PHARMACOVIGILANCE
AND
ADES OF ANTIMICROBIALS
Dr. Sherif Kamal RPh, MSc, DHCM
57357 Chief pharmacists, Pharmacy Programs Director Health Sciences
Academy, ACPE CPE Administrator, Egyptian Fellowship Clinical Pharmacy
Trainer, and European Society of Oncology Pharmacy Board Member.
Pharmacovigilance /post-marketing surveillance
1. Pharmacovigilance or post-marketing surveillance aims to identify
and quantify the risks associated with the use of drugs.
Moore N, Biour M, Paux G, Loupi E, Begaud B, Boismare F, Royer RJ. Adverse drug reaction monitoring: doing it the French way. Lancet 1985; 2:
1056–8.
2. ADRs represent a common clinical problem and can be responsible
for an increased number and/or duration of hospitalisations.
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Lee CE, Zembower TR, Fotis MA, Postelnick MJ, Greenberger PA, Peterson LR, Noskin GA. The incidence of antimicrobial allergies in
hospitalised patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch InternMed2000; 160: 2819–22
Bordet R, Gautier S, Le Louet H, Dupuis B, Caron J. Analysis of the direct cost of adverse drug reactions in hospitalised patients. Eur J Clin
Pharmacol 2001; 56: 935–41
3. An ADR is associated with a significantly prolonged length of stay,
increased economic burden, morbidity, and an almost 2-fold
increased risk of death.
Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP. Adverse drug events in hospitalised patients. Excess length of stay, extra costs,and
attributable mortality. JAMA 1977; 277: 301–6.
Antibiotics
• Antibiotics are some of the major contributors to drug
hypersensitivity and represent the most frequently used
drugs in hospital practice.
1-Żukiewicz-Sobczak WA et al. Drugs as important factors causing allergies Postep Derm Alergol 2015; XXXII (5): 388–392
2-: Alemkere G, Tenna A, Engidawork E .Antibiotic use practice and predictors of hospital outcome among patients with systemic bacterial infection: Identifying targets for antibiotic and health care
resource stewardship. PLoS ONE ,201914(2): e0212661
3- Jung IY et al. Antibiotic-Related Adverse Drug Reactions at a Tertiary Care Hospital in South Korea BioMed Research International Volume 2017
Association of Adverse Drug Events with Broadspectrum Antibiotic Use in Hospitalized Patients
A Single-center Study
• The 3 most frequently prescribed antibiotics were piperacillin/tazobactam
(PIPC/TAZ) , meropenem , and vancomycin .
• (17.1%) experienced ADEs, including gastrointestinal (6.4%), hepatobiliary (4.2%),
dermatologic (2.5%), and renal (2.3%) manifestations.
• Patients treated with PIPC/TAZ, meropenem, doripenem, vancomycin, daptomycin,
and teicoplanin developed ADEs at rates of 20.7%, 16.0%, 15.4%, 19.6%, 11.8%,
and 10.9%, respectively.
Hagiya H. Association of Adverse Drug Events with Broad-spectrum Antibiotic Use in Hospitalized Patients: A
Single-center StudyIntern Med 58: 2621-2625, 2019
Criteria for Antibiotic-associated Adverse Drug Events
Hagiya H. Association of Adverse Drug Events with Broad-spectrum Antibiotic Use in Hospitalized Patients: A Single-center StudyIntern Med 58: 2621-2625, 2019
CONCLUSION
Hagiya H. Association of Adverse Drug Events with Broad-spectrum Antibiotic Use in Hospitalized Patients: A Single-center StudyIntern Med 58:
2621-2625, 2019
Antibiotic –associated Adverse –drug events
Antibiotic-associated ADEs, accounting for 22.3%
• Beta-lactam antibiotics constitute more than half of the
cases
• common ADE was :
• Dermatologic abnormalities (53.4%), followed by
• Liver dysfunction (9.7%) and
• Gastrointestinal symptoms (8.9%).
• Oral third-generation cephalosporins were frequently
reported as offending 29.5% of beta-lactam ADEs and
46.3% of cephem ADEs.
