Lec.1
INFECTIONInfection is the establishment of foreign organisms, or infectious agents, in or on a human host. This may result in colonisation, if the microorganism exists at an anatomical site without establishing overt tissue injury, or infectious disease, when the interaction between the host and pathogenic organism (or pathogen) induces tissue damage and clinical illness.
Communicable infectious diseases are caused by organisms transmitted between hosts.
Endogenous diseases are caused by colonising organisms already established in the host.
Opportunistic infections, which may be communicable or endogenous, are those which arise only in individuals with impaired host defence.
There are six essential elements (figure 1) for transmission of infectious disease, these are:
1- infectious agent.
2- reservoir :(the place where the population of an infectious agent is maintained)
3- portal of exit:( point from which the infectious agent leaves the reservoir
4- transmission:( directly or via a vector or fomite which is In animate object))
5- portal of entry (body site that is first accessed by the infectious agent).
6- Susceptible host.
SHAPE \* MERGEFORMAT
Figure 1: Elements of transmission of infection.
Concept of infection
The concept of an infectious agent was established by Robert Koch in the late 19th century. Although fulfillment of Kochs postulates became the standard for the definition of an infectious agent, they do not apply to organisms which cannot be grown in culture (e.g. Mycobacterium leprae, Tropheryma whipplei) or members of the normal human flora (e.g. Escherichia coli, Candida spp.).Kochs postulates
1. The same organism must be present in every case of the disease
2. The organism must be isolated from the diseased host and grown in pure culture
3. The isolate must cause the disease, when inoculated into a healthy, susceptible animal.
4. The organism must be re-isolated from the inoculated, Diseased animal
FEVER
Defining normal body temperature is somewhat problematic because it is dependent on both physiology and the method of measurement. Normal oral temperature in 99% of the population ranges from 36.0 to 37.7 C, with a circadian variation of 1 C or more between the morning nadir and the evening peak. Mean oral temperature in healthy adults is 36.8 0.4 C, with women exhibiting slightly higher values than men (36.9 vs. 36.7 C). In menstruating women, the morning temperature may rise by 0.6 C with ovulation and remain higher until menses occur. Measured rectal temperatures are 0.4 C higher than oral and 0.8 C higher than aural (tympanic membrane) temperatures. However, considerable individual variability exists.
Fever is defined as an elevated core body temperature > 38.0 C,( i.e. above the normal daily variation).
Fever is a response to cytokines and acute phase proteins and is a common manifestation of infection, although it also occurs in other conditions Figure 2.
Figure 2: Pathophysiology of fever
Clinical assessment of a febrile patientThe differential diagnosis is very broad and there is a long list of potential investigations, so any clues from the clinical features which help to focus the investigations are extremely valuable.
In most patients, the potential site of infection is apparent after clinical evaluation , and the likelihood of infection may be reinforced by typical abnormalities on the initial screening investigations (e.g. neutrophilia and raised ESR and CRP in bacterial infections).
On the other side, Not all apparently localising symptoms are reliable, however; headache, breathlessness and diarrhea can occur in sepsis without localised infection in the central nervous system (CNS), respiratory tract or gastrointestinal tract.
Investigations
If the cause is not obvious, e.g. in a patient with purulent sputum or symptoms of urinary tract infection, then initial screening investigations should include:a full blood count (FBC) with differential, including eosinophil count
urea and electrolytes, liver function tests (LFTs), blood glucose and muscle enzymes
inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
autoantibodies, including antinuclear antibodies (ANA)
chest X-ray and electrocardiogram (ECG)
urinalysis and urine culture
blood culture (a minimum of 20 mL blood in three sets of blood culture bottles)
throat swab for culture
other specimens, as indicated by history and examination, e.g. wound swab; sputum culture; stool culture, microscopy for ova and parasites and Clostridium difficile toxin assay; if relevant, malaria films on 3 consecutive days or a malaria rapid diagnostic test (antigen detection by lateral flow immunochromatography.
Management
1- Fever and its associated systemic symptoms can be treated with paracetamol, and by
2- tepid sponging to cool the skin.
