Utilization pattern, safety profile and cost analysis of antimicrobials prescribed in an intensive care unit of a teaching hospital

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Submitted to

THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfilment of the requirements for the award of the degree of

M.D PHARMACOLOGY Branch VI

May2018

INTENSIVE CARE UNIT OF A TEACHING HOSPITAL

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Submitted to

THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfilment of the requirements for the award of the degree of

M.D PHARMACOLOGY Branch VI

May 2018

INTENSIVE CARE UNIT OF A TEACHING HOSPITAL

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In the first place, I would like to express my gratitude to my professor, mentor and guide Dr. Reneega Gangadhar, for her valuable and constant guidance, supervision and support throughout the study. Her patience and understanding during times of difficulties in the study period helped me a lot under such circumstances. Her constant motivation has helped me to overcome all the challenges and difficulties that I came across this research work. Her encouragement from the inception of this research to its culmination has always been profound. It has been an extraordinary experience working under her.

I am very much grateful to my co-guide Dr. Kaniraj Peter. J, Professor for valuable support and guidance in carrying out the study.

I extend my sincere heartfelt thanks to Dr. Velayuthan Nair, Chairman and Dr. Rema. V. Nair, Director, for providing facilities to accomplish my dissertation work. I also thank the Principal of the Institution Dr. Padmakumar for his valuable support extended to me.

I thank my Associate professor Dr. Ganesh. V, for his help and support throughout the study period.

I am thankful to Dr. V. M. Sandeep, Assistant Professor for his help, support, valuable suggestions and encouragement throughout the study period.

I also thank my Assistant Professor Mr. Sarath Babu. K for his critical inputs at all stages of my study. His suggestions never failed to help me in times of difficulties during the study.

I express my special thanks to my colleague Dr. Suhaina. A. S for giving me constant support and encouragement as well as for her constructive criticism and valuable inputs. I also thank my senior Post Graduates Dr. Prathab Asir. A,

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support.

Mrs. Florence Vimala. P and Mrs. Sangeetha. M deserves special mention for their technical help and support.

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ABBREVIATIONS

ADR Adverse Drug Reaction

AE Adverse Event

AIDS Acquired Immunodeficiency Syndrome

ALI Acute Lung Injury

AMAs Antimicrobial Agents

AMR Antimicrobial Resistance

ARDS Acute Respiratory Distress Syndrome

ARF Acute Renal Failure

ASHP American Society Of Health-System Pharmacists

AST Antibiotic Susceptibility Testing

ATC Anatomical Therapeutic Chemical

BMI Body Mass Index

BSI Blood Stream Infection

CAP Community Acquired Pneumonia

CNS Central Nervous System

DDD Defined Daily Dose

DDS Dapsone

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DNA Deoxyribonucleic Acid

DUS Drug Utilization Study

EDL Essential Drug List

ESBLs Extended Spectrum Beta-Lactamases

FDC Fixed Drug Combination

G6PD Glucose-6-Phosphate Dehydrogenase Deficiency

GIT Gastrointestinal Tract

ICP Intracranial Pressure

ICU Intensive Care Unit

IHEC Institutional Human Ethics Committee

ICM Intensive Care Management

IM Intramuscular

IMCU Intensive Medical Care Unit

IV Intravenous

LRT Lower Respiratory Tract

MAC Mycobacterium Avium Complex

MDR Multi Drug Resistance

MIC Minimum Inhibitory Concentration

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MICU Medical Intensive Care Unit

MODS Multi Organ Dysfunction Syndrome

MRSA Methicillin Resistant Staphylococcus Aureus

NDM-1 New Delhi Metallo-Lactamase

NI Nosocomial Infection

NTS Non Typhoidal Salmonella

OPD Out Patients Department

PAS Paraaminosalicylic Acid

PDD Prescribed Daily Dose

PSURs Periodic Safety Updates Regulators

RNTCP Revised National Tuberculosis Control Program

SSI Surgical Site Infection

ToRs Terms Of Reference

UTI Urinary Tract Infection

VAP Ventilator-Associated Pneumonia

WHO World Health Organization

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Introduction

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1 | | | | P a g eP a g eP a g eP a g e

Introduction

Infectious diseases were the major cause of morbidity and mortality before the discovery of antimicrobial agents (AMAs).¹Antimicrobial agentsare the frequently utilized drugs in an intensive care unit (ICU) setting.²In ICU a large number of drugs are administered to patients, most of the patients are critically ill and suffering from multiple complications.³These patients have frequent infection and are more prone for developing new infections.⁴ICU is a place where there is frequent use of antibiotics, poor adherence with evidence- based guidelines and broad-spectrum antibiotic overuse.⁵

The total AMA consumption in ICU is approximately ten times higher than the general hospital wards.⁴ Bacterial resistance is increased due to inappropriate use of antibiotics. Antimicrobial agents are also used empirically in ICU without culture sensitivity test.⁶Antibiotic resistance due to hospital acquired infections is a worldwide problem and it is one of the reason for increased morbidity, mortality, length of hospital stay, and healthcare expenditures. Overuse or misuse of antibiotics increases burden of antibiotic resistance, adverse effects of these drugs along with treatment costs.⁷

Drug utilization study is an essential part of pharmaco-epidemiology.⁷ Drug utilization research was defined by World Health Organization (WHO) in 1977 as “the marketing distribution and use of drugs in a society, with special emphasis on the resulting medical, social and economic consequences”. This type of research provides an overview about the pattern, quality, determinations and outcome of use. The aim of drug utilization research is to motivate the

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2 | | | | P a g eP a g eP a g eP a g e rational use of medications by the clinicians while delivering health care. It is an important tool to study the clinical use of drugs in populations and its impact on the health care system.³Drug utilization studies are useful for information about drug use patterns and for identifying high cost drugs. Such analysis not only improves the standards of medical treatment, but also helps in the identification of problems related to drug use such as poly pharmacy, drug interaction and adverse drug reaction.⁹