Kokado R et al. Antibiotic-associated adverse drug events at a Japanese
academic hospit . J Infect Chemother. 2018
Association of adverse events with antibiotic
use in hospital patients
• A total of 298 (20%) patients experienced at least 1
antibiotic-associated ADE.
• Furthermore, 56 (20%) non–clinically indicated antibiotic
regimens were associated with an ADE, including 7 cases
of C difficile infection.
• Every additional 10 days of antibiotic therapy conferred a
3%increased risk of an ADE
• The most common ADEs were gastrointestinal, renal, and
hematologic abnormalities, accounting for 78 (42%), 45
(24%), and 28 (15%) 30-day ADEs, respectively.
• Notable differences were identified between the
incidence of ADEs associated with specific antibiotics.
Tamma PD et al. Association of Adverse Events With Antibiotic Use in Hospitalized Patients .JAMA Intern Med. 2017;177(9):1308-1315.
Criteria Used for Antibiotic-Associated Adverse Drud Events
Tamma PD et al. Association of Adverse Events With Antibiotic Use in Hospitalized Patients .JAMA Intern Med. 2017;177(9):1308-1315.
Antibiotic associated Adverse Drug Events (ADE)
• 20% of hospitalized patients receiving at least 24 hours of
antibiotic therapy developed an antibiotic associated ADE.
• Every 10 DOTs conferred an additional 3% risk of an ADE.
• The importance of avoiding unnecessary antibiotic
prescribing to reduce the harm that can result from
antibiotic-associated ADEs.
Tamma PD et al. Association of Adverse Events With Antibiotic Use in Hospitalized Patients .JAMA Intern Med. 2017;177(9):1308-1315.
Antibiotic –related adverse drug reactions at
a tertiary care hospital
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3.4% of patients experienced serious ADRs.
Reported that 17.7% of ADRs were serious
Penicillin and quinolones were responsible for the majority of ADRs.
Penicillin allergies are more common in females
In outpatients, sulfonamides followed by penicillin were reported to
be the most common causative antibiotics
Jung IY et al. Antibiotic-Related Adverse Drug Reactions at a Tertiary Care Hospital in South Korea BioMed Research International Volume 2017
Antibiotic –related adverse drug reactions at
a tertiary care hospital
• Quinolones, ciprofloxacin in particular, are another common
causative antibiotic
• Geer et al. reported that antituberculosis drugs accounted for
13.15% of all ADRs
• Maciel et al. reported that up to 83.54% of ADRs were caused by
antituberculosis drugs.
• Gastrointestinal symptoms (22%) and hepatotoxicity (35.7%) were
frequently experienced ADRs caused by antituberculosis drugs .
Jung IY et al. Antibiotic-Related Adverse Drug Reactions at a Tertiary Care Hospital in South Korea BioMed Research International Volume 2017
Frequency (%) of ADRs in symptom organ class and most
common causative antibiotics
• Quinolones, penicillin, third generation cephalosporins, and glycopeptides were the most common causative
antibiotics for skin and subcutaneous related ADRs.
Jung IY et al. Antibiotic-Related Adverse Drug Reactions at a Tertiary Care Hospital in South Korea BioMed Research International Volume 2017
Adverse drug reaction monitoring during antimicrobial
therapy for septicemia patients
• ADRs in selected hospitalized patients of septicemia was found to be
in 26.5% .
• 12 ADRs were confirmed occurring in 9, out of 34 admitted patients.
• Pediatric patients experienced maximum ADRs, 44.4%.
• Females experienced a significantly higher incidence of ADRs, 66.7%.
• According to Naranjo’s probability scale, 8.3% of ADRs were found to
be definite, 58.3% as probable, and 33.3% as possible.
• A higher proportion of these ADRs, 66.7% were preventable in nature.
• Severity assessment showed that more than half of ADRs were
moderate.
• Teicoplanin was found to be the commonest antimicrobial agent
associated with ADRs, followed by gemifloxacin and ofloxacin.