3- Replacement of salt and water is important in patients with drenching sweats.
4- Further management is focused on the underlying cause.
Pyrexia of unknown origin (PUO)
PUO is defined as a temperature persistently above 38.0 C for more than 3 weeks, without diagnosis despite initial investigation during 3 days of inpatient care or after more than two outpatient visits.Up to one-third of cases of PUO remain undiagnosed
Aetiology of pyrexia of unknown origin
1- Infections (about 30%)A- Specific locations
Abscesses: hepatobiliary, diverticular, urinary tract.
(including prostate), pulmonary, CNS
Infections of oral cavity (including dental), head and neck
(including sinuses)
Bone and joint infections
Infective endocarditis.
B- Specific organisms
Tuberculosis (particularly extrapulmonary).
HIV-1 infection
Other viral infections (cytomegalovirus (CMV), EpsteinBarr virus (EBV))
Fungal infections (e.g. Aspergillus spp., Candida spp. Or dimorphic fungi)
Infections with fastidious organisms (e.g. Bartonella spp., Tropheryma whipplei )
C- Specific patient groups
Imported infections
Malaria, dengue, rickettsial infections, Brucella spp., amoebic liver abscess, enteric fevers, Leishmania spp. (southern Europe, India, Africa and Latin America), Burkholderia pseudomallei (South-east Asia), HIV and respiratory tract infections
Nosocomial infections
Infections related to prosthetic materials and surgical procedures
HIV-positive individuals
Acute retroviral syndrome
AIDS-defining infections (disseminated Mycobacterium avium complex (DMAC), Pneumocystis jirovecii (carinii ) pneumonia (PCP), CMV and others)
2- Malignancy (about 20%)
A- Haematological malignancy
Lymphoma, leukaemia and myeloma
B- Solid tumours
Renal, liver, colon, stomach, pancreas, kidney
3- Connective tissue disorders (about 15%)
A- Older adultsTemporal arteritis/polymyalgia rheumatica
B- Younger adults
Stills disease (juvenile rheumatoid arthritis)
Systemic lupus erythematosus (SLE)
Vasculitic disorders (including polyarteritis nodosa, rheumatoid
disease with vasculitis and Wegeners granulomatosis)
Polymyositis
Behets disease
Rheumatic fever
3- Miscellaneous (about 20%)
A- Cardiovascular
Atrial myxoma, aortitis, aortic dissection
B- Respiratory
Sarcoidosis, pulmonary embolism and other thromboembolic disease, extrinsic allergic alveolitis
C- Gastrointestinal
Inflammatory bowel disease, granulomatous hepatitis, alcoholic liver disease, pancreatitis
D- Endocrine/metabolic
Thyrotoxicosis, thyroiditis, hypothalamic lesions, phaeochromocytoma, adrenal insufficiency, hypertriglyceridaemia
E- Haematological
Haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, thrombotic thrombocytopenic purpura, myeloproliferative disorders, Castlemans disease, graft-versus-host disease (after allogeneic bone marrow transplantation)
F- Inherited
Familial Mediterranean fever and periodic fever syndromes
G- Drug reactions,
e.g. Antibiotic fever, drug hypersensitivity reactions etc.
H- Factitious fever.
4- Idiopathic (about 15%)
Investigations
If initial investigation of fever is negative, a series of further microbiological and non-microbiological investigations should be considered . These will usually include:
induced sputum or other specimens for mycobacterial stains and culture
serological tests
imaging of the abdomen by ultrasonography or computed tomography (CT)
echocardiography.
Prognosis
The overall mortality of PUO is 3040%, mainly attributable to malignancy in older patients. $If no cause is found, the long-term mortality is low and fever often settles spontaneously.Principles of antimicrobial therapy
Antimicrobial action and spectrumAntimicrobial agents bring about killing by inhibiting, damaging or destroying a target that is a required component of the organism. Every antimicrobial agent is able to kill a specific range of microorganisms, and this must be considered in selecting appropriate antimicrobial therapy. In severe infections and/or immunocompromised patients, it is customary to use bactericidal agents in preference to bacteriostatic agents.
