Part 17-2. Infectious Diseases

Section 3. Bacterial Infections

Chapter 174. Staphylococcal Infection

174.1. Infection Due To Staphylococcus Aureus

Etiology

 : group I - group IV

 * Toxin released from S. aureus

★Exotoxin

4 Immunological Distinct Hemolysin

   ① α-hemolysin: cell membrane에 작용

                   tissue necrosis, injury to leukocyte, platelet aggregation, smooth m. spasm

   ② β-hemolysin: degrade spingomyelin

                   → RBC hemolysis

   ③ δ-hemolysin: detergent like action

                   → membrane disruption

   ④ γ-hemolysin: act on cell membrane

Leukocidin

   : phagocytic cell의 phospholipid와 combine하여 permeability증가

     leakage of protein, eventual death of neutorphil & macrophage

Exfoliative Toxin A & B

    ; dermatologic localized (e.g. bullous impetigo) or generalized (e.g. scalded skin syndrome, scarletiniform eruption) complication

    ; A - chromosomal gene product

  ; B - plasmid gene product

Staphylococcal Enterotoxin

    ; type A, B, C1, C2, D, E

  ; Enterotoxin A or B ingestion

   ① vomiting, diarrhea, profound hypotension

   ② enterotoxin A & enterotoxin B: associated with nonmenstrual TSS

TSS toxin-1 (TSST-1)

   ① associated with TSS related to mensturation & focal staphyloccal inf.

   ② produce interleukin I & tumor necrosis factor

      : hypotension, fever multisystem involvement

Enzyme

  1. coagulase: S. aureus, S. epidermis, & other coagulase-negative staphylococcus구분

               → fibrinogen과 interacting에 의해 plasma clot

  2. catalase: inactivate H2O2, promoting intracellular survival

  3. penicillinase or beta-lactamase: inactivate penicilline at molecular level

  4. hyaluronidase: spreading factor

  5. lipase

  6. phosphodiesterase

Agglutinogen (Protein A)

  1. S. aureus대부분 종에서 가지고 있음

  2. react with Fc fragment of IgG

  3. generate C'-derived chemotactic factor

     antiphagocytic activities

Capsular antigen 5, 8

    : 70%에서 phagocyte에 resistant

Cell Wall Peptidoglycan

  1. polysaccharide polymer

  2. endogenous pyrogen production from monocytes

  3. chemotactic effect

  4. C' activation

  5. endotoxin like effect

  6. opsonic antibody production stimulation

Loose Polysaccharide Capsule Or Slime Layer

Epidemiology

 1. 생후 1주내에 20-30%의 neonate에서 ant. nare에 colonization

 2. transmission

  ① direct contact or spread of heavy particle (6ft이하)

  ② spread by fomite: rare

  ③ autoinfection: common

  ④ minor infection (e.g., styes, pustules, paronychia)

 3. heavily colonized individuals, perianal carriers

   : 특히 effective한 disseminators

 4. neonate에서 most common site of colonization

   : nasopharynx, skin, perineum, umbilical stump

Pathogenesis

 1. staphylococcal disease development is related to

    ① infection에 대한 host의 resistance

    ② virulance of the organism

 2. mucocutaneous barriers defect

    ① by: trauma, surgery, foreign surfaces(e.g., sutures, shunts, intravascular catheters), burns

    ② S. aureus가 cell wall의 teichoic acid에 의해 mucosal cell adhesion.

     submucous, subcutaneous site에 exposure는 fibrinogen, fibronectin, laminin, collagen IV에

     adhesion증가

 3. protein A

    ① S. aureus에서는 나오고 S. epidermis에서는 생성 안됨

    ② bacteria의 outermost coat에 위치

    ③ IgG1, IgG2, IgG4와 react

    ④ serum Ig을 absorb

    ⑤ inhibiting phagocytosis

 4. G-I tract에서의 S. aureus의 infection은 other bacterial species의 prevalence에 의해 control 되는데, 이

    balance가 항생제치료중 깨지면 Staphylococcus가 proliferation & bowel wall invasion.

   G-I tract내에서 Staphylococcus의 enterotoxin의 elaboration. performed enterotoxin의 ingestion으로

    tissue invasion없이 disease유발 가능함.

 5. antibody가 존재한다고 해서 staphylococcal disease를 언제나 protect할수 있는 것은 아님

   : 즉 healthy infant에서 disseminated S. aureus ds.는 viral inf.선행후 발생할수 있음.

     viral infection은 neutrophil or respiratory epithelial cell function suppress.

 6. Staphylococcal infection의 risk가 증가되는 경우

  ① C' system의 congenital or acquired defect

  ② defective chemotaxis (Job, Chediak-Higashi, Wiskott-Aldrich, & lazy leukocytes synd.)

  ③ defective phagocytosis

  ④ defective humoral immunity (antibodies required for opsonization)

  ⑤ impaired intracellular bacterial capacity

 7. impaired mobilization of PMNL in

  ① children with DKA

  ② healthy individual following ingestion of alcohol

Clinical Manifestion

 : most common located in the skin as a infection site

Newborn

    : general sepsis, meningitis, pneumonia, otitis media, conjunctivitis, ostemyelitis, & septic

      arthritis

Skin

    ; *impetigo contagiosa, ecthyma, bullous impetigo, folliculitis, hydradenitis, furuncles, carbuncles, SSSS(Ritter disease), syndrome resembling scarlet fever

    ; recurrent furunculitis

           - unknown etiology,

                          repeated pyoderma over several months to yrs.