The defined daily dose (DDD) concept was developed to overcome objections against traditional units of measurement of drug consumption. The DDD is defined as the assumed average maintenance dose per day for a drug used for its main indication in adults.³

World Health Organization has defined adverse drug reaction (ADR) as

“a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the modification of physiological function”.⁹ ADRs is one of the major causes of iatrogenic disease. ADRs may result in hospital admission or prolonged hospitalization but also may lead to permanent disability or even death.⁶Pharmaceutical cost are the fastest growing health care expense. Cost of the drug play a crucial role in patient care especially in developing countries.¹⁰ Pharmacoeconomic analysis is comparison with of two or more drug therapies with respect to their costs and consequences.¹¹

In the light of above mentioned information, monitoring and evaluation of prescription patterns of antimicrobial agents are one of the recommended

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3 | | | | P a g eP a g eP a g eP a g e strategies to control resistance and also to improve the prescribing practices.

ADRs due to antibiotics are the most common in the our country because these are the most commonly used drug in therapy.¹²It is always safe to keep the numbers of drugs per prescription low to minimize the risk of drug interactions, development of bacterial resistance and cost in hospital. It is always good to have a complete prescription with name, age, sex, and diagnosis with drug treatment using less number of drugs, correct dose and administration duration.

There is need to conduct many studies to educate the prescribers, the rational drug therapy for safety and benefit to the patient.¹³

Till date no study on utilization pattern, safety profile and economic outcome of antimicrobial use has been conducted in this institution. Hence it was thought worthwhile to conduct a study to evaluate the utilization pattern, safety profile and cost analysis of antimicrobial use in the Medical ICU of this institute.

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Review of Literature

Review of Literature Review of Literature

Review of Literature

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Review of literature

Intensive care has been defined as “a service for patients with potentially recoverable conditions who can benefit from more detailed observation and invasive treatment than can safely be provided in general wards or high dependency areas.” The most commonly supported organ is the lung, but facilities should also exist for the diagnosis, prevention, and treatment of other organ dysfunction.¹⁴

The Intensive Care Unit (ICU) management of patients is targeted towards,¹⁵

• Respiratory system

• Cardiovascular system

• Alimentary system

• Nosocomial infection and infection surveillance

• Anticoagulation

• Patient comfort

Common Reasons for ICU Care

There are many reasons a patient may need care in an ICU. Some of the more common problems and conditions that may bring a patient to an ICU or that may develop while a patient is under ICU care.¹⁵

A. Pneumonia

B. Urinary tract infection(UTI) C. Blood stream infection(BSI) D. Shock

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5 | | | | P a g eP a g eP a g eP a g e E. Acute Respiratory Distress Syndrome (ARDS)

F. Chronic Respiratory failure G. Renal failure

H. Neurological conditions I. Bleeding & clotting

J. Multi Organ Dysfunction Syndrome(MODS) K. Nosocomial Infection(NI)

A. Pneumonia

The most common nosocomial infection in ICU patients is pneumonia and is usually associated with mechanical ventilation (ventilator-associated pneumonia/VAP). Common risk factors for nosocomial pneumonia are old age, premature infants, chronic lung disease, previous abdominal thoracic surgery, endotracheal intubation, duration of mechanical ventilation, nasogastric tube, immunosuppression, prior antibiotic use, supine position, poor pulmonary toilet, increased gastric pH and aspiration.¹⁶ The common causative agents were Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Moraxella catarrhalis and Staphylococcus aureus. Although less frequently isolated, Streptococcus pneumoniae had become a worldwide problem because of its increasing resistance to penicillins and most other beta-lactams. They are often very difficult to diagnose because of multiple causes of pulmonary infiltrates, including ARDS, pulmonary hemorrhage or embolus and cardiogenic shock.¹⁷

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6 | | | | P a g eP a g eP a g eP a g e B. Urinary tract infections (UTIs)

Nosocomial UTIs were the second most common infection in the ICU and constituted a major source for nosocomial septicemia and related mortality.

Usually, UTI presented with fever or with other signs of systemic illness.

Common risk factors included indwelling bladder catheters, duration of catheterization and other factors like female gender, old age, premature infants, diabetes mellitus, renal failure, and metal colonization. Both condom catheters and transurethral catheters posed significant risk for UTI.¹⁸ The microorganisms usually responsible for catheter-associated UTIs were derived from the fecal flora of the patient or originated from the hospital environment, and included Escherichia coli, Enterococcus spp., Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis and Candida albicans.¹⁷

C. Bloodstream infections (BSIs)

BSIs are usually the third most common nosocomial infection in ICUs, and are commonly divided into primary and secondary. Primary BSIs were associated with intravascular devices like catheters, and secondary BSIs arose from an infection at another site (e.g., an intra-abdominal infection). There were several sources of bacteraemia, mainly nosocomial pneumonia, UTI and other foci of infection such as skin and soft tissue infections (particularly in burn patients) and surgical wounds.¹⁹Gram positive organisms like MRSA and coagulase-negative staphylococci are more likely causative agents, particularly in relation to the presence of IV devices, central lines or peripheral IV catheters. Coagulase-negative staphylococci produce an extracellular slime

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7 | | | | P a g eP a g eP a g eP a g e matrix in which bacteria are embedded and which interferes with the penetration of antibiotics and hence cannot be eliminated by traditional antimicrobial therapy.²⁰

D. Shock

Shock is an acute or hyperacute physiological derangement, a systemic syndrome characterized by signs and symptoms, which are the response of different organs to a situation of hypoperfusion for their cells basic metabolic needs. Perfusion means oxygen and nutrients delivery via blood flow.²¹Shock results from four potential, and not necessarily exclusive, pathophysiological mechanisms,²²

• Hypovolemia shock: Internal or external fluid loss

• Cardiogenic Shock: Acute myocardial infarction, end-stage cardiomyopathy, advanced valvular heart disease, myocarditis, or cardiac arrhythmias

• Obstruction Shock: Pulmonaryem embolism, cardiac tamponade, or tension pneumothorax

• Distributive factors: severe sepsis or anaphylaxis from the release of inflammatory mediators

Whatever causes it, shock is a situation of relative hypoxaemia due to failure of the circulation in delivering and distributing enough oxygen for the oxidative processes leading to ATP formation.²¹

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8 | | | | P a g eP a g eP a g eP a g e E. Acute respiratory distress syndrome (ARDS)

Acute lung injury (ALI) is a clinical syndrome of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary infiltrates leading to respiratory failure, a ratio of arterial oxygen tension to fraction of inspired oxygen (PaO 2 /FiO 2 ) of 201-300 mmHg, in the absence of cardiac failure.