Shamshir Alam M et al. Adverse drug reaction monitoring during antimicrobial therapy for septicemia patients at
a university hospital in New Delhi Korean J Intern Med 2018;33:1203-1209
. Relationship between adverse drug reactions to
antibacterial agents and the Klebsiella
pneumoniae carbapenemaseproducing (KPC)
• A total of 16,329 ADR reports were collected in the three spontaneous reporting systems ( SRSs), with meropenem
(42.6%) and gentamicin (36.9%) having the highest number of reports.
• Significant increase in total and serious ADR reports after the Klebsiella pneumoniae carbapenemase producing (KPC )
outbreak compared to previous 10 years was found for colistin, meropenem and gentamicin (p < 0.01).
• No significant increase in tigecycline ADRs was reported in Adverse Event Reporting System (FAERS) and UK database.
• Unexpected safety signals involving selected antibiotics were not detected.
• Significant positive relationship between overall and serious ADR reports and KPC isolates per year for both Italy (p <
0.01; p = 0.005) and UK (p = 0.032; p = 0.013) was found.
• KPC outbreak led to significant increase in ADRs to selected antibiotic
Gatti M et al. Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemaseproducing (KPC)
Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study .BMC Pharmacology and Toxicology (2019) 20:65
Relationship between carbapenem-resistant Kp isolates per year
and overall and serious ADR reports
Gatti M et al. Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemaseproducing (KPC)
Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study .BMC Pharmacology and Toxicology (2019) 20:65
Adverse drug events in hospitals: a systematic review
• In order to guarantee the safe use of medicines, it is necessary to monitor
the occurrence of post-registration/post-marketing ADEs, a process known
as pharmacovigilance.
• This strategy aims to assist regulatory activities in the patient safety area.
• A pioneering initiative in monitoring adverse drug reactions in inpatients
was the Boston Collaborative Drug Surveillance Program (BDSCP), launched
in 1966, which conducted an active search for events and collected data on
35,000 patients in ten years
• Other active search conducted for events and estimated their frequency at
13.6% among inpatients
• In 1998, a meta-analysis estimated the incidenceof severe ADRs at 6.7%
(5.2%-8.2%) but this finding should be interpreted with caution due to
various sources of heterogeneity among the studies .
Cad. Saúde Pública, Rio de Janeiro. ADVERSE DRUG EVENTS IN HOSPITAL 25 Sup 3:S360-S372, 2009
Adverse drug events in hospitals: a systematic review
• The early 1990s witnessed a new stage in the issue of drug safety,
which in addition to recognizing the production of adverse events,
even when drugs are used appropriately, also identifies the possibility
that drugs can cause harmful effects due to flaws or errors during the
complex process of their clinical utilization.
• The proportion of patients or admissions with ADEs during
hospitalization varied from 1.6 to 41.4%, and the rates ranged from
1.7 to 51.5 events per 100 hospitalizations and from 4.4 to 7.0
events per 100 patient-days.
Cad. Saúde Pública, Rio de Janeiro. ADVERSE DRUG EVENTS IN HOSPITAL 25 Sup 3:S360-S372, 2009
Antibiotics & adverse events relation ship
• Antibiotics were responsible for 92 (44.9%) out of 205 episodes of ADRs.
• In particular, 22 episodes (23.9%) were observed after penicillin G
administration, 19 episodes (20.7%) following ceftazidime and
cefotaxime administration, 16 episodes (17.4%) after therapy with
ampicillin, and 35 reactions (38%) were further reported during
treatments with other antibiotics.
• We determined that the drug–ADR relationship was certain in 63% of
the reports; withdrawal of the suspected drug led to recovery in 95% of
cases.
Gallelli L et al ADVERSE DRUG REACTIONS TO ANTIBIOTICS OBSERVED IN TWO PULMONOLOGY DIVISIONS OF CATANZARO, ITALY:
A SIX-YEAR RETROSPECTIVE STUDY Pharmacological Research Volume 46, Issue 5, November 2002, Pages 395-400
The six axes and total score in
kramer’s algorithm for ADRs
Causality of ADRs
• In order to assess the likelihood that ADRs
were determined by antibiotics, a
causality rating was assigned to each
antibiotic using the validate Kramer’s
algorithm .
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63% were classified as certain,
29% as probable and
8% as possible.