                          should evaluate for immunity

Respiratory Tracts

  1. rare: URI, otitis media & sinusitis, suppurative parotitis, tonsillopharyngitis

          cystic fibrosis나 WBC function defects가진 환아에서 Staphylococcal sinusitis는

           common

  2. tracheitis: croup과 유사

   ① high fever, leukocytosis, upper airway obstruction evidence

   ② normal epiglottitis with subglottic narrowing

      thick purulent secretion within the trachea

       (direct laryngoscopy or bronchoscopy)

  3. pneumonia

   ① 1세이하에서는 일시적으로 acute bronchiolitis동반

   ② high fever, abd. pain, tachypnea, dyspnea, localized or diffuse bronchopneumonia or

      lobar disease

   ③ cause necrotizing penumonitis

      : empyema, pneumatocele, pyopneumothorax, bronchopleural fistula

   ④ nonproductive coughing

  4. sepsis

   ① if appropriate antibiotic Tx.

      : blood culture may remain (+) for 24-48hr.

   ② fever decreased

      : median 22 hr (8-90hr)

   ③ return of body temperature to normal

      : 58 hr (12-180hr)

   ④ DDx sepsis with endocarditis

     a. echocardiographic evidence of vegetation

     b. intravenous drug abuse

     c. presence of immune complex & antistaphylococcal antibody

     d. absence of primary focus of infection

Muscle

   ① tropical pyomyositis: localized staphylococcal abscess in muscle, muscle enzyme증가,

                          septicemia (-)

   ② multiple abscess in 30-40% of cases

Bone & Joints

CNS

    : meningitis associated with

     a. cranial trauma

        neurosurgery (e.g., craniotomy, CSF shunt placement)

     b. endocarditis, parameningeal foci (e.g., epidural or brain abscess), DM

        less frequently with malignancy

Heart

# *acute bacterial endocarditis

    ; native valve common cause

Kidney

: UTI is unusual

Toxic Shock Syndrome

Intestinal Tract

# Sta. enterocolitis

       : overgrowth of normal bowel flora by Sta.

         most common follow use of broad spectrum oral antibiotic Tx.

# peitonitis: CAPD pt.에서 common

                 → catheter tunnel involve로

# food poisoning

    ; caused by enterotoxin ingestion

    ; 2-7hr후에 sudden, severe vomiting

           --> *watery diarrhea : fever is absent or low

    ; *not persist longer than 12-24hr

Diagnosis

 1. isolation of the organism: skin lesions, abscess cavities, blood, CSF, or other site of inf.

 2. identification by Gram stain, coagulase, mannitol reactivity

Differential Diagnosis

 1. skin lesion by S. aureus & group A β-hemolytic staphylococcus

 2. staphylococcal pneumonia & other bact. (Klebsiella, many anaerobes) origin pn.

 3. fluctant skin & soft tissue lesion

    lesion by: Mycobacterium, Francisella tularensis, various fungi, cat-scratch ds.

Prevention

# ★Strict Attention To Handwashing Technique

  ; *▲effective measure for prevention of spread

2. used detergents

   : iodopher, chlorhexidine, hexachlorphene

 3. infectious disease control measures (Table 174-1)

 4. ICU에서 stress ulcer의 risk검토위해 H2-blocker보다 Sucralfate를 씀으로서 S. aureus의 gastric

   colonization을 감소시킬 수 있다. 이것은 sucralfate로 natural gastric acidity를 유지 함으로써

   2차적으로 colonization의 감소를 가져온다. 이러한 차이는 pneumonia에서도 감소를 가져온다.

 5. patient with recurrent staphylococcal frunculosis

    : Tx. with hexachlorophene & dicloxacilline or clindamycin to prevent recurrence

 6. food poisoning

Treatment

# ★Children With Abscesses

    ; *AB alone is rarely effective

    ; *should be relieved by incision & drainage

# ★Initial AB

    ; penicillinase-resistant antibiotics

    ; methicillin, nafcilline

  ① this stability가 large bacterial burden이 있을때 β-lactam antibiotics의 antibacterial activity를

     neutralize시키는 inoculum effect에 대해 가장 중요한 요소다.

  ② general dose: 200mg/kg/24hr (IV in six divided doses)

 3. Staphylococcal pn.

  ① 72시간이상 열이 없거나 다른 infection sign이 없을 때까지 IV antibiotics 선택

  ② 그후 oral antibiotics를 적어도 3주이상 사용

# ★Meningitis, Osteomyelitis, Endocarditis

  ; *IV 치료 끝나도 계속해서 PO로 치료를 지속해야 한다.

           - *Dicloxacillin 50-75mg/kg/24hr in four divided oral doses

                   / due to well absorption & quite effective

# skin & soft tissue infection & minor upper respiratory infection

  ① managed by oral therapy alone or initial brief course of antibiotics provided parenterally,

        followed by oral medication

    : dicloxacillin (25-50mg/kg/24hr), oxacillin (100mg/kg/24hr), nafcillin (100mg/kg/24hr)

  ② amoxacillin (40mg/kg/24hr in three divided dose) + clavulonic acid

    : also effective

 6. very mild, localized skin infection

  ① repeated cleasing with a mild antiseptic & use of topical antibiotics

    (bacitracin, mupirocin)

  ② penicillin should not be applied topically

  ③ penicillin G: vitro에서 S. aureus에 대해 sensitivity보이면 infection Tx.에 사용

  ④ penicillin에 sensitive한 pt.의 5%에서 cephalosporin에 sensitive

# ★Clindamycin, Lincomycin

  ; effective for skin, soft tissue, bone, joint infection

    ; *should not be used in endocarditis, brain abscess, meningitis

    ; clindamycin IV or oral: total daily dose - 30-40mg/kg/24hr #3-4

# vancomycin

  ① penicillin에 sensitive한 pt의 endocarditis에 사용

  ② peak S-conc.: 25-40μg/ml

  ③ dosage: 10-15mg/kg/dose q 6hrs IV

 9. vancomycin or teicoplanin: semisynthetic penicillin종류에 resistant한 severe bacteremic

                              staphylococcal infection에 사용

 

 10. ciprofloxacin, other quinolone antibiotics

    : serious staphylococcal infection시 지속적인 high cure rate를 얻을 수 없어서 should not be used