ALI/ARDS results from direct causes like pneumonia, aspiration of gastric contents, pulmonary contusion, etc. and indirect causes like sepsis, trauma, fractures, pancreatitis, burns, etc. is usually treated with some AMAs.

Reductions in ARDS/ALI mortality are largely the result of general advances in the care of critically ill patients and in ventilatory strategies.²³ F. Renal Failure

Acute renal failure (ARF) is associated with pre persistent high mortality in critically ill patients in intensive care units. It is failure of the kidneys (renal failure) to eliminate fluid and waste from the patient’s body.

Sepsis, dehydration, toxic substances, and hypertension are some of the causes.

In case of severity dialysis is done.²⁴ H. Neurological Conditions

ICUs in neuroscience centres tend to deal with the management of primary diseases of the central and peripheral nervous system which may cause encephalopathy, raised intracranial pressure (ICP), ventilatory, autonomic and bulbar insufficiency or profound neuromuscular weakness. ²⁵

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9 | | | | P a g eP a g eP a g eP a g e I. Bleeding and Clotting

Many critically ill patients develop hemostatic abnormalities, ranging from isolated thrombocytopenia or prolonged global clotting tests to complex defects, such as disseminated intravascular coagulation.²⁶

J. Multiple Organ Dysfunction Syndrome – MODS

MODS is defined as the concurrent dysfunction of two or more organs or systems including respiratory, cardiovascular, haematological, neurological, gastrointestinal, hepatic and renal. A common and deadly condition, is frequently observed in ICU. ²⁷

K. Nosocomial infection

A nosocomial infection is defined as an infection that is not present or incubating when the patient is admitted to hospital or other health care facility.

Nosocomial infections in the ICU is about 2 to 5 times higher than in the general in-patient hospital population.²⁸ Patients may present with a community-acquired, bacteraemia-related illness, but the majority develop bacteraemia as a secondary nosocomial event. This occurs as a consequence of host defence alteration through their underlying diseases, extensive use of invasive procedures like surgery, tubes, catheters, drains, etc., and coexisting endogenous or exogenous immunosuppression. The incidence of nosocomial bacteraemia in ICU patients ranges from 2.5% to 26%. Associated mortality remains high at 21–56%. ²⁹

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Therapeutic Measures in ICU A. Fluid & Electrolytes

B. Cardiovascular Drug C. Corticosteroid D. GIT Drug E. Insulin Therapy F. Bronchodilators G. Anticonvulsants

H. Sedatives and analgesics I. Antimicrobial agents

Antimicrobial Agents

Antimicrobial drugs have caused a dramatic change not only of the treatment of infectious diseases but of a fate of mankind.³⁰ Infections are very common in critically ill patients because of immobility, invasive procedures, compromised immune status and exposure to cross infections.³¹ Once the source of sepsis is known, the antimicrobial therapy should be tailored according to the possible infecting pathogens and their relative antibiotic susceptibilities.³²

The infections usually encountered are pneumonia, bloodstream and urinary tract infections. Pneumonia and bloodstream infections were the most common serious infections in ICUs.¹⁶

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11 11 11

11 | | | | P a g eP a g eP a g eP a g e The term “antimicrobials” include all agents that act against all types of microorganisms – bacteria (antibacterial), viruses (antiviral), fungi (antifungal) and protozoa (antiprotozoal).⁷

If an improper antimicrobial agent happens to be chosen for the treatment of infection with drug-resistant microorganisms, the therapy may not achieve beneficial effect, and moreover, may lead to a worse prognosis.³⁰

Every institution should have an antibiotic policy and guideline in place which should be based on local susceptibility pattern of pathogens.Guidelines will help physicians to prescribe rationally and to choose the best effective, most appropriate empiric antibiotic for the patient.⁴

History of AMAs

Year Scientist Drug Noble Prize Year

1910 Paul Ehrlich Arsphenamine

(salvarsan)

1935 Gerhard Domagk Sulfanilamide 1939

1928 Alexander Fleming Penicillin 1945

1943 Selman Abraham Waksman

Streptomycin 1952

Table 1: Table 1: Table 1: Table 1: Historical landmark and the scientists who contributed to AMA³⁰

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1910 Arsphenamine

1928 Penicillin

1935 Sulfanilamide

1943 Streptomycin

1944 Aminoglycosides

1949 Chloramphenicol

1950 Tetracyclines

1952 Macrolides⁄Lincosamides⁄ Streptogramins

1956 Glycopeptides

1957 Rifamycins

1959 Nitromidiazoles

1960 Penicillinase-stable methicillin

1960s Cephems

1962 Nalidixic acid

1962 Quinolones

1968 Trimethoprim

Table 2:

Table 2: Table 2:

Table 2: Discovery of AMA³⁰

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Definitions^7,33

Antibiotic is a low molecular substance produced by a microorganism that at a low concentration inhibits or kills other microorganisms.

Antimicrobial is any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of microorganisms but causes little or no damage to the host.

Initial antimicrobial use (<72 hours of starting therapy) was defined as any antimicrobial treatment initiated for empiric coverage while microbiologic results were pending or for definitive therapy in which a pathogen was already known.

