary/spontaneous nature of reporting. Risk factor correlation was not studied in the current study.
| ~ Conclusion|| |
The results of current study suggest that ADRs due to antibiotics is a significant health problem.
| ~ Acknowledgement|| |
The author acknowledge the IPC, for all support provided under PvPI and WHO-For this important Initiative on Patient Safety.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]