 11. staphylococcal infection of the CNS

  ① IV methicillin or nafcillin

  ② in penicillin allergic pt: vancomycin, bactrim, imipenem

  ③ surgery때에는 vancomycin에 synergic effect위해 rifampin추가

Methicillin Resistant Staphylococcus Aureus: MRSA

   : become major nosocomial pathogen

 1. most MRSA belong to phage group II (type 77, 83A, 84, 85)

    그외, phage type I & nontypable strain에서 report됨

 2. MRSA stains

  ① methicillin sensitive한 counterpart에 대해서도 virulent한 effect보임

  ② 이경우

     : vancomycin (drug of choice) & teicoplanin이 effective

  ③ cepahlosporin과 imipenem에 대해서는 resistant

     trimethoprim-sulfamethoxasole, ciprofloxacin에는 sensitive

 3. MRSA발견시 감염받은 환자의 격리가 prevention의 most effective method

Prognosis

 1. untreated staphylococcal septicemia: 80%이상의 mortality

    적절한 antibiotic treatment로 20%이상의 mortality줄임

 2. grave prognostic sign

  ① WBC < 5,000/mm³

  ② PMNL response < 50%

 3. prognosis에 영향을 주는 factors

  ① nutrition

  ② immunologic competence

  ③ presence or absence of other debilitating disease

174.2. Infection Due To Coagulase Negative Staphylococcus

 1. S. epidermis: CONS 11종 중 1종류

    : 실제 avirulant commensal bacteria이나 nosocomial infection을 아래의 경우 일으킬 수 있다.

  ① indwelling foreign device

     a. IV catheters - sepsis

     b. hemodialysis shunts & grafts - sepsis

     c. CSF shunts - meningitis

     d. peritoneal dialysis catheters - peritonitis

     e. pacemaker wires & electrodes - pocket infection

     f. prosthetic cardiac valves - endocarditis

     g. urinary catheters - pyelonephritis

     h. prosthetic joints - arthritis

  ② surgical trauma

    : sternal ostoemyelitis, endophthalmitis

  ③ immunocompromized state

    : malignancy, granulocytopenia, neonates

  ④ community acquired disease in patient with no underlying disease

    : UTI, osteomyelitis

Epidemiology

 1. CONS는 skin, throat, mouth, vagina, urethra의 normal inhibitant

 2. S. epidermis : skin과 mucous membrane에 존재하는 staphylococci의 65-90%를 차지하는 most common & persistant species.

 3. CONS의 epidemiologic purpose

    : identified organism by

  ① phage typing

  ② antibiotic sensitivity

  ③ slime layer production

  ④ molecular DNA method

    (chromosomal & phage DNA hybridization restriction enzyme analysis)

Pathogenesis

 * S. epidermis는 exopolysaccharide production biofilm (slime) 생산

    role 1. enhance adlhesion to foreign surface

        2. resist phagocytosis

        3. impair penetration of antibiotics

Clinical manifestation

 1) Clinical features

  1. bacteremia

  2. endocarditis

  3. central venous catheter infection

  4. central venous system CSF shunt

  5. UTI

 2) bacteremia

    : CONS중 S. epidermis가 most common cause of nosocomial bacteremia

  1. neonate에서의 S. epdermis bacteremia clinical manifestation

     : apnea, bradycardia, temperature instability, abdominal distension, hematochezia, cutaneous

       abscess, CSF pleocytosis (-) meningitis

       적절한 antibiotic Tx.에도 불구하고 (2주이상) persistant positive blood culture

  2. malignancy or BM transplantation 받은 환자의 S. epidermis bacteremia

    : associated with neutropenia, central venous access (Hickman or Broviac catheters), & G-I obstruction

  3. 보통 overwhelming sepsis shock (-), indolent

 3) endocarditis

 4) central venous catheter infection

 5) central venous system CSF shunt

  1. S. epidermis: CSF shunt meningitis의 most common pathogen

  2. most (70-80%) infection: 수술 2 mo.내에 발현

 6) UTI

  1. S. epidermis: asymptomatic UTI

                  most common pathogen for peritonitis in patients on continuous ambulatory

                   peritoneal diaylsis

  2. S. saprophyticus: symptomatic UTI, in previously healthy & sexually active teenage girls

Diagnosis

 * bacteremia를 suspect할 수 있는 소견

  1. blood culture상 rapid growth (24시간이내)

  2. 동일한 CONS에 대해 2번 이상의 blood cuture에서 positive

  3. central venous catheter보다 peripheral venous blood culture에서 quantitative colony count 보일 때

Treatment

 1. vancomycin

    : drug of choice for methicillin resistant S. epidermis

 2. quinolone & teicoplanin

    : some activity against CONS, vancomycin에 rifampin, GM추가는 efficacy증가

 3. CONS infection이 foreign body, catheter valve, shunt등과 관련시 cure위해 모두 제거

    : central line의 사용을 preserve하기 위해 IV vancomycin Tx.를 시도하기도 함

 4. peritonitis in pt. in CAPD

    : dialysis catheter뽑지 않고 IV or intraperitoneal antibiotics로 Tx시 발생할 수 있는

      another infection

Prognosis

  poor prognosis asso. with malignancy, neutropenia, infected prosthetic or native Ht. valve

174.3 Toxic Shock Syndrome

 * 정의: acute multisystemic disease

   특징: high fever, hypotonia, vomiting, abd. pain, diarrhea, myalgia, non focal neurologic

         abnormalities, erythematous rash

Etiology & Epidemiology

 1. many cases: tampon혹은 vaginal devices (e.g., diaphragm, contraceptive sponge)사용하는 15-25세의

                menstruating woman에서 발생. S. aureus의 toxin-producing strain의 vaginal colonization

                혹은 infection동반

 2. nonmenstrual TSS associated with

    : wounds, nasal packing, sinusitis, tracheitis, pneumonia, empyema, abscess, burn,

      osteomyelitis, primary bacteremia

 3. antibiotic Tx. (-)때 menstural TSS에서

    : original episode 3mo.이내에 overall mortality rate - 3%

# phage group I sta. aureus

    ; major isolated strain from confirmed cases

    ; not invasive, not adhere to vaginal epithelium

    ; produce extracellular toxins : TSST-I

        --> *massive fluid loss from intravascular space

                - *by directly or by producing interleukin I & TNF

  ③ TSST-I negative strain이 TSS가진 patient에서 발견됨. 이것은 다른 toxin이 관계하는 것으로 여겨짐.