Empiric antimicrobial use was defined as antimicrobial use that occurred within 72 hours of initiation of therapy while microbiologic cultures results were pending or antimicrobial use in situations after 72 hours of initiation when microbiologic cultures did not yield a pathogen.

Definitive (therapeutic) antimicrobial use was defined as any antimicrobial use at a time when microbiologic culture results and susceptibility data were available. This could have occurred at initiation of therapy or after empiric antimicrobial use was initiated once microbiologic culture results were available.

1984 Norfloxacin

2000 Oxazolidinones

2003 Lipopeptides

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14 | | | | P a g eP a g eP a g eP a g e End antimicrobial usage was defined as the final choice of antimicrobial regimen selected for the indication being treated. This category includes definitive antimicrobial use in which a pathogen was isolated or empiric antimicrobial use in which no pathogen was ever isolated or microbiologic cultures were never obtained.

Epidemiology:

In India the infectious disease burden was among the highest in the world and recent report showed the inappropriate and irrational use of antimicrobial agents against these diseases, which led to increase in development of antimicrobial resistance.³⁴

Antimicrobial use in hospitalized patients was common, with patients receiving antibiotics on 70% of their ICU days, and patients on the general inpatient wards receiving antimicrobials on ≥40% of their inpatient days.³³ World Health Organization has proposed regional strategy on antimicrobial resistance with the goal to minimize the morbidity and mortality due to antimicrobial resistant infection, to preserve the effectiveness of antimicrobial agents in the treatment and prevention of microbial infections.³⁴

For monitoring use and misuse of antibiotics: Schedule H of the drug and cosmetics act contains a list of 536 drugs which are required to be dispensed on the prescriptions of a registered medical practitioner.³⁵

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15 | | | | P a g eP a g eP a g eP a g e Classification of AMA

Patients in ICU were commonly prescribed multiple broad spectrum antibiotics.³²

Antimicrobial drugs can be classified in many ways, based on,³⁶ A. Chemical structure

B. Mechanism of Action

C. Type of organism against which primarily active D. Spectrum of activity

E. Type of action

F. Source of Antibiotics A. Chemical structure

Table 3: Antimicrobial drugs classified based on chemical structure Sulfonamides and related drugs Sulfadiazine, Sulfones—Dapsone

(DDS), Paraaminosalicylic acid (PAS).

Diaminopyrimidines Trimethoprim, Pyrimethamine Quinolones Nalidixic acid, Norfloxacin,

Ciprofloxacin, Prulifloxacin, etc β-Lactam antibiotics Penicillins, Cephalosporins,

Monobactams, Carbapenems

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16 | | | | P a g eP a g eP a g eP a g e Tetracyclines Oxytetracycline, Doxycycline, etc

Nitrobenzene derivative Chloramphenicol

Aminoglycosides Streptomycin, Gentamicin, Amikacin, Neomycin, etc.

Macrolide antibiotics Erythromycin, Clarithromycin, Azithromycin, etc

Lincosamide antibiotics Lincomycin, Clindamycin Glycopeptide antibiotics Vancomycin, Teicoplanin

Oxazolidinone Linezolid.

Polypeptide antibiotics Polymyxin-B, Colistin, Bacitracin, Tyrothricin

Nitrofuran derivatives Nitrofurantoin, Furazolidone.

Nitroimidazoles Metronidazole, Tinidazole, etc.

Nicotinic acid derivatives Isoniazid, Pyrazinamide, Ethionamide Polyene antibiotics Nystatin, Amphotericin- B, Hamycin Azole derivatives Miconazole, Clotrimazole,Ketoconazole,

Fluconazole

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17 | | | | P a g eP a g eP a g eP a g e Others Rifampin, Spectinomycin, Sod. fusidate,

Cycloserine, Viomycin, Ethambutol, Thiacetazone, Clofazimine, Griseofulvin B. Mechanism of action

Table 4: Antimicrobial drugs classified based on Mechanism of action Inhibit cell wall synthesis Penicillins, Cephalosporins,

Cycloserine, Vancomycin, Bacitracin Cause leakage from cell

membranes

Polypeptides—Polymyxins, Colistin, Bacitracin.

Polyenes—Amphotericin B, Nystatin, Hamycin

Inhibit protein synthesis Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid Cause misreading of m-RNA

code and affect permeability

Aminoglycosides— Streptomycin, Gentamicin, etc

Inhibit DNA gyrase Fluoroquinolones—Ciprofloxacin and others.

Interfere with DNA function Rifampin

Interfere with DNA synthesis Acyclovir, Zidovudine

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18 | | | | P a g eP a g eP a g eP a g e Interfere with intermediary

metabolism

Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Metronidazole

C. Type of organisms against which primarily active

Table 5: Antimicrobial drugs classified based on Type of organisms Antibacterial Penicillins, Aminoglycosides,

Erythromycin, Fluoroquinolones

Antifungal Griseofulvin, Amphotericin B,

Ketoconazole

Antiviral Acyclovir, Amantadine, Zidovudine

Antiprotozoal Chloroquine, Pyrimethamine, Metronidazole, Diloxanide

Anthelmintic Mebendazole, Pyrantel,

Niclosamide, Diethyl carbamazine

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19 | | | | P a g eP a g eP a g eP a g e D. Spectrum of activity

Table 6: Antimicrobial drugs classified based on spectrum of activity Narrow-spectrum PenicillinG, Erythromycin

Broad-spectrum Tetracyclines, Chloramphenicol,

Extended spectrum penicillins Newer cephalosporins, aminoglycosides, fluoroquinolones

E. Type of action

Table 7: Antimicrobial drugs classified based on Type of action Primarily bacteriostatic Sulfonamides, Erythromycin,

Tetracyclines, Clindamycin, Chloramphenicol, Linezolid, Ethambutol

Primarily bactericidal Penicillins, Cephalosporins, Aminoglycosides, Vancomycin,

Ciprofloxacin, Rifampin, Metronidazole, Isoniazid, Cotrimoxazole, Pyrazinamide Some primarily static drugs may become cidal at higher concentrations (as attained in the urinary tract), e.g. erythromycin, nitrofurantoin. On the other

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20 | | | | P a g eP a g eP a g eP a g e hand, some cidal drugs, e.g. cotrimoxazole, streptomycin may only be static under certain circumstances.