Empiric versus targeted therapy
Empiric antimicrobial therapy is selected to treat a clinical syndrome (e.g. meningitis) before a microbiological diagnosis has been made.Targeted therapy is aimed at the causal pathogen(s) of known antimicrobial sensitivity.
Ideally, broad-spectrum agents are used in empiric therapy, and narrow-spectrum agents in targeted therapy. Optimum empiric therapy differs according to clinical presentation (e.g. pneumonia versus meningitis), patient groups (e.g. children, immunocompromised hosts) and local antimicrobial resistance patterns.
Combination therapy
Antimicrobial combination therapy is usually restricted to three settings:to increase efficacy (e.g. enterococcal endocarditis, where a -lactam/aminoglycoside combination results in better outcomes than a -lactam alone). when no single agents spectrum covers all potential pathogens (e.g. in polymicrobial infection or empiric treatment of sepsis)
to reduce antimicrobial resistance, as the organism would need to develop resistance to multiple agents simultaneously (e.g. antituberculous chemotherapy, highly active anti-retroviral therapy (HAART, p. 403)).
when no single agents spectrum covers all potential pathogens (e.g. in polymicrobial
infection or empiric treatment of sepsis)
to reduce antimicrobial resistance, as the organism would need to develop resistance to multiple agents simultaneously (e.g. antituberculous chemotherapy, highly active anti-retroviral therapy (HAART, p. 403)).
Antimicrobial resistance
Factors implicated in the emergence of antimicrobial resistance include:
1- The inappropriate use of antibiotics when not indicated (e.g. in viral infections),
inadequate dosage or treatment duration.
2- Excessive use of broad- spectrum agents, and
3- Use of antimicrobials as growth-promoters in agriculture.
Resistance may be an innate property of a microorganism (intrinsic resistance) or may be acquired, by either spontaneous mutation or horizontal transfer of genetic material from another organism. Extended spectrum -lactamases (ESBL) are encoded on plasmids, which are transferred relatively easily between bacteria including Enterobacteriaceae. Plasmid-mediated carbapenemases have been detected in strains of Klebsiella pneumoniae.
Antimicrobial prophylaxis
Prophylaxis is used when there is a risk of infection from a procedure or exposure .It may be combined with (or replaced by) passive immunisation .
Ideally, prophylaxis should be of:
1- short duration.
2- have minimal adverse effects.
3- not encourage growth of resistant pathogens.
Pharmacokinetics and pharmacodynamics
Pharmacokinetics of antimicrobial agents determine whether adequate concentrations are obtained at the primary site of infection and likely areas of dissemination. For example, achieving a therapeutic blood level of gentamicin is of little practical use in treating meningitis, as CSF penetration of the drug is severely limited. Knowledge of routes of elimination is also critical in antimicrobial therapy; for instance, a urinary tract infection is more appropriately treated with a drug that is excreted unchanged in the urine than one which is fully eliminated by hepatic metabolism.Pharmacodynamics describes the relationship between antimicrobial concentration and microbial killing.
Beta-lactam antibiotics
These antibiotics have a -lactam ring structure and exert a bactericidal action by inhibiting enzymes involved in cell wall synthesis (penicillin-binding proteins, PBP).They are classified
A- Penicillins
Natural penicillins: benzylpenicillin, phenoxymethylpenicillin
Penicillinase-resistant penicillins: meticillin, flucloxacillin, nafcillin, oxacillin
Aminopenicillins: ampicillin, amoxicillin
Carboxy- and ureido-penicillins: ticarcillin, piperacillin
B- Cephalosporins
C- Monobactams
Aztreonam
D- Carbapenems
Imipenem, meropenem, ertapenem
Pharmacokinetics
Good drug levels are achieved in lung, kidney, bone, muscle and liver, and in pleural, synovial, pericardial and peritoneal fluids.
CSF levels are low, except in the presence of inflammation.
Activity is not inhibited in abscess (e.g. by low pH and PO2, high protein and polymorphonuclear cells).
-lactams are subject to an inoculum effect activity is reduced in the presence of a high organism burden (PBP expression is down-regulated by high organism density).
