Infections of the upper respiratory tract

Clinical syndromes

Etiopathogeny• Normal flora of the upper respiratory tract:

– microbial flora dominated by anaerobic bacteria;– aerobic and facultative anaerobic bacteria (viridans

streptococci, non-fastidious-neisseria, coagulase negative staphylococci, ocasional: S. aureus, diphtherioids bacili, β-hemolitic streptococci, pneumococci, Haemophilus spp., Actinomyces spp.), Candida

• Gram negative bacilli for elderly and for patients with severe disease.

• Antibacterial treatment – pharynx dysbiosis Staphylococcus aureus, gram negative bacilli, Candida.

• Clinical signs prediction for bacterial etiology of pharyngitis is very low.

Etiologia sindroamelor clinice

ESCMID MANUAL

Pharyngitis - etiology

• viruses (70% of cases):– rhinovirus, – adenovirus, – Herpes simplex virus 1, – Coxsackie A,– influenza and – parainfluenzae.

• bacteria: – Streptococcus pyogenes (group A)

- determine the majority of bacterial pharingytis (37% sore throat among children)

– ß- hemolitici streptococci (group B, C or G)

– Chlamydophila pneumoniae– Corynebacterium diphtheriae– Mycoplasma pneumoniae– Arcanobacterium haemolyticum– Gonococci– Candida albicans (new-born,

premature)

Common symptoms

• Fever• Sore throat• Enlarged lymph nodes

Rapid Strep A test

Swabs sampling from pharynx

• Necessary: sterile buffer, source of light, mask.• Procedure:

– before or after 3 – 4 hours of oral toilet – adequate illumination – wipe out with the swab the tonsil: firm but easy– avoid the tongue touch

• Transport and preservation: maximum 3 hours after sampling

Quality criteria

• Sampling before antibiotic treatment.

• Sampling under good visual control of the pharynx by adequate illumination.

• The absence of the growth in the cultivated surface with the swab, means, a grave error of sampling / preservation, more frequently.

• Any person has normal flora in the oral cavity.

What if the symptoms in streptococcus pharyngitis persist under treatment with penicillin ?

• Viral angina can be supper infected with streptococci (the same viral simptomatology which is not influenced by antibiotic treatment)

• Colonization of pharynx with bacteria producing β-lactamases;

• Re-infection with S. pyogenes in family environment or in small promiscuity collectivities.

Microbial diagnosis of the throat

• Sampling and transport (ulcerations, diphtheria, N. gonorrhoeae, Candida spp.)

• Bacteriological examination– Microscopic examination– Culture and antimicrobial susceptibility testing

(A. haemolyticum, N. gonorrhoeae)• Interpretation

– No need to list bacteria from normal flora

Antibiogram

• β-hemolitic streptococci (grup A, C or G) have kept the sensitivity to penicillin.

• Antibiogram is not necessary.

• Can be performed for patients allergic at penicillin (erythromicin).

Case 1Young girl, 16 years old, present fever from 2 days 39.8°C,

dysphagia, headache.

No important medical history.

Clinical findings: inflammation, hypertrofic tonsils, purulent exsudate, tender cervical lymph nodes.

Laboratory findingsL = 18.000/mmc, 87% PMNESR = 24mm/1 hour

Pharynx exsudate: present beta-hemolitic streptococci, group A (+4); present Staphylococcus aureus (+2)

Case 2Child, 2,5 years old, present fever and right otalgy.

Clinical findings: congestive tympanum.

Laboratory data: S. pneumoniae was isolated from the ear pus. The results of testing

S.pneumoniae to antibiotic are:

Oxacillin - R MIC Penicillin - 0,75 mg/L (I)Erythromicin - R MIC Cefotaxime - 0,5 mg/L

(S)Clindamicin - RTetracyclin - SCloramfenicole - SCotrimoxazole - R

The resistance phenotypes of Streptococcus pneumoniae to antibiotics

• Beta lactamins resistance: before the ’90 the antibiogram for pneumococci was considered unuseful.

• Resistance of pneumococci to peniciline G grew year by year and was spread all over the world.

• Resistance to penicillin is cross resistance with all the beta lactams.