F. Source of Antibiotics:

Table 8: Antimicrobial drugs classified based on Orgin

Fungi Penicillin, Griseofulvin, Cephalosporin

Bacteria Polymyxin B, Tyrothricin, Colistin Aztreonam, Bacitracin

Actinomycetes Aminoglycosides , Macrolides

Tetracyclines, Polyenes, Chloramphenicol

Individual classes of Drugs:

A. Beta – Lactam Antibiotics³⁷

The β lactam antibiotics are useful and frequently prescribed antimicrobial agents- Penicillins, cephalosporins, monobactams and carbapenems have a β lactam ring in their molecular structure. These bactericidal antibiotics act primarily on the bacterial cell wall by inhibition of synthesis of the bacterial peptidoglycan. Although some bacteria produce β lactamase and have developed resistance, these drugs on the whole remain useful in treating many different types of infections.

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21 | | | | P a g eP a g eP a g eP a g e Penicillins

Penicillin is active against Streptococci, Neisserriae, Spirochaetes, some anaerobes including Clostridia and a few other organisms. About 80 - 90% of the Staphylococcus aureus are β lactamase producers and hence are resistant to penicillin G and aminopenicillins. The prevalence of penicillinase producing Neisseria gonorrhoea is on the increase. There are reports of decreased susceptibility of pneumococci and streptococci to penicillin from other parts of the world. The only serious disadvantage of penicillins is hypersensitivity reaction.

Penicillin formulations available are:

1. Penicillin G (Crystalline Penicillin or Benzyl Penicillin) – for intravenous (IV) use. Needs to be given frequently (4 – 6 hourly).

2. Procaine Penicillin – Intramuscular (IM) preparation with a longer duration of action. Needs to be administered less frequently i.e. daily.

3. Benzathine Penicillin – given IM provides low levels of penicillin in the circulation for 3-4 weeks.

4. Penicillin V (Phenoxymethyl Penicillin) – an oral preparation, intrinsically less active than Penicillin G

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22 | | | | P a g eP a g eP a g eP a g e Penicillin is the drug of choice for the treatment of the following infections:

1. Streptococcal infections e.g. tonsillopharyngitis 2. Infections due to Streptococcus pneumoniae.

3. Meningococcal infections e.g. meningitis, septicaemia 4. Syphilis

5. Clostridial infections, anthrax, diphtheria 6. Leptospirosis

Aminopenicillins³⁷

Ampicillin and amoxycillin are destroyed by staphlococcal β lactamases but have a slightly broader spectrum than penicillins because of their activity against some gram negative bacilli like E.coli, salmonella sp and shigella sp.

They also have better activity against H.influenzae and enterococci compared with penicillin. Although initially sensitive, resistance to these drugs among E.coli is now widespread. Many strains of H.influenzae also produce β lactamases, which can destroy these drugs.

Amoxycillin is better absorbed than ampicillin and has a longer half life and hence is preferred for oral therapy. These drugs are used in empirical treatment of respiratory infections and in the treatment of susceptible urinary tract infections. They may be used for typhoid fever.

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23 | | | | P a g eP a g eP a g eP a g e Anti –Staphylococcal Penicillins

These are narrow spectrum penicillins, resistant to Staphylococcal β lactamases. Methicillin, oxacillin, and cloxacillins fall into this category. Of these only cloxacillin, flucloxacillin and dicloxacillin are clinically useful and are to be used only for proven or suspected staphylococcal infections.

Flucloxacillin, suitable for oral administration, can cause cholestatic jaundice in some patients. Some staphylococci have developed resistance to this group, by mechanisms other than β lactamase. These methicillin resistant Staphylococcus aureus (MRSA) will be resistant to all other β lactams (i.e. all penicillin, cephalosporins, monobactams and carbapenems).

Anti – Pseudomonal Penicillins³⁷

Newer penicillins with a high grade of activity against gram negative bacteria including pseudomonas, e.g. piperacillin, ticarcillin

β lactam and β lactamase inhibitor combinations

Eg Clavulanic acid, Sulbactam

Augmentin is a preparation containing amoxycillin and clavulanic acid.

Clavulanic acid has minimal antibacterial activity but inhibits β lactamase effectively. This combination is useful in the treatment of β lactamase producing bacteria. Sulbactam is another β lactam inhibitor used in combination with penicillins.

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24 | | | | P a g eP a g eP a g eP a g e Combinations are more expensive and so should be used only while treating infections with known β lactamase producers. Amoxycillin/ clavulanic acid combination can cause cholestasis.

Cephalosporins ³⁷

The cephalosporins have been traditionally divided into to three generations based on their spectrum of activity. In general, cephalosporins are less prone to hypersensitivity reactions, are more stable to staphylococcal penicillinases and have a broader spectrum than penicillins. However, they are expensive and have very little action on enterococci. None of them are effective against MRSA.

First generation cephalopsorins include among others, cephalexin(oral), cephalothin and cefazolin (parenteral). The spectrum of activity is similar, being effective against penicillinase producing staphylococci and other Gram-positive cocci (except MRSA and enterococci) and a few gram- negative enteric bacilli. There is no special advantage for any one first generation cephalosporins over another. They are not usually first choice for any infection. They may be used in some patients with penicillin hypersensitivity - those without immediate (IgE mediated) hypersensitivity.

Second generation drugs Cephamandole (parenteral), cefuroxime axetil and cefaclor (oral) are more stable to some Gram-negative β-lactamase.