12% of side effects were classified as
serious ARDs
Gallelli L et al ADVERSE DRUG REACTIONS TO ANTIBIOTICS OBSERVED IN TWO PULMONOLOGY DIVISIONS OF CATANZARO, ITALY: A SIX-YEAR
RETROSPECTIVE STUDY Pharmacological Research Volume 46, Issue 5, November 2002, Pages 395-400
Results
• During the study period, 4612 clinical records and 18 464
prescriptions were analysed.
• According to the definition of ADRs and Kramer’s causality algorithm,
we reported that within 205 suspects of ADRs (1.11% of total
prescriptions), 92 were induced by antibiotics (44.9%).
• Patients with ADRs induced by antibiotics and by other drugs, did not
show any significant difference in the sex ratio (man 53.2% and
woman 46.8%; man 56.2% and woman 43.8%, respectively).
Gallelli L et al ADVERSE DRUG REACTIONS TO ANTIBIOTICS OBSERVED IN TWO PULMONOLOGY DIVISIONS OF CATANZARO, ITALY: A SIX-YEAR
RETROSPECTIVE STUDY Pharmacological Research Volume 46, Issue 5, November 2002, Pages 395-400
Results
• The percentage of patients with a reported ADR varied among the six
age groups. In fact, older patients were more likely to suffer an ADR in
comparison with all drug-treated patients, as well as with respect to
antibiotic-treated patients (P <0.0001 for total ADRs vs total number
of patients; P = 0.0160 for ADRs induced by antibiotics vs total
number of patients treated with antibiotics)
• The most frequently reported side effects were cutaneous(70.5%),
gastrointestinal (7.6%) and cardiovascular(7.6%) disturbances
• Most of the side effects involved penicillins and cephalosporines
Gallelli L et al ADVERSE DRUG REACTIONS TO ANTIBIOTICS OBSERVED IN TWO PULMONOLOGY DIVISIONS OF CATANZARO, ITALY: A SIX-YEAR
RETROSPECTIVE STUDY Pharmacological Research Volume 46, Issue 5, November 2002, Pages 395-400
Antibiotics involved in ADRs
Gallelli L et al ADVERSE DRUG REACTIONS TO ANTIBIOTICS OBSERVED IN TWO PULMONOLOGY DIVISIONS OF CATANZARO, ITALY: A SIX-YEAR
RETROSPECTIVE STUDY Pharmacological Research Volume 46, Issue 5, November 2002, Pages 395-400
Serious ADRs induces by Antibiotics
Gallelli L et al ADVERSE DRUG REACTIONS TO ANTIBIOTICS OBSERVED IN TWO PULMONOLOGY DIVISIONS OF CATANZARO, ITALY: A SIX-YEAR
RETROSPECTIVE STUDY Pharmacological Research Volume 46, Issue 5, November 2002, Pages 395-400
‘Pharmaco-EcoMicrobiology’’,
Shahid M et al. Pharmaco-EcoMicrobiology: A newer component of medical sciences bridging pharmacovigilance,
ecology, and environmental microbiologyJournal of Infection and Public Health (2010) 3, 1—4
Pharmaco- EcoMicrobiology
• ‘‘Pharmaco- EcoMicrobiology’’ to define the interplay
between pharmacological antimicrobial agent and animate
microbial ecology.
• A detailed algorithm describing the components of this
newer domain and the adverse drug effects (ADEs) occurring
and to be monitored under this domain
Shahid M et al. Pharmaco-EcoMicrobiology: A newer component of medical sciences bridging pharmacovigilance, ecology, and
environmental microbiologyJournal of Infection and Public Health (2010) 3, 1—4
Pharmaco- EcoMicrobiology
• According to the World Health Organization (WHO), ‘‘Pharmacovigilance’’
activities are done to monitor detection, assessment, understanding and
prevention of any obnoxious adverse reactions to drugs at therapeutic
concentration on animals and humans.
• However, in recent years, environmental scientists have raised a great
concern on the impacts of drugs on the environment and surrounding
Shahid M et al. Pharmaco-EcoMicrobiology: A newer component of medical sciences bridging pharmacovigilance, ecology, and environmental
microbiologyJournal of Infection and Public Health (2010) 3, 1—4
Thank you