    즉 TSST-I이 essential한 pathogenic factor는 아님

    virtro study에서 이들 toxin들은 neutral pH, high Pco2, "aerobic" Pco2의 환경에서 선택적으로 생산되는데 

    이것은 menstruation tampon 사용하는 vagina에서 발견되는 condition이다.

Clinical Manifestation

★Table 174-2

 1. at onset

    : abrupt high fever, vomiting, diarrhea, sore throat, headache, myalgia

 2. diffuse erythematous macular rash (sunburn-like) within 24hr

    : petechia may developed on 3-4 day

 3. other Sx.

    : 의식장애, oliguria

      hypotension (shock or DIC를 보이는 severe case로 발전가능)

 4. most frequent manifestation

    : diarrhea(98%) > myalgia(96%) > emesis(92%) > 40℃이상의 fever(87%)

      > headache(72%) > sore throat(75%)

    * desquamation (특히 palm & sole)과 함께 7-10일 내에 recover됨

       1-2mo후 hair & nail loss (+)

 5. the most frequent laboratory sign

    : Cr.↑(69%) > thrombocytopenia (59%) > hypocalcemia (58%)

      > azotemia(57%) > hyperbilirubinemia (54%) > liver enzyme↑(50%)

      > WBC>15,000 (48%)

      → no specific laboratory test

Differential diagnosis

 * Kawasaki disease

  1. 유사점

   ① fever unresponsive to antibiotics

   ② hyperemia of mucous membrane

   ③ erythematous rash with subsequent desquamation

  2. Kawasaki disease에 없는 소견

   ① diffuse myalgia

   ② vomiting

   ③ abd. pain

   ④ diarrhea

   ⑤ azotemia

   ⑥ hypotension

   ⑦ adult respiratory distress synd

   ⑧ shock

   ⑨ age (Kawasaki는 보통 5세이하)

Prevention & Treatment

    : the low risk of acquired TSS (6.2 case/100,000)

 * management of adolescents suspected of having TSS

  1. careful removal of any retained tampon

  2. cardiovascular collapse에 대한 aggressive fluid therapy

  3. inotropic agent for shock

  4. corticosteroid & IV immune globulin for severe case

  5. parenteral β-lactamase resistant antistaphylococcal antibiotics

   ① nafcilline, oxacilline, methicilline

   ② 150-200mg/kg/day # 4-6 ( x 10-14 days)

   ③ not affected immediate outcome, but prevent reccurence in menstrual TSS

   ④ penicilline allergy: clindamycin, EM, rifampin, bactrim

 * culture

    menstrual TSS - from vagina

    nonmenstrual TSS - infected or colonized site

Chapter 175. Streptococcal Infections

 

 1. most common cause of bact. inf. in infancy & children

 2. Group A streptococci

  ① most common bacterial cause of acute pharyngitis

  ② nonsuppurative sequelae: rheumatic fever, GN

 3. Group B β-hemolytic streptococci

    : 3 mo.이내에서 common

      bacteremia, meningitis, osteomyelitis, septic arthritis등 유발

Etiology

★Table 175-1

# classification of streptococci

  ; by RBC hemolysis

        ① β-hemolysis: complete hemolysis

        ② α-hemolysis: partial hemolysis

                 produce green color on sheep erythrocytes (Viridan group)

        ③γ-hemolysis: no hemolysis

    ; by C-carbohydrate in the cell wall (Lancefield classification)

           - A through H & K through V

# several antigenic proteins

    ; on outer layer of cell wall contain

  ; ★M protein (acquired immunity is directed)

        - *▲important

           - resistant to phagocytosis

           - *major virulence factor

    ; ※lipoteichoic acid

           - *promotes colonization by binding to fibronectin on surface of epithelial cells

           - another virulence factor

    ; hyaluronic acid capsules

           - resists phagocytosis further facilitating virulence

 4. greatest clinical significance를 가지는 extracellular products

  ① pyrogenic (formely erythrogenic) toxin (A, B & C)

     : responsible for the rash of scarlet fever & for shock in toxic shock-like illness

  ② streptolysin O

     : lyses RBC & toxic to neutrophils, platelets & mammalian heart muscle

  ③ streptolysin S

     : largely cell bound & damage membranes of neutrophils & platelets

  ④ NADase

  ⑤ streptokinase (A & B)

  ⑥ DNase (A, B, C & D)

  ⑦ hyaluronidase

  ⑧ proteinase: associated with tissue destruction of severe invasive streptococcal disease

  ⑨ amylase

  ⑩ esterase

 5. Group A streptococcus infection의 diagnosis에 유용한 antibody

    Ab to streptolysin O (ASO), DNase B, hyaluronidase, NADase, streptokinase

Group A Streptococci

Epidermiology

 1. normal inhabitant로 nasopharynx에 존재

    colonization rate: 15-20%

# ★Incidence Depend On

    1) age of child

       ; *▲lowest incidenc among infant

                   - due to transplacental acquisitions of type-specific Ab & lack of pharyngeal receptor for streptococcal binding