Their activity against Gram-positive organisms is similar to, or less than, that of the first generation cephalosporins and they have varying degrees of activity

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25 | | | | P a g eP a g eP a g eP a g e against anaerobes. These drugs have a limited role in therapy and are more expensive.

Third generation cephalosporins (ceftriaxone, ceftazidime, cefotaxime) is active against gram-negative bacilli. They have some activity on gram-positive cocci and that against anaerobes varies. A major advantage of these agents is their ability to reach the central nervous system. Ceftazidime has specific antipseudomonal activity. Ceftriaxone and cefotaxime are useful in hospital-acquired and any other gramnegative septicaemia and meningitis.

Monobactams (Aztreonam) and Carbapenem (Imipenem)³⁷

Aztreonam is active against gram-negative bacteria including pseudomonas and β-lactamase producing enterobacteriaceae. Carbapenems have a much broader spectrum, including gram-positive, gram-negative and some anaerobic bacteria.

B. Aminoglycosides ³⁷

This group of antibiotics (gentamicin, tobramycin, netilmicin, amikacin, Kanamycin, neomycin, streptomycin) act by inhibiting protein synthesis in bacteria. They have good activity against aerobic gram-negative bacilli, including brucella. When given together with penicillin, they have good activity against enterococci. Streptomycin is useful against mycobacteria.

Aminoglycosides are not absorbed when given orally and should be administered parenterally for systemic effects. Aminoglycosides are ototoxic

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26 | | | | P a g eP a g eP a g eP a g e and nephrotoxic. The therapeutic index is low and blood levels need to be monitored if used for prolonged courses of either directed or empirical therapy for longer than 3 days. In spite of this disadvantage, they are used widely for their action on gram-negative bacilli.

Gentamicin is the least expensive and has good activity against 90% of gram-negative bacilli. It is the aminoglycoside of choice for empirical treatment of severe gram-negative sepsis including nosocomial infections.

The primary indication for aminoglycosides is as short-term empirical therapy pending the outcome of investigations. Their value as empirical drugs relates to their rapid bactericidal activity and the comparatively low levels of resistance in many community and health care–associated Gram-negative pathogens. When used empirically, no further doses should be given beyond 48 hours and if continuing empirical IV therapy is required (ie an organism is not grown) therapy should be changed to an alternative less toxic drug. Monitoring of aminoglycoside plasma concentrations is not required if the clinical plan is to cease therapy within 72 hours of commencement.

Aminoglycosides are indicated for directed therapy in only a few circumstances. These include, but are not restricted to:

• Infections when resistance to other safer antimicrobials has been shown

• Combination therapy for serious Pseudomonas aeruginosa infections and brucellosis

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• Low doses as synergistic treatment for streptococcal and enterococcal endocarditis.

Monitoring plasma concentrations of aminoglycosides is recommended in these patients and should commence on the first dose of directed therapy.

The recommended initial dose of gentamicin is 4-6mg/kg/day as a single daily dose given slowly over 20 minutes. However single daily dose is not recommended in pregnant women and endocarditis. The first dose is given irrespective of renal function as follows:

Age Initial dose of gentamicin

Neonates less than 34 weeks postconception 3mg/kg Neonates 34-44 weeks postconception 3.5mg/kg

Infants and children less than 10 years 7.5mg/kg to maximum of 320mg

10-29 years 6mg/kg to maximum of 560mg

30-59 years 5mg/kg to maximum of 480mg

Greater than 60 years 4mg/kg to maximum of 400mg

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28 | | | | P a g eP a g eP a g eP a g e After the first dose, subsequent doses of the same size should be given for up to 3 days at intervals determined by the patient’s renal function as follows:

Estimated creatinine clearance

Dosing interval Maximum number of doses

Greater than 60ml/min 24 hours 3 (at 0, 24 and 48 hours) 40-60 ml/min 36 hours 2 (at 0 and 36 hours) 30-40 ml/min 48 hours 2 (at 0 and 48 hours) Less than 30 ml/min No further doses 1 (at 0 hours)

For prolonged courses (longer than 3 days), it is important to determine trough serum gentamicin levels periodically (at least twice a week) and to adjust the dosage to maintain the desirable serum levels. In general trough levels not exceeding 0.5 to 1 µg/mL are sought.

C. Tetracyclines³⁷

Tetracyclines also act by inhibiting protein synthesis and have broad spectrum of activity. This includes staphylococci, neisseriae, H.influenzae, some members of enterobacteriaceae, mycoplasma, clamydiae, rickettsiae and spirochaetes. For chlamydial and rickettsial infections this is the drug of choice.

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29 | | | | P a g eP a g eP a g eP a g e This group also has action against protozoa like Entamoeba histolytica and plasmodium sp. The spectrum of activity of different tetracyclines is similar, but they are different in their pharmacokinetics. Most tetracyclines are excreted through the kidneys except doxycycline, which is safer in patients with renal impairment, but caution is required in patients with hepatic disease.

Tetracycline should be used with caution in patients with pre–existing hepatic or renal disease, as they can lead to worsening of function. Doxycycline has a longer half-life than tetracycline. Because of their effect on growing bones and teeth, these drugs are contraindicated in pregnancy, lactating mothers and in children.

D. Chloramphenicol³⁷

Also a broad-spectrum antibiotic, it acts by inhibiting protein synthesis.

The spectrum includes both aerobes and anaerobes. It can be used topically, orally or parentally. Bioavailability after oral administration is as good as parenteral use and the oral preparation can be used to initiate treatment in emergencies if the injection is not available. Chloramphenicol is not safe in pregnancy and in neonates as it may cause Grey baby syndrome. This drug can also cause bone marrow suppression. Its use as far as possible should be limited to specific indications like typhoid fever, invasive salmonellosis, meningitis, brain abscess and occasionally anaerobic infections.