• Resistance to beta lactamines is associated in 50% of cases with resistance at one or many antibiotics families, like tetraciclines, cloramphenicol or trimetroprim – sulfametoxazol

Proportion of Macrolides Resistant (R) Streptococcus pneumoniae Isolates in Participating Countries in 2011

Proportion of Penicillins Resistant (R) Streptococcus pneumoniae Isolates in Participating Countries in 2011

The comparative activity of different beta lactamines against pneumococci with low sensitivity to

penicillin G (MIC for penicillin G: > 0.06 mg/dl)

Beta lactamines more active

Penicilin G Beta lactamines less active

Imipenem Ampicilin Piperacilin

Amoxicilin Cefpodoxim Cefuroxim

CefotaximeCeftriaxone

CefoperazonOxacilinCefiximCefaclorCefotetan

Resistance to MLSK:

• the resistance is MLSB type, due to methylation of ARN 23S, which decrease the affinity of macrolides for their target.

• This is a cross resistance for all macrolides, linconsamides and for streptogramines which can be inducible or constitutive.

• These strains had the erm gene, responsible for ribosomal modification.

The resistance phenotypes for S. pneumoniae to MLSK

Mechanism Genotype Fenotype M14M15

M16 LIN CLIN PRI I PRI II PRI(4)

KET(5)

Target modification

Erm MLSBI R R R R R S S S

Efflux mefE M R S S S S S S S

Legend:M14: eritromycin, roxitromycin, claritromycin, diritromycinM15: azitromycinM16: spiramicin, josamycin, midecamycin, tilosin4: pristinamycin5: ketolides

Chilonoles resistance:

• pneumococci are naturally resistant to chinolones from first generation, and they are having low sensitivity to pefloxacin, ofloxacin, ciprofloxacin.

• some chinolones like levofloxacines, moxifloxacine are active against pneumococci. The acquired resistance to fluorochinolones can be:– resistance by active efflux;– resistance due to mutations, mainly due to parC gene

and gyrA.

Penicillin non-susceptible Streptococcus pneumoniae

• Importance of detection of resistance:» required for antimicrobial susceptibility categorization; » infection control; » public health.

Definition

• S. pneumoniae isolates with reduced susceptibility (MICs above those of the wild type, i.e. > 0.06 mg/L) to penicillin due to the presence of modified penicillin-binding protein (PBPs) with lower affinity to β-lactams.

Recommended methods for detection of penicillin non-susceptible S. pneumoniae

• Penicillin non-susceptibility can be detected phenotypically by MIC or disk diffusion methods.

• The European Committee on Antimicrobial Susceptibility Testing - EUCAST

Disk diffusion method• The disk diffusion method with 1μg oxacillin disks is an

effective screening method for the detection of penicillin non-susceptible pneumococci.

• The method is very sensitive, but is not highly specific as strains with zone diameters ≤ 19 mm may have variable susceptibility to benzylpenicillin, and the benzylpenicillin

• MIC should be determined for all isolates that are non-susceptible with the screening method.

• For β-lactams other than benzylpenicillin the oxacillin zone diameter can be used to predict susceptibility.

Clinical breakpoints

• The penicillin breakpoints were primarily designed to ensure the success of therapy for pneumococcal meningitis.

• However, clinical studies demonstrated that the outcome of pneumococcal pneumonia caused by strains with intermediate susceptibility to penicillin and treated with parenteral penicillin was no different to that for patients treated with other agents.

• Considering microbiological, pharmacokinetic and pharmacodynamic data, the clinical breakpoints for benzylpenicillin for non-meningitis isolates were revisited and current EUCAST breakpoints are as listed in the next table.

Screening for β-lactams resistance in S. pneumoniae

Reporting of benzylpenicillin susceptibility in meningitis and non-meningitis

Case 2Child, 2,5 years old, present fever and right otalgy.

Clinical findings: congestive tympanum.