       ; St. infection of skin

                   - *▲common in younger than 6yr

       ; St. pharyngitis

                   - *▲common at 5-15yr

       ; scarlet fever

                   - *uncommon less than 3yr

  2) season of the year

           ; St. pharyngitis

                   - higher in temperate climate

         - increased incidence & severity in cold weather

  3) climate & geographic location

           ; St. skin disease

                   - *prevalent in tropical climate, warmer weather in temperate climate

  4) degree of contact with infected individuals

# distruption of the cut. epithelium predispose to

    → streptococcal pyoderma & impetigo

    acquisiton from an infected individual is most common during

    → acute illness (3-5 days)

    decreased during the colonization stage

    colonization may preceed or follow (2-6wks) overt infection

# immunity

    ; type-specific

    ; *induced by carriage of organism or by overt infection

Pathogenesis

 1. inhalation or ingestion

    : streptococci attach to resp. epithelial cell by surface fibrils & cell wall lipoteichoic acid

      # fibrils + capsular hyaluronic acid: phagocytic reaction

 2. extracellular digestive enzyme

    : fasciliate the spread infection by

     ① interfering with local thrombosis (streptolysins)

     ② pus formation (DNase)

     ③ enhanced connective tissue digestion (hyaluronidase, proteinase)

 3. suppurative Cx. follow

  ① local inflammation (peritonsillar, retropharyngeal abscess)

  ② direct extension (OM, sinusitis)

  ③ lymphagitic spread (lymphadenitis)

  ④ bacteremia (sepsis, osteomyelitis, pneumonia)

 4. role of pyogenic toxin

  ① hypersensitivity reaction (rash produced)

  ② exhibit pyogencicity, cytotoxicity

  ③ enhance the effect of endotoxin

 5. streptococcal pyogenic exotoxin A

    : staphylococcal toxic shock의 staphylococcal enterotoxin B와 부분적으로 amino acid 상동관계 가짐

Clinical manifestation

# ▲common infection sites

    ; respiratory tract, skin, soft tissue, blood

Scarlet Fever

    ; *pyrogenic(erythrogenic) exotoxins(A-C)중에 하나를 생산하는 streptococci에 의해 발생

    ; incubation period : 1-7 days average 3 days

Clinical Manifestation

    ; *fever, vomiting, headache, toxicity, pharyngitis & chills

           - fever

                   / *up to 39.6-40℃ on the 2nd day

                / if Tx.(-), normalized within 5-7days

         / if Tx.(+), normalized within 12-24hr

           - tonsil

            / hyperemic & edematous

                   / covered with gray white exudate

       - pharynx

            / inflamed, covered with membrane in severe case

           - tongue

               / wihite strawberry tongue

                   : 초기에 red & edematous papillae project와 tongue dorsum에 white coat (+)

               / red strawberry tongue, raspberry tongue

                   : 수일후 white coat desquamated되고 prominent papillae가 산재해 있는 red tongue지속

    ; abdominal pain

    ; *rash within 12-48hr

           - red, punctate, finely papular, branches on pressure

           - texture of gooseflesh or coarse sandpaper

       - *initially appears in axilla, groin, neck and generalized within 24hr

7. forehead, cheek: flushing

     area around the mouth: pale (circumoral pallor)

  8. Pastia lines

     :antecubital fossa등 deep crease에서의 hyperpigmentation부분에 pressure를 가해도 blanch 나타나지 않는

        sign

  9. miliary sudamina

     : severe case의 abdomen, hand, feet에 나타나는 small vesicular lesion

  10. desquamation

      : face → trunk → hand & feet

        1주 말에 나타나서 길게는 6주까지 지속되는 경우도 있다.

# ★Other Causes Of Scarlets Fevers

    ; infection of wounds (surgical scarlet fever)

  ; burn

  ; streptococcal skin infection

    ; certain strain of staphylococci infection producing exfoliative toxin

Differential Diagnosis

   ⓐ meales: conjunctivitis, photophobia, dry cough, Koplik's spot

   ⓑ rubella: mild, postauricular lymphadenopathy, throat cultrue (-)

   ⓒ viral exanthem

   ⓓ infectious mononucleosis: photophobia, rash, lymphadenopathy, splenomegaly, atypical

                 lymphocyte

   ⓔ exanthem by sereveral enterovirus: DDx course of disease, associated Sx. culture result

   ⓕ roseolar: rash (+)로 fever cessation

   ⓖ Kawasaki disease: older age, conjunctival involvement (-), group A streptococci의

                        recovery in scarlet fever

   ⓗ drug eruption

   ⓘ toxic shock syndrome

   ⓙ Arcanobacterium hemolyticum: adolescent, young adult

   ⓚ severe sun burn

Skin Infection

Impetigo

    ; ▲common form

    ; superficial pyoderma

   ① colonization of unbroken skin: pyoderma 10일전

   ② deeper soft tissue infectin 올수 있다.

   ③ cellulitis

   ④ lymphangitis, lymphadenitis: common

   ⑤ soft tissue abscess (rare): contaminated needle로 immunization시 옴.

Erysipelas

   ① face & ext.: acute well-demarcated infection of the skin with lymphangitis involving

                  the face (asso. with pharyngitis) & extremities (wounds)

   ② erythematous indurated skin, advancing margin: raised firm border

   ③ asso. with fever, vomiting, irritability

   ④ lymphatic barrier break로 spread되어 subcutaneous abscess, bacteremia, metastatic foci

      of infection가능

   ⑤ streptococcal cellulitis와 동반되어 bacteremia, death가 생길수 있으며

      : rapid progression으로 penicillin에 effect (-)수도 있다.

Bacteremia

  1. local cutaneous & resp. infection일으킴

  2. poorest prognosis: underlying malignancy (+) pt.

Vaginitis

    : in prepubertal girl

Diagnosis

; sore throat있는 children의 30% → throat culture (+)

  - 이중 50% → positive Ab response (active infection)

; St. pharyngitis pt의 50%에서 tonsillar exudate (-)

# Throat Culture

    ; *most useful diagnostic method in acute tonsillitis or pharyngitis

    ; *normal inhibitant of nasopharynx in well children

           --> *hemolytic streptococci (+)가 확진은 안된다.