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30 | | | | P a g eP a g eP a g eP a g e E. Macrolides

Erythromycin, roxithromycin, azithromycin and clarithromycin act by inhibiting protein synthesis. They have similar antimicrobial spectra but differ in their pharmacokinetics and adverse effects. They are active against gram- positive organisms, H.influenzae, neisseriae, mycoplasma sp, chlamydia and rikettsiae. They also act on toxoplasma, which is a protozoa.

Erythromycin is absorbed orally and is distributed well. It does not cross the blood brain barrier. The main adverse reaction is gastric irritation. Some patients develop jaundice. Parenteral preparations can cause phlebitis and occasional cardiac arrhythmias (in high doses).

Its main use is in respiratory infections and as an alternative to penicillin in those hypersensitive to penicillin. It is the drug of choice in neonatal and obstetric chlamydial infection and is used in campylobacter infection.

The newer macrolides have better bioavailability and fewer side effects.

Azithromycin, in addition to its use similar to that of erythromycin, is also used to treat toxoplasmosis. Clarithromycin is used in treating mycobacterium avium complex (MAC) infections and H.Pylori.

F. Quinolones³⁷

These drugs interfere with transcription of DNA. The first drug to be used in this group, nalidixic acid, had a very narrow spectrum mainly limited to gram-negative bacilli. This drug is used widely in the treatment of UTI, since

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31 | | | | P a g eP a g eP a g eP a g e high concentration attained in urine (20–50 times that in plasma), Norfloxacin and ciprofloxacin have a broader spectrum of activity. Norfloxacin is used in the treatment of urinary and gastrointestinal infections. Ciprofloxacin reaches high levels in the blood and is very effective against enterobacteriaceae, pseudomonas sp, and mycobacteria. Ciprofloxacin is not very effective against Streptococcus pneumoniae. It is therefore useful in treating gram-negative infections like hospital acquired septicaemias and gram-negative pneumonias.

It is also useful in treating chloramphenicol resistant Salmonella typhi infections. Bacterial resistance develops rapidly if these agents are widely used.

They are well absorbed when given orally and have a good penetration into cells like macrophages. They do not cross the blood brain-barrier. Unlike many other antibiotics they reach the prostate.

Nalidixic acid can cause GI upset and skin reactions. Quinolones have many adverse effects including dizziness, depression, and they can precipitate seizures. They may interact with many other drugs, for example theophylline.

Quinolones is not recommended in pregnant women, infants, children and breastfeeding mothers.

G. Rifampicin³⁷

Rifampicin is used in the treatment of tuberculosis and infections with S.aureus. Rifabutin is used in the treatment and prophylaxis of MAC infection.

Since resistance emerges rapidly, these drugs should always be used in combination with other antibiotics. Rifampicin colours urine, tears and other

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32 | | | | P a g eP a g eP a g eP a g e body fluids red. It can accelerate the metabolism of other drugs including oral contraceptives, warfarin, and phenytoin.

H. Nitroimidazoles³⁷

Metronidazole and tinidazole are active against all anaerobic bacteria and protozoa like T. vaginalis, G. lamblia and E. hystolitica. Metronidazole is well absorbed and can be administered IV, orally or rectally. The rectal preparation produces high levels and can be used to treat serious infections. It crosses the blood brain barrier.

Metronidazole is usually well tolerated. Common minor side effects include nausea, vomiting, metallic taste in mouth and disulfiram like reaction with alcohol.

Tinidazole has longer half-life and therefore can be administered less frequently.

I. Glycopeptides³⁷

Vancomycin acts by inhibiting peptidoglycan (cell wall) synthesis. All gram-positive organisms are susceptible. However, the drug is reserved for treating Gram-positive infections resistant to β lactams (MRSA and Ampicillin/

Gentamicin resistant enterococci) and some patients hypersensitive to β lactams. Its oral use for antibiotic associated diarrhoea should be limited to those caused by Clostridium difficle and unresponsive to metronidazole.

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33 | | | | P a g eP a g eP a g eP a g e Vancomycin is given IV slowly over at least over one hour (10mg/ min) to prevent anaphylactoid reaction. Renal toxicity can occur, especially if given with aminoglycosides. Therefore, pay attention to dosage schedules and monitor serum levels and renal function.

Antimicrobial Resistance (AMR)

Factors contributing to the development of Antimicrobial Resistance:

Antimicrobial resistance can be defined as loss or decreased responsiveness to the conventional doses of AMAs, which is a commonly encountered problem in the ICU involving various factors like,^{38, 39}

A. Cross transmission B. Host defense C. Antimicrobial use

D. Duration of hospital stay E. Use of invasive devices A. Cross transmission

Several factors unique to ICUs contribute to cross transmission of antimicrobial-resistant pathogens. The urgent nature of critical care often does not allow for necessary aseptic precautions or hand washing. Hence, antimicrobial-resistant pathogens are carried from patient to patient via unwashed hands of health care workers. The large number and wide variety of health care workers attending to patients needs have inconsistent training and compliance with hand washing, gloving and gowning, the degree of asepsis

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34 | | | | P a g eP a g eP a g eP a g e used in maintaining invasive devices and the level of crowding in ICUs may impact on the cross transmission of these pathogens. Introduction of antimicrobial-resistant bacteria into an ICU may occur upon transfer of critically ill patients who are unknowingly colonized or infected with such bacteria from other facilities.⁴⁰

B. Host defense

Colonization of ICU patients with antimicrobial-resistant pathogens can lead to clinical infection because of breakdown of normal host defenses. ICU patients are particularly susceptible to nosocomial infections because the normal skin and mucosal barriers to infection are commonly compromised by the use of invasive devices. It is no surprise that the incidence of nosocomial infections in ICU patients is correlated with the use of invasive devices.⁴¹ In addition, ICU patients often have severe underlying illnesses, suppressed immune systems, malnutrition and a history of frequent hospitalization. These patients may be more likely to be colonized or infected with an antimicrobial- resistant pathogen from exposures during a previous health care encounter. All of these factors, especially the need to use antimicrobial agents in ICU patients, contribute to the increased risk of developing nosocomial infections with antimicrobial-resistant pathogens.⁴²

C. Antimicrobial use

Perhaps no other factor is more important in the development of antimicrobial resistance than antimicrobial use. Many studies have established a correlation between antimicrobial use and antimicrobial resistance at the

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35 | | | | P a g eP a g eP a g eP a g e hospital level. At least 7 days of mechanical ventilation, previous antibiotic use and previous use of broad-spectrum antibiotics (third-generation cephalosporins, fluoroquinolones, carbapenem, or a combination) were the most important risk factors associated with the development of ventilator- associated pneumonia caused by antibiotic-resistant pathogens.⁴³

D. Duration of stay

Prolonged length of hospital stay also seems to predispose patients to infection with antibiotic-resistant bacteria. This may be due, in part, to the greater likelihood over time of becoming colonized with such bacteria from either horizontal nosocomial transmission or endogenous emergence of resistance.³⁹

E. Use of invasive devices

Invasive devices such as endotracheal tubes, intravascular catheters, and urinary catheters also seem to encourage resistant infections.³⁹

Drug-resistant organisms

WHO report on the global status of AMR and surveillance, information was compiled on resistance to antibacterial drugs commonly used to treat infections caused by nine bacteria of international concern.³⁸

• Escherichia coli: resistance to third-generation cephalosporins, including resistance conferred by extended spectrum beta-lactamases (ESBLs), and to fluoroquinolones

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• Klebsiella pneumoniae: resistance to third-generation cephalosporins, including resistance conferred by ESBLs, and to carbapenems

• Staphylococcus aureus: resistance to beta-lactam antibacterial drugs (methicillin, methicillin-resistant S. aureus)

• Streptococcus pneumoniae: resistance or nonsusceptibility to penicillin (or both)

• Nontyphoidal Salmonella (NTS): resistance to fluoroquinolones

• Shigella species: resistance to fluoroquinolones

• Neisseria gonorrhoeae: decreased susceptibility to third-generation cephalosporins.

Clinical Implications of Increasing Antimicrobial Resistance In general, infections caused by multidrug resistant pathogens are associated with higher in-hospital mortality rates, longer duration of hospital stay and increased health care costs and may also increase the likelihood of initial inadequate antimicrobial treatment as these pathogens may not be susceptible to initial empirical therapy.³⁸

Antimicrobial Resistance Monitoring

Antimicrobial resistance in pathogens causing important communicable diseases has become a matter of great public health concern globally including our country. Resistance has emerged even to newer, more potent antimicrobial agents like carbapenems. The factors responsible for this are widespread use and availability of practically all the antimicrobials across the counter meant

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37 | | | | P a g eP a g eP a g eP a g e for human, animal and industrial consumption. There are definite policies / guidelines for appropriate use of antimicrobials at national level in specific national health programmes being run in the country e.g. RNTCP, National AIDS control programme, etc. For other diseases of public health importance like enteric fever, diarrhoeal disease, respiratory infections, etc the individual hospitals are following their own antimicrobial policies and hospital infection control guidelines. ³³

To monitor antimicrobial resistance it is necessary to have regulations for use and misuse of antibiotics in the country, creation of national surveillance system for antibiotic resistance, mechanism of monitoring prescription audits, regulatory provision for monitoring use of antibiotics in human, veterinary & industrial sectors and identification of specific intervention measures for rational use of antibiotics. Work plan for monitoring of antimicrobial resistance in the country. Briefly the action plan of various ToRs[Terms of Reference] is as follows:³³

A. For monitoring use and misuse of antibiotics: ³³

Schedule H of the drug and cosmetics act contains a list of 536 drugs which are required to be dispensed on the prescriptions of a registered medical practitioner. In order to have separate regulation to check unauthorized sale of antibiotics, a separate schedule as Schedule H1 may be introduced under the Drugs and Cosmetics Rules to regulate sale of antibiotics exclusively.

Corresponding provisions under the Rules could be framed for their implementation. A system of colour coding of third generation antibiotics and

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38 | | | | P a g eP a g eP a g eP a g e all newer molecules like Carbapenems (Ertapenem, Imipenem, Meropenem), Tigecycline, Daptomycin may be put in place restricting their access to only tertiary hospitals. Appropriate steps should be taken to curtail the availability of fixed dose combination of antibiotics in the market

B. Hospital based sentinel Surveillance System for monitoring antibiotic³³ Resistance will be set up with the identification of one of more Central Institutions under the ministry of health as coordinating centers at the National Level. The design for AMR surveillance consists of,

• Identification of pathogens/diseases of public health importance

• Creation of network of Antibiotic Susceptibility Testing (AST)

• Standardizing methodology for microbial identification and AST

• The laboratories will perform AST using standardized methods and carbapenem resistant isolates will be stocked and sent to designated central laboratory for further analysis, like identification of NDM-1 [New Delhi Metallo-Lactamase ]isolates.

• Strengthen Quality Systems in the network laboratories

C. For documenting prescription patterns and establishing a monitoring system³³

• To study the consumption of various antibiotics in tertiary care public hospitals in Delhi under central government

• To study the trends in antibiotic use in these hospitals of Delhi

Utilization pattern, safety profile and cost analysis of antimicrobials prescribed in an intensive care unit of a teaching hospital

Submitted to

THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfilment of the requirements for the award of the degree of

M.D PHARMACOLOGY Branch VI

May2018

INTENSIVE CARE UNIT OF A TEACHING HOSPITAL

Submitted to

THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

In partial fulfilment of the requirements for the award of the degree of

M.D PHARMACOLOGY Branch VI

May 2018

INTENSIVE CARE UNIT OF A TEACHING HOSPITAL

CONTENTS

ABBREVIATIONS

Introduction

Introduction

Introduction

Introduction

Introduction

Review of Literature

Review of Literature Review of Literature

Review of Literature

Review of literature