Laboratory data: S. pneumoniae was isolated from the ear pus. The results of testing

S.pneumoniae to antibiotic are:

Oxacillin - R MIC Penicillin - 0,75 mg/L (I)Erythromicin - R MIC Cefotaxime - 0,5 mg/L

(S)Clindamicin - RTetracyclin - SCloramfenicole - SCotrimoxazole - R

Case 2

Interpretative antibiogram

• The resistance to penicillin appreciated by difusimetric testing for Oxacilline, exigent of MIC testing

• The resistance for low level for this antibiotic permit the using of one penicillin (penicilline G, Amoxicillin) in treatment of medium otitis.

• Alternative of treatment– cephalosporins from second generation (cefuroxime) or third generation (cefotaxim or ceftriaxone);

• Tetraciclin is unadvisable at children under 8 years old.

Infections of the lower respiratory tract

Defense mechanisms of the lower respiratory tract

Etiopathogeny

• Primary infections. • Secondary infections: decrease of local

antimicrobial defense.– Removal bacteria from the respiratory tract after:

• primary infections;• allergy• acute bronchitis• chronic bronchitis• tumors• tracheostomy

– Abortive colonization / for a long period. – Virulent bacteria produced supper-infections.

Clinical considerations• Acute bronchitis

– viruses, Mycoplasma pneumoniae, Chlamydophila pneumoniae– Bacteria supperinfections: Haemophilus influenzae,

Streptococcus pneumoniae, Klebsiella penumoniae, Staphylococcus aureus, Moraxella catarrhalis.

• Chronic bronchitis (smooking, atmosphere pollution)

– Cilliate cell destruction, squamos metaplazya, hipertrophy of mucus producing gland

– Periodical ingravescence of the chronic bronchitis.• Acute pnemonia

– Immunocompetent host: viruses, M. pneumoniae, Chlamydia, Coxiella burnetii (difficult to cultivate ) – primary pneumonia – atypical pneumonia.

– Bacterian supperinfection with: S. pneumoniae, H. influenzae, S. aureus lobar pneumonia or brocho – pneumonia.

– Exposure to aerosols ( elderly) - Legionella pneumophila

Clinical considerations

• Hospital condition / immunosupresion– Gram negative bacilli (over 50% of cases): Escherichia coli,

K. pneumoniae, Enterobacter spp., Serratia spp., Acinetobacter spp., Pseudomonas aeruginosa

• Aspiration pneumonia – mixt infections with aerobic and facultative anaerobic bacteria from normal flora of the oropharynx.

• Chronic pneumonia – bacteria with slow growing– TB bacilli – Atypical micobacteria (Mycobacterium avium-intracellulare,

M. kansasii ) – Actinomyces spp.– Nocardia spp. – Fungi.

Sampling • Expectoration: Sputum

– Early, under the nurse supervision– Toilet of the oral cavity– Deep coughing; expectoration can be

stimulated by inhalation of warm aerosols with salt 10%.

– Petri dish, or box with lid.– If it is saliva repeat the sampling – Rapid transport, without refrigeration, for cyto-

bacteriological examination.

Sampling

• Tracheal aspirate – Tracheostomy – Precoccious (early stage) tracheo – bronchitis with

aspirate microorganisms from extern media– Difficult to appreciate the result

• Swab and nasopharynx aspirate– Only for the diagnosis of low respiratory tract

infections with primer pathogens (viruses, Mycoplasma pneumoniae, Coxiella burneti, Chlamydophila pneumoniae etc.) – different from normal flora.

Wrong procedures:

• Give the jar to the patient in the evening before sampling, with the supperficial indication : ”cough and slave”, without checking if the patient know the what “expectorate” means.

• Ask sputum examination in aspiration pneumonia, which are mixt infections with anaerobic and facultative aerobic bacteria from oral cavity.

Quality criteria and interpretation of the result of sputum cultivation

• Macroscopic examination after sampling

• Cytologic examination – O quality score – P = 100x

• Q = Σ (IC + SEC +/- fibrin)• Q> 1: sputum• Q < 1: saliva• Has clinical significance

isolating of bacteria in high quantity – for primary pathogens: (e.g., pneumococi, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis).

No cell IC SEC

1 - 9 0 0

10 - 24 +1 -1

> 25 +2 -2

Case 1

Man, 41 years old, present: fever, stitch chest, coughing, mucopurulent, aeruginous expectoration.

Case history – smoker

Before 7 days, the patient presented asthenia, fever 390C, dried cough non-productive cough.

Clinical findings: T= 400C, labial herpes, pulse= 120/min, tahipnea, blood pressure = 90/50mmHg

Case 1X-ray: opacity on the right lob lung, liquid

Lab findings:Hb = 13g/dl, Ht=41%L=24.000/mmc, metamielocyte 1%, nonsegmentated 6%, PMN 76%,

limfocyte 17%Tr = 250.000/mmc

Cytologic examination: >25 inflammatory cell/ field, <10 epithelial squamos cell, fibrin (x100) > 10 gram-pozitive diplococci / microscopic field, lancet shape,

capsulated, with PMNs (x1000)Sputum culture – presence of S. pneumoniae in high ammount (3, 4

sectors) Antibiogram: S. pneumoniae resistent to penicillin.

Case 2

Woman, 26 years old, accuse since one week muscular and articular, dysphagia, fever, coughing, at the beginning dried and after 2 days become grey – greenish.

Case history: insuline dependent diabetus

Clinical findings: T=40 0C, (tahypnea), pulse = 110/min, regulat

blood pressure =90/60 mmHgLaboratory data:X ray: lung disseminate condensation:Hb=13 g /dl, L=30.000/ mmc, NS=8%, PMNs =70%, E=3%,

Lf=16%, monocytes =3%Glucose in blood: 192 mg /dl

Case 2

Blood culture: MRSA: Methyciline Resistant Staphylococcus aureus (MRSA)

Serologic exam: (serum sampling in the first day of hospitalisation):anti- influenza type A = 1280anti- influenza type B = 40anti-Mycoplasma < 40 anti-Chlamydia < 40anti-Coxiella burnetti < 40

Seroconversion / Significant dinamic

Promoting Antimicrobial Stewardship in Human Medicine• Antimicrobial stewardship refers to coordinated interventions designed to improve

and measure the appropriate use of antimicrobials by promoting the selection of the optimal antimicrobial drug regimen, dose, duration of therapy, and route of administration. 

• Antimicrobial stewards seek to achieve optimal clinical outcomes related to antimicrobial use, minimize toxicity and other adverse events, reduce the costs of health care for infections, and limit the selection for antimicrobial resistant strains. 

• http://www.idsociety.org/stewardship_policy/#sthash.6D6Rl3wS.dpuf

Antimicrobial Stewardship Program

• Antibiotic resistance is now a major issue confronting healthcare providers and their patients.

• Changing antibiotic resistance patterns, rising antibiotic costs and the introduction of new antibiotics have made selecting optimal antibiotic regimens more difficult now than ever before.

• Furthermore, history has taught us that if we do not use antibiotics carefully, they will lose their efficacy.

• As a response to these challenges, the Johns Hopkins Antimicrobial Stewardship Program was created in July 2001.

Antimicrobial Stewardship Initiative

• Inappropriate and over use of antimicrobials contributes to the emergence of resistant bacteria and causes patient harm. Patients with antimicrobial-resistant infections are more likely to experience ineffective treatment, recurrent infection, delayed recovery or even death.

• Antimicrobial stewardship (AMS) programs have been shown to decrease inappropriate antimicrobial usage, improve patient outcomes and reduce adverse consequences of antimicrobial use (including antimicrobial resistance, toxicity and unnecessary costs). Along with infection prevention and control, hand hygiene and surveillance, antimicrobial stewardship is considered a key strategy in local and national programs to prevent the emergence of antimicrobial resistance and decrease preventable healthcare associated infection.

• The aim of the Antimicrobial Stewardship Initiative is to improve the safe and appropriate use of antimicrobials, reduce patient harm and decrease the incidence of antimicrobial resistance in Australian hospitals.

The antimicrobial stewardship criterion requires that all healthcare services

• Have an antimicrobial stewardship program in place

• Provide clinicians prescribing antimicrobials access to current endorsed Therapeutic Guidelines on antimicrobial usage

• Undertake monitoring of antimicrobial  usage and resistance

• Take action to improve the effectiveness of antimicrobial stewardship.