# rapid antigen detection test

    ; not sufficiently sensitive to be used without a back-upculture

# ASO titer

    ; untreated children의 80%이상에서 166 todd unit이상 증가

     (감염받은 첫 3-6주사이)

   1. very high ASO titer: rheumatic fever

   2. weakly (+) or not elevated: streptococcal pyoderma

   3. variable: glomerulonephritis

# Anti-DNase B

    : best serologic test for streptococcal pyoderma, infection받은 6-8주후부터 증가.

 4) pyoderma나 pharyngitis양경우 모두에서 antihyaluronidase titier증가

    ASO titier는 비례하지 않음

# 2 min, inexpensive streptozyme slide test

  1. multiple streptococcal extracellular Ag에 대한 Ab detect위해 개발

  2. 다른 single test보다 더 많은 환자에서 Ab titer↑볼 수 있는 유용함이 있다.

  3. infection 7-10일 내에 Ab detection 가능

  4. 단점

     : not specific for Ab to extracellular product of group A streptococci

# ESR↑ & CRP↑

    : Dx을 establish하는데 not helpful

Differential Diagnosis

Complication

 1. by extension of St. infection from the nasopharynx

    : sinusitis, otitis media, mastitis, cervical adenitis, bronchopeumonia

      retropharyngeal or parapharyngeal abscess

 2. hematogenous dissemination

    : meningitis, osteomyelitis, septic arthritis

 3. nonsuppurative late Cx.

    : rheumatic fever, glomerulonephritis

Prevention

 1. Sx onset전에 PC투여로 대부분의 경우에 prevention

    정확한 Ix.은 unclear

 2. Institutional epidemics

  ① oral PC G or V: 400,000 u/dose qid x 10 days

  ② 600,000 u benzathine PC + 600,000 u aqueous procaine PC

     : single IM

 3. carrier of group A β-hemolytic St. management: conroversal

 4. available streptococcal vaccine: still not exist

 5. frequent viral resp. infection을 갖는 carrier는 recurrent resp. inf.으로 생각할수 있는데 nonPc antibiotics

         (cephalosphorin, EM, clindamycin)는 carrier state를 근절하는데 도움

Treatment

# goal of therapy

    ; decrease Sx.

  ; prevent septic, suppurative, nonsuppurative Cx.

# *maintained for at least 10days

# children with streptococcal pharyngitis

  ; *PC 125-250mg/dose tid for 10days

           - penicillin G or penicillin V

    ; long-acting benzathine penicillin G single im

           < 60lb : 600.000 u

     > 60lb : 1,200,000 u

           - indication

                   / all noncompliant patient, those have nausea, vomiting or diarrhea

# allergy to penicillin

    ; EM 40mg/kg/24hr

  ; clindamycin 30mg/kg/24hr

  ; cefadroxil monohydrate 15mg/kg/24hr

# *TC, sulfonamide 사용해서는 안됨

# Tx. failure

  1. due to

   ① poor compliance

   ② reinfection

   ③ the presence of β-lactamase producing oral flora

   ④ presence of carrier state

  2. 치료가 모두 끝난 뒤에도 streptococci계속 남아 있는 상태로 5-20%의 환아에서 나타나며

     oral에서가 IM에서 보다 높다.

 6) repeat throat culture in risk situation

    : 이전에 rheumatic fever를 앓은 Hx.가 있는 patient

 7) persistance after 2nd course of antibiotic Tx.: carrier state

    * carrier state: rheumatic fever의 risk가 낮고 furthre Tx.는 필요(-)

 8) IV Pc Tx.가 꼭 유용한 경우

  1. severe scarlet fever

  2. streptococcal bacteremia

  3. pneumonia

  4. meningitis

  5. deep soft tissue infection

  6. erysipelas

  7. streptococcal toxic shock syndrome

  8. Cx. of streptococcal phyryngitis

 9) in most severe infection

    : Pc 400,000 u/kg/24hr

신10) severe, necrotizing infection

    : complete bacterial killing을 위해 second antibiotic (e.g. clindamycin)의 추가가 필요

175.1 Rheumatic fever

Etiology

; group A β-hemolytic streptococcus

    - not all

    - some serotype : no recurrence

    - other serotype : 20-50% 의 recurrence

; rheumatogenecity

           / M type 4

           / M type 1, 3, 5, 6 18, 24

; clinician assume that all group A streptococci cause rheumatic fever

※94,96 Epidermiology

; essentially epidermiology of Group A streptococcal pharyngitis

; *5-15 yr

    - *▲frequently

    - ▲susceptible to group A streptococcal infection

; also evidence in old age group &  outbreak in specific closed population such as military recruits

; increased cases in socially, economically disadvanced group

; ※94 increased incidence of fall, winter, early spring

; Group A streptococcal impetigo

    - RF (-), PSGN (+)

; ※Major Risk Factor

    - *streptococcal pharyngitis

; attack rate

    - 3% of untreated or inadequately treated infection patients

Pathogenesis

: unknown

      1. two basic theories

          toxic effect

         Group A streptococci의 extracellular toxin에 의해 target organ ( myocardium, valves, synovium, brain )           에 toxic effect의 produced.

          abnormal immune response by the human host.

      2. streptolysin O가 animal에서 cardiotoxic 하지만 in vivo toxic effect는 확립되지 못했다.

      3. most popular hypothesis

         Group A streptococcus 의 undefined component에 의한 human host 의 abnormal immune response

          --> resulting Ab

          --> immunologic damage

          --> clinical manifestation.

      4. latent period : 1-3 wk

      5. Two streptococcal antigen은 clinical manifestation을 일어키는 abnormal immunologic response의 excellent           example이다.

           Group specific polysaccharide of the Group A B-hemolytic streptococcal cell wall은 human과 bovine의             cardiac valve에서 발견되는 glycoprotein과 antigenically similar 하다.