Generally safe in pregnancy (except imipenem/ cilastatin).
Adverse reactions
Generalised allergy to penicillin occurs in 0.710% of cases anaphylaxis in 0.0040.015%.. There is a relationship between allergy to penicillin and allergy to cephalosporins depends on the specific cephalosporin used.There is significant cross-reactivity with first-generation cephalosporins, cross-reactivity to
second- and third-generation cephalosporins is much less common (and may be negligible with some agents). However, it is usually recommended to avoid cephalosporins in patients who have a type 1 penicillin allergy (e.g. anaphylaxis, urticaria, angio-oedema).
Drug interactions
Synergism occurs in combination with aminoglycosides. Simultaneous dual -lactam administration can result in either synergy or antagonism. Ampicillin decreases the biological effect of oral contraceptives and the whole class is significantly affected by concurrent administration of probenecid, producing a 2- 4 fold increase in the peak serum concentration.A- Penicillins
Natural penicillins are primarily effective against Gram-positive organisms (except staphylococci, most of which produce a penicillinase) and anaerobic organisms.
Strep. pyogenes has remained sensitive to natural penicillins world-wide.
- Penicillinase-resistant penicillins are the mainstay of treatment for infections with Staph. aureus, other than meticillin- resistant strains (MRSA).
- Aminopenicillins have the same spectrum of activity as the natural penicillins, with additional Gram- negative cover against Enterobacteriaceae. Amoxicillin has much better oral absorption than ampicillin.
Resistance to these agents is widesprea, mainly due to -lactamase production, but can be overcome by the addition of - lactamase inhibitors (clavulanic acid or sulbactam).
- Carboxy- and ureidopenicillins are particularly active against Gram-negative organisms, especially Pseudomonas spp. which are resistant to the aminopenicillins. Beta-lactamase inhibitors may be added to extend their spectrum of activity.
B- Cephalosporins and cephamycins
Cephalosporins are safe and reliable and have a broad spectrum of activity. The more active compounds are only available in intravenous form. The group has no activity against Enterococcus spp. And little anti-anaerobic activity (with the exception of cephamycins).
Cephalosporins
First generation have excellent activity against Gram-positive organisms and some activity against Gram-negative ones.
Cefalexin, cefradine (oral) Cefazolin (i.v.)
Second generation retain Gram-positive activity but have extended Gram-negative activity.
Cefuroxime (oral/i.v.)
Cefoxitin (i.v.) which belong to Cephamycins has excellent activity against anaerobic gram negative bacilli
Cefaclor (oral)
Third generation further improve anti- Gram-negative cover.
Cefixime (oral)Ceftriaxone (i.v.) Cefotaxime (i.v.) have excellent Gram negative activity and retain good activity against Strep. pneumoniae and -haemolytic streptococci.,
Ceftazidime (i.v.)
Fourth generation
Cefepime (i.v.) have an extremely broad spectrum of activity, including Pseudomonas spp., Staph. aureus and streptococci.
Next generation
Ceftobiprole (i.v.) Ceftaroline (i.v.), have a fourth-generation spectrum enhanced to include MRSA.
C- Monobactams
Aztreonam is the only agent available in this class. It has excellent Gram-negative activity but no useful activity against Gram-positive organisms or anaerobes. It is available only as a parenteral preparation. It can be used safely in penicillin-allergic patients.
D- Carbapenems
These have the broadest antibiotic activity of the beta- lactam antibiotics and include activity against anaerobes. They are available in intravenous formulation only.
Macrolide and lincosamide antibiotics
Macrolides (erythromycin, clarithromycin and azithromycin) and lincosamides (lincomycin, clindamycin) have related properties and are bacteriostatic agents.
They should not be used together as both of them bind to the same element of ribosome, and they will competate to the same site of binding.
Macrolides are used in Gram ositive infections in penicillin-allergic patients and in Mycoplasma and Chlamydia infections. Clarithromycin and azithromycin are also used to treat legionellosis.
Ketolides
Telithromycin is administered orally and as useful activity against common bacterial causes of respiratory infection, as well as Mycoplasma, Chlamydia nd Legionella spp.
Aminoglycosides
Aminoglycosides are very effective anti-Gram- Negative ntibiotics, e.g. in intra-abdominal and urinary tract sepsis. They act synergistically with -lactam antibiotics and are particularly useful where -lactam or quinolone resistance occurs in health care-acquired infections. They cause very little local irritation at injection sites and negligible allergic responses.Oto- and nephrotoxicity must be avoided by monitoring of renal function and drug levels and use of short treatment regimens. Aminoglycosides are not subject to an inoculum effect and they all exhibit a post-antibiotic effect .
Quinolones and fluoroquinolones
These are bactericidal agents that are usually well Tolerated and effective. The quinolones have purely anti-Gram-negative activity, whereas the fluoroquinolones are broad-spectrum agents.Ciprofloxacin has anti-pseudomonal activity but resistance emerges rapidly.
Glycopeptides
Glycopeptides (vancomycin and teicoplanin) are only effective against Gram-positive organisms, and are used against MRSA and ampicillin-resistant enterococci. Some staphylococci and enterococci demonstrate intermediate sensitivity or resistance. Vancomycin use should be restricted, particularly in the management of C. difficile infections, to limit emergence of resistant strains.Teicoplanin is not available in all countries. Neither drug is absorbed after oral administration, but vancomycin is used orally in the treatment of C. difficile infection.
Tetracyclines and glycylcyclines
TetracyclinesOf this mainly bacteriostatic class, the newer drugs doxycycline and minocycline show better absorption and distribution than older ones. Most streptococci and Gram-negative bacteria are now resistant, in part due to use in animals.
Tetracyclines are indicated for Mycoplasma spp., Chlamydia spp., Rickettsia spp., Coxiella spp., Bartonella spp., Borrelia spp., Helicobacter pylori, Treponema pallidum and atypical mycobacterial infections.
Minocycline is occasionally used in chronic staphylococcal infections.
Folate antagonists
These bacteriostatic antibiotics interfere with the prokaryotic cell metabolism of para-aminobenzoic acid to folic acid. A combination of a sulphonamide and either trimethoprim or pyrimethamine is most commonly used and interferes with two consecutive steps in the metabolic pathway. Combinations in use include trimethoprim/ sulfamethoxazole (co-trimoxazole) and pyrimethamine with either sulfadoxine (used to treat malaria) or sulfadiazine (used in toxoplasmosis). Co-trimoxazole in high dosage (120 mg/kg daily in 24 divided doses) is the first-line drug for Pneumocystis jirovecii (carinii) infection in HIV
disease. The clinical use of these agents is limited by adverse effects. Folate supplements should be given if these agents are used in pregnancy.
Nitroimidazoles (metronidazole, tinidazole)
Nitroimidazoles are highly active against strictly anaerobic bacteria, especially B. fragilis, C. difficile and other Clostridium spp. They also have significant anti-protozoal activity against amoebae and Giardia lamblia.Other antibacterial agents
ChloramphenicolThis is a potent and cheap antibiotic, still widely prescribed throughout the world despite its potential toxicity. Side effects:
Dose-dependent grey baby syndrome in infants (cyanosis and circulatory collapse dueto inability to conjugate drug and excrete active form in urine).
Reversible dose-dependent bone marrow depression in adults if > 4 g per day administered or cumulative dose > 25 g.
Severe idiopathic aplastic anaemia in 1:25 00040 000 exposures (unrelated to dose, duration of therapy or route of administration)
.Its use, however, is increasingly reserved for severe and life-threatening infections where other antibiotics are either unavailable or impractical. It is bacteriostatic to most organisms but apparently bactericidal to H. influenzae, Strep. pneumoniae and N. meningitidis. It has a very broad spectrum of activity against aerobic and anaerobic organisms, spirochaetes, Rickettsia, Chlamydia and Mycoplasma spp. It also has quite useful activity against anaerobes such as Bacteroides fragilis. It competes with macrolides and lincosamides for ribosomal binding sites, so should not be used in combination with these agents.