Antimicrobials associated adverse drug reaction profiling: a four years retrospective study (Pharmacovigilance study)

Figures & data

Figure 1. Flow-chart diagram for plan of study

Table 1. Analysis of demographic, and causality of adverse drug reactions (ADRs)

Parameter	No. of ADRs (n = 414)	Frequency %
Gender
Male	192	46.38
Female	222	53.62
Age
Neonate (below 27 days)	1	0.24
Infant (28 days to 1 yr)	3	0.73
Child (2–11 yrs)	37	8.94
Adolescent (12–18 yrs)	19	4.59
Adult (19–65 yrs)	345	83.33
Elderly (66 yrs and above)	9	2.17
Causality
Certain	23	5.56
Probable	268	64.73
Possible	123	29.71
Unlikely	0	0
Unclassified	0	0
Unclassifiable	0	0

Table 2. Individual drug frequency reported in individual case safety reports [(ICSRs) n = 414].^a

Antimicrobial Class Total no. of drugs (Frequency %)	Types of antimicrobial Drugs involved in different ICSRs (n = 54)	No. of Individual antimicrobials (frequency %)
Sulfonamides-12 (2.89%)	Sulfamethoxazole/Trimethoprim	11 (2.65)
	Pyrimethamine/Sulfadoxine	1 (0.24)
Quinolones-33 (7.97%)	Ciprofloxacin	24 (5.78)
	Ofloxacin	4 (0.96)
	Norfloxacin	2 (0.48)
	Levofloxacin	2(0.48)
	Moxifloxacin	1 (0.24)
Penicillins-78 (18.84%)	Penicillin	1 (0.24)
	Ampicillin	2 (0.48)
	Amoxicillin	2 (0.48)
	Amoxicillin/Clavulanic acid	49 (11.83)
	Piperacillin/Tazobactam	24 (5.79)
Cephalosporins-104 (25.12%)	Ceftriaxone	75 (18.11)
	Cefixime	20 (4.83)
	Cefpodoxime	4 (0.96)
	Cephalexin	1 (0.24)
	Cefuroxime	1 (0.24)
	Cefoperazone/Sulbactam	2 (0.48)
	Cefotaxime	1 (0.24)
Other betalactum- 7 (1.69%)	Meropenem	7 (1.69)
Tetracyclines-2 (0.48%)	Minocycline	1 (0.24)
	Doxycycline	1 (0.24)
Aminoglycoside-8 (1.93%)	Gentamicin	5 (1.20)
	Streptomycin	1 (0.24)
	Amikacin	2 (0.48)
Macrolides-10 (2.41%)	Azithromycin	8 (1.93)
	Clindamycin	1 (0.24)
	Clarithromycin	1 (0.24)
Miscellaneous antibacterials-14 (3.38%)	Vancomycin	7 (1.69)
	Linezolid	5 (1.20)
	Nitrofurantoin	2 (0.48)
Antileprotic-9 (2.17%)	Dapsone	9 (2.17)
Antifungal-9 (2.17%)	Fluconazole	3 (0.72)
	Terbinafine	1 (0.24)
	Itraconazole	3 (0.72)
	Sertaconazole	1 (0.24)
	Clotrimazole	1 (0.24)
Antiviral-90 (21.73%)	TLE	68 (16.42)
	T/TL	5 (1.20)
	ZLN	6 (1.44)
	ZL	5 (1.20)
	ZLE	3 (0.72)
	Abacavir	1 (0.24)
	Acyclovir	1 (0.24)
	Ritonavir	1 (0.24)
Antimalarials-3 (0.72%)	Artemether/Lumefantrine	2 (0.48)
	Sulfadoxine/Pyrimethamine	1 (0.24)
Antiprotozoal- 33(7.97%)	Metronidazole	16 (3.86)
	Ornidazole	2 (0.48)
	Tinidazole	2 (0.48)
	Ofloxacin/Ornidazole	7 (1.69)
	Norfloxacin/Tinidazole	5 (1.20)
	Ciprofloxacin/Tinidazole	1 (0.24)
Antiscabicidal-2 (0.48%)	Permethrin	2 (0.48)

^aE: Efavirenz; L: Lamivudine; N: Nevirapine; T: Tenofovir; Z: Zidovudine.

Table 3. Antimicrobial-associated adverse drug reactions (ADRs) involved in skin and subcutaneous tissue (SOC).^a.

Class of Drugs involved in Skin and subcutaneous tissue	Individual drugs	Frequency of ADRs	Most common types of ADRs
Sulfonamides	Cotrimoxazole	9	Rash, pruritus, urticaria, Erythema multiforme
Quinolones	Ciprofloxacin	18	Angioedema, rash and pruritus
	Ofloxacin	3	Angioedema, fixed drug eruption and vomiting
	Norfloxacin	2	Skin hyperpigmentation and whiteheads, itching
	Levofloxacin	1	Itching
	Moxifloxacin	1	Rash
Penicillins	Penicillin	1	SJS
	Ampicillin	1	Erythematous skin rash
	Amoxicillin	2	Rash and skin peeling
	Amoxicillin/Clavulanic acid	29	SJS, rash, bullous eruptions, vascular purpura and diarrhea
	Piperacillin/Tazobactam	23	Eczematous rash, dermatitis, maculopapular rash, itching, angioedema
Cephalosporins	Ceftriaxone	36	Rash, maculopapular rash bullous eruptions
	Cefixime	21	Erythematous skin rash, pruritic rash, urticaria SJS
	Cefpodoxime	3	TEN, Pruritic rash, acute diarrhea
	Cefalexin	1	Rash
	Cefuroxime	1	Rash
	Cefoperazone/Sulbactum	1	Itching
	Cefotaxime	1	Lip angioedema
Other betalactum	Meropenem	7	SJS, Rash, skin peeling, bullous eruption
Aminoglycoside	Gentamicin	4	Rash, lip angioedema
	Amikacin	2	Macular rash
Macrolides	Azithromycin	3	Erythematous rash
	Clindamycin	1	Maculopapular rash
Miscellaneous antibacterials	Vancomycin	5	Erythematous rash, itching, Redman syndrome
	Linezolid	1	Pruritic rash
Antileprotic	Dapsone	5	Dapsone syndrome, Erythema nodosum, hypersensitivity reaction
Antifungal	Fluconazole	3	Erythematous rash and bullous eruptions
	Itraconazole	2	Erythematous rash and papular rash
	Sertaconazole	1	Application site itching
	Clotrimazole	1	Itching
Antiviral	Tenofovir+Lamivudine+Efavirenz	48	Maculo-papular, urticaria, itching and skin peeling
	Zidovudine+Lamivudine+Nevirapine	12	Pruritic rash, hyperpigmentation, itching and skin peeling
	Acyclovir	1	Rash
	Ritonavir	3	Rash
	Artemether/Lumefantrine	1	Rash
Antimalarials	Sulfadoxine/Pyrimethamine	1	Toxic epidermal necrolysis
	Metronidazole	4	Angioedema, urticaria and rash
Antiprotozoal	Ornidazole	3	Itching, Fixed drug eruptions, TEN
	Tinidazole	2	Rash
	Ofloxacin/Ornidazole	6	Erythema multiforme, photosensitivity, bullous eruptions, urticaria
	Norfloxacin/Tinidazole4	4	Bullous eruptions, pruritic rash
	Ciprofloxacin/Tinidazole	1	SJS
Antiscabicidal	Permethrin	2	Bullous eruptions, itching

^aSJS: Steven Johnson syndrome; TEN: Toxic Epidermal Necrosis.

Table 4. Antimicrobial-associated adverse drug reactions (ADRs) involved in different system organ class (SOC).^a.

system organ class (SOC)	Antimicrobial class	Individual drugs	Frequency of ADRs	Most common types of ADRs
Gastrointestinal disorders	Quinolones	Ciprofloxacin	2	Abdominal pain, Diarrhea
		Ofloxacin	1	Vomiting
		Levofloxacin	1	Constipation
	Penicillins	Amoxicillin	1	Black tongue
		Amoxicillin/Clavulanic acid	13	Diarrhea and vomiting
		Piperacillin/Tazobactam	1	Vomiting
	Cephalosporins	Ceftriaxone	5	Vomiting, Abdominal pain
		Cefixime	3	Vomiting
		Cefpodoxime	1	Vomiting
		Ceftazidime	1	Abdominal cramps
	Other beta-lactums	Meropenem	2	Vomiting
	Aminoglycoside	Gentamicin	1	Vomiting
	Miscellaneous antibacterials	Linezolid	2	Vomiting
	Antileprotic	Dapsone	1	Diarrhea
	Antiviral	TLE	14	Oral ulcer, Diarhhoea and vomiting
		ZLN	1	Vomiting
		Atazanavi/Ritonavir	1	Vomiting
	Antiprotozoal	Metronidazole	5	Vomiting
		Ofloxacin/Ornidazole	1	Lip swelling
		Norfloxacin/Tinidazole	2	Lip swelling
General disorders and administration site conditions	Quinolones	Ciprofloxacin	3	Generalized edema, warmth sensation
	Penicillins	Amoxicillin/Clavulanic acid	8	Shivering, rigor, generalized edema
		Piperacillin/Tazobactam	2	Generalized edema
	Cephalosporins	Ceftriaxone	15	Rigor and shivering
		Cefixime	2	Tiredness and edema
		Cefalaxin	1	Chest tightness
		Cefoperazone/Sulbactum	1	Swelling at injection site
	Aminoglycoside	Gentamicin	1	Rigor
	Miscellaneous	Vancomycin	1	Shivering
		Nitrofurantoin	1	Swelling at injection site
	Antiviral	TLE	7	Generalized edema, tiredness and weakness
		ZLN	4	Fatigue, rigor
	Antiprotozoal	Metronidazole	6	Chills, rigors warmth sensation
	Antiscabicidal	Permethrin	1	Itching at application site
Nervous system disorders	Quinolones	Ciprofloxacin	3	Convulsion, impaired concentration, burning sensation
		Norfloxacin	1	Lethargy
	Penicillin	Amoxicillin/Clavulanic acid	2	Shoulder numbness and dizziness
	Cephalosporins	Ceftriaxone	7	Convulsion and dizziness
	Macrolides	Azithromycin	1	Anosmia
	Miscellaneous antibacterial	Linezolid	1	Giddiness
		Nitrofurantoin	3	Headache, dizziness, burning sensation all over body
	Antiviral	TLE	8	Headache, dizziness, loss of taste, convulsion, numbness
		Atazanavir	1	Lethargy
	Antiprotozoal	Metronidazole	2	Headache
Respiratory, thoracic and mediastinal disorders	Penicillins	Amoxicillin/Clavulanic acid	5	Dyspnea, respiratory distress
		Piperacillin/Tazobactam	1	Dyspnea
	Cephalosporins	Ceftriaxone	7	Dyspnea
		Ceftazidime	1	Dyspnea
		Ciprofloxacin	1	Respiratory distress
	Macrolides	Azithromycin	1	Throat irritation
	Miscellaneous antibacterial	Linezolid	1	Dyspnea
	Antiprotozoal	Metronidazole	3	Dyspnea
	Miscellaneous antibiotic	Nitrofurantoin	1	Breathing difficulty
Musculoskeletal and connective tissue disorders	Quinolones	Ciprofloxacin	1	Muscle cramps
	Penicillins	Amoxicillin/Clavulanic acid	1	Myalgia
		Piperacillin/Tazobactam	2	Muscle twitching
	Cephalosporins	Ceftriaxone	5	Muscle burning sensation
	Tetracycline	Minocycline	1	Systemic lupus erythromatosis
	Macrolides	Clarithromycin	2	Myalgia, arthralgia
	Antifungal	Itraconazole	2	Cervical pain and generalized myalgia
	Antiviral	TLE	1	Arthralgia
Investigations	Sulfonamides	Cotrimoxazole	3	Raised serum creatinine
	Penicillins	Amoxicillin/Clavulanic acid	1	Decreased oxygen saturation
	Miscellaneous antibacterial	Linezolid	1	Decreased platelet count
	Antiviral	TLE	7	Raised serum creatinine
		ZLN	1	Raised serum creatinine
		Abacavir	1	Raised serum creatinine
Ear and labyrinth disorders	Cephalosporins	Ceftriaxone	2	Vertigo
	Macrolides	Azithromycin	1	Plugged ears
	Antiviral	TLE	6	Vertigo
Reproductive system and breast disorders	Penicillins	Amoxicillin/Clavulanic acid	2	Vaginal itching
	Cephalosporins	Ceftriaxone	1	Vaginal itching
	Macrolides	Azithromicin	1	Vaginal itching
	Antiviral	TLE	4	Gynecomastia
Immune system disorders	Penicillins	Amoxicillin/Clavulanic acid	2	Anaphylactic reaction
	Cephalosporins	Ceftriaxone	4	Anaphylactic reaction
	Antileprotic	Dapsone	1	Anaphylactic reaction
Metabolism and nutrition disorders	Macrolides	Azithromycin	1	Anorexia
	Miscellaneous antibacterial	Linezolid	1	Anorexia
	Antiviral	TLE	3	Anorexia
		ZLN	1	Anorexia
Eye disorders	Quinolones	Ciprofloxacin	1	Stinging eyes
	Cephalosporins	Ceftriaxone	4	Diminished vision, eye bleeding, periorbital edema
Hepatobiliary disorders	Penicillins	Piperacillin/Tazobactam	1	Hepatitis
	Antileprotic	Dapsone	1	Hepatitis
	Antimalarial	Artemether/Lumefantrine	1	Hepatomegaly
Cardiac disorders	Cephalosporins	Ceftriaxone	1	Bradycardia
		Cefixime	2	Palpitations
	Miscellaneous	Vancomycin	1	Tachycardia
Vascular disorders	Penicillins	Amoxicillin/Clavulanic acid	3	Hypotension, hypertension and flushing
	Cephalosporins	Ceftriaxone	1	Hypertension
Psychiatric disorders	Penicillins	Ampicillin	1	Irritable mood
	Macrolides	Azithromycin	1	Restlessness
	Antiviral	TLE	1	Insomnia
Blood and lymphatic system disorders	Cephalosporins	Ceftriaxone	1	Thrombocytopenia
	Antileprotic	Dapsone	1	Microcytic anemia
	Antiviral	ZLN	1	Hemolytic anemia
Renal and urinary disorders	Penicillins	Amoxicillin/Clavulanic acid	1	Burning micturition
	Macrolides	Azithromycin	1	Scanty urine
Injury, poisoning and procedural complications	Quinolones	Ciprofloxacin	1	Accident
	Cephalosporins	Ceftriaxone	1	Documented hypersensitivity to administered drug
Infections and infestations	Antileprotic	Dapsone	1	Dapsone syndrome
Pregnancy, puerperium and perinatal conditions	Penicillin	Amoxiclav	1	Eclampsia
Social circumstances	Quinolones	Ciprofloxacin	1	Driving ability disturbed

³E: Efavirenz; L: Lamivudine; N: Nevirapine; T: Tenofovir; Z: Zidovudine.

Figure 2. System organ class (SOC) involved in adverse drug reactions (ADRs)

Table 5. Severity of adverse drug reactions (ADRs) as per modified Hartwig and Siegel severity assessment scale

Level	Modified Hartwig and Siegel Severity Assessment Scale	No of cases	Severity, Frequency (%)
Level 1	An ADR occurred but required no change in treatment with the suspected drug.	59	Mild 256 (61.3)
Level 2	An ADR required that the treatment with the suspected drug be held, discontinued, or otherwise changed. No antidote or other treatment requirement was required. No increase in length of stay.	197
Level 3	An ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed. AND/OR An antidote or other treatment requirement was required. No increase in length of stay.	69	Moderate 133 (32.12)
Level 4	Any level 3 ADR which increases the length of stay by at least 1 day. OR The ADR was the reason for admission.	64
Level 5	Any level 4 ADR which require intensive medical care.	18	Severe 25 (6.03)
Level 6	The ADR caused permanent harm to the patient.	3
Level 7	The ADR either directly or indirectly lead to the death of the patient.	4