           : chronic Rheumatic valvular heart disease를 가진이에서 acute nephritis나 uncomplicated streptococcal               infection에서 회복된 이들 보다 Group A polysaccharide에 대한 Ab가 prolonged persistence하다.

           cross relative antigen이 cell membrane이나 cell wall에서 originally described

           ---> cross-reactivity between Group A streptococci M proteins and human tissue.

           ---> abnormal immune response야기.

       6. genetic influence에도 불구하고, Rheumatic individual 의 70-90%에서

         non-T lymphocyte에 specific allergen (+)이고 control에서는 30%에서 (+)

       7. Group A Streptococci에 의한 URI후 RF의 pathogenetic mechanism은 organism의 specific charateristics와           아직 확실하게 밝혀지지 않은 human host의 genetic predisposition의 combination에 의한다.

Clinical Manifestation & Diagnosis

㉿Table 175-2

Major Criteria

Carditis

    ; 40-80%

    ; pancarditis involving peri-, epi-, myo-, & endocardium

    ; *only residual symptom resulting in chronic change

    ; common manifestation

         - vavular insufficiency

                   / *present in acute stage

                   / *MV : ▲common

                   / MV with AV

           - scarring with typical fishmouth abnormality or calcified valve --> stenosis.

                   / later in chronic stage

    ; other manifestation

           - pericarditis, pericardial effusion, arrhythmia (usually 1st heart block but 3rd complete heart block may occur)

Polyarthritis

    ; ▲confusing major criteria

    ; tender, migratory

    ; affect several different joint, elbow, knee, ankle, wrist

  ; *need not symmetric

    ; *not result in chronic joint disease

    ; following anti-inflammatory therapy, *disappear in 12-24hr.

Chorea

    ; 10%이하

    ; *occur much later than other manifestation

    ; ▲best signs in school aged children

           - marked deterioration in handwritting

    ; disappear within weeks to months.

Erythma Marginatum

    ; onset early in disease

    ; nonspecific pink macule over trunk

           --> branching in the middle of the lesion

    --> serpiginous-looking lesion

    ; worse with application of heat

    ; *dose not itching

Subcutaneous Nodule

    ; *▲commonly observed in pt with servere carditis

    ; pea sized nodule, firm, *not tender, no inflammation

  ; *extensor surface of joint (knee, elbow,spines)

Minor Criteria

# fever

    ; no higher than 101-102℉

    ; 103 or 104℉ 이상시 reevaluation & consideration of other ds

Evidence Of Group A Streptococcal Infection

; positive throat culture, a hitory of scalet fever, elevated streptococcal Ab

; streptococcal Ab

    - antistreptolysin O (ASO)

    - antideoxyribonuclease B (anti-DNase B)

    - antihyalunidase (AH)

Differential Diagnosis

Complication

; rheumatic valvular heart disease

    - *▲major complication

Laboratory Findings

# Throat Culture

    ; *gold standard for confirmation of the presence of group A streptococcus

    ; *at least one throat culture before antibiotics therapy

# Streptococcal Ab Test

    ; ASO

           - *▲commonly used

           - peak 3-6 wk after infection

    ; anti-DNase B test

           - peak 6-8 wk after infection

  ; AH test

# acute phase reactant

    ; ESR, CRP

    ; nonspecific

# reumatoid factor, ANA, complement, serum gammaglobuline elevation

    ; rare helpfull

# EKG

    ; 1st degree heart block, rarely 2nd, 3rd degree heart block

  ; 1st attack

           - EKG unremarkable

  ; chronic rheumatic heart disease

           - LAE

# Echocardiogram

# Chest PA

Treatment

# ♥3 Approaches

  1) treatment of the group A streptococcal infection that lead to the disease

    2) use of anti-inflammatory agents to control the clinical manifestation of the disease

    3) other supportive therapy, including CHF

# Treatment Of Streptococcal Infection

    ; *10 full days of oral agents

           or *single im injection of 1200000 units of benzathine penicillin G

    ; sulfadiazine

           - not an appropriate agent for acute streptococcal pharyngitis

# Control Of Clinical Manifestation

    ; *three systemic manifestatio given acute treatment

           - Arthritis, Carditis, Sydenham chorea

    ; Salicylates

       - prompt, dramatic relief of arthritis

                   / within 12-24 hr

                   / early salicylates --> interuption of diagnosis for arthritis

                           : *recommend small doses of codeine or similar durgs

           - mild carditis without CHF

                   / Salicylate alone

           - CHF or significant manifestation of carditis

                   / corticosteroid + salicylates

                   / *given during last week of corticosteroid therapy

                           and then *continued for 3-4wks after steroid discontinued

           - *90-120mg/kg/24hr #4

                   / blood levels 20-25 mg/dl

                   / carful monitoring of LFT

    ; Corticosteroid

           - congestive heart failure or other significant manifestation of carditis

    - *PRS 2.5 mg/kg/24 hr, # 2

       - short course : 2-3 wk

                   / if SE, alternate-day steroid Tx

    ; Treatment of Sydenham chorea ( controversal )

         - P-b, *CPZ(more papular)

         - diazepam

                   / recently used for mild chorea

           - *haloperidol

                   / severe chorea

# other supportive therapy

    ; CHF

           - diuretics or cardiac glycosides

           - bed rests

                   / not neccessary long-term priods

                   / *during therapy of patients with CHF

    ; Erythma marginatum & subcutaneous nodule

           - no specific therapy

Prevention

㉿Table 175-3 Primary and secondary prevention of rheumatic fever

Chapter176. Pneumococcal Infection

Etiology

    - Streptococcus pneumoniae

   1. G(+), lacet shaped, encapsulated diplococcus

   2. serotype

       : identified by type specific capsular polysaccharide

   3. cross-react of antisera

       ① other pneumococcal types

       ② other bactetrial species ; E coli, group B streptococcus

                                   H. influenza type b

   4. virulence

       - related to the size of the capsule (같은 size라도 다를 수 있음)

       - human pathogen : smooth, encapsulated strains

       - capsular matrial ; phagocytosis 방해

        # fully encapsulated strain (type 3) --> extraordinarily virulent

   5. quellung reaction

       : pneumococcal을 homologus type-specific antisera에 exposure 했을때

        antiserum은 각각의 capsular polysaccharide와 combine하여

        capsule이 refractile해짐

   6. incomplete (alpha) hemolysis on solid media

        --> unpigmented, umbilicated colony

   7. 그외 antigen

      ① C-substance

             - cell wall Ag.

             - species를 나타냄

             - teichoic acid-containing phosphocholine/and galactosamine 6-phosphate

             - precipitate with an acute beta-globulin

             - C-reactive protein

                   : activate complement and stimulation phagocytosis

      ② R antigen

             - species specific protein

      ③ A type specific protein (M antigen)

             - dose not confer significant antiphagocytic properties

                 --> negligible immunity

   8. antibodies

      ① antibodies to pneumococcal surface protein A (PspA)

          - protective against some pneumococcal strains

      ② antibodies to the capsular polysaccharide

   9. toxins - human ds.에 있어 pathogenesis는 밝혀져 있지 않음

      ① hemolytic toxin (pneumolysin)

      ② toxic neuramidase

      ③ purpura-producing factor : autolysis때 분비

Epidemiology

   1. isolation peak age : first 2yr of life

# carriage rate

    ; *highest in Desember to April

  ; lowest in July to September

# ★Peak Incidence

    ; meningitis - 3-5mo

    ; otitis media - 6-12mo

  ; pneumonia - 13-18mo

# bacteremia, pneumonia, otitis media

    ; *▲common bacterial cause : S. pneumoniae

# meningitis     

    ; 3rd bacterial cause : S. pneumoniae

# 2세이하의 children에 있어서  polysacharride capsule antigen에 대한

       antibody를 생성하는 능력 감소

      -->① increased suseptibility to pneumococcal inf.

          ② decreased vaccine effectiveness

# male > female

# native American and black > white

# *occurs sporadically

    ; person to person spread by respiratory droplet

# disease의 frequency와 severity가 증가하는 경우

        ① sickle cell ds

        ② asplenia, splenosis

        ③ deficiencies in humoral (B cell) immunity

        ④ AIDS

        ⑤ malignancy (leukemia, lymphoma)

        ⑥ complement deficiency

Pathogenesis & Pathology

# *produce disease by invasion

   1. host defence mechanism

        ① presence of other bacteria in nasopharynx

            --> limit the multiplication of pneumococci

        ② epiglottic reflex, cilia of the respiratory epithelium

            --> move infected mucus upward toward the pharynx

        ③ interaction of the bacteria with alveolar macrophages

            --> interaction of bacteria with alveolar macrophages

# *frequently follow viral respiratory infection

        ① produce mucosal damage

        ② diminish the epithelial ciliary activity

        ③ depress the function of alveolar macrophages

   3. phgocytosis may be impeded by respiratory secretion and the alveolar exudate

   4. spread

        ① lymphatics

        ② blood stream (bacteremia)

        ③ direct extension from a local site

   5. severity related to

        ① virulence & number of organism

        ② integrity of specific host defenses

   6. poor prognosis

        ① large numbers of pneumococci

        ② significant concentration of capsular polysaccharide in the circulation

   7. complement deficiency

        ① terminal component (C₃- C  )deficiency

            : recurrent pyogenic infection (S. pneumoniae)

        ② C₂deficiency

            : S. pneumoniae infection

   8. asplenic patient

        ① deficient opsonization

        ② abscence of filtering function of spleen

   9. Sickle cell disease and other hamoglobinopathies에서의 pneumococcal infection

        ① more prevalent

        ② 2세이하 -- high risk (Ab. production이 attenuated)

        ③ deficit in Ab-independent properidin (alternate) pathway of complement activation

        ④ properidin deficiency and deficient Ab production

             --> defect in Ab-independent and Ab-dependent opsonophagocytosis

                    of pneumococcus

        ⑤ 나이들면 anti-capsular Ab.를 만들어 Ab-dependent opsonophagocytosis를

              augmenting

  10. B and T cell immunodeficiency syndrome

      : phagocytosis efficacy 감소

       - lack of opsonic anticapsular Ab. 와 failure to produce lysis and agglutination

           of bacteria

  11. Opsonization of pneumonia infection

     a) classic and properidin (or alterative) complement pathway에 달려있다.

     b) disease의 회복은 opsonin으로 작용하는 anticapsular Ab ( enhancing phagocytosis and

          ultimately killing the pneumococcus)의 development에 달려있다.

  12. Spread of infection

       : enhanced by the antiphagocytic properties of pneumococcal capsule

Clinical Manifestation

  1. related to the site of infection

        ① pneumonia

        ② otitis media

        ③ sinusitis & pharyngitis

        ④ abscess of the upper airway

        ⑤ laryngotracheobronchitis

        ⑥ peritonitis

        ⑦ bacteremia

  2. local infection

        ① empyema

        ② pericarditis

        ③ mastiditis

        ④ epidural abscess

        ⑤ meningitis (rare)

  3. bacteremia

        ① meningitis

        ② septic arthritis

        ③ osteomyelitis

        ④ endocarditis

        ⑤ brain abscess

        ⑥ renal glomerular-caplillary and cortical arteriolar thrombosis

        ⑦ localized gingival lesion

        ⑧ gangrenous areas of skin on the face or extremities

        ⑨ immune complex glomerulonephritis

        ⑩ DIC

Dignosis

  1. recovery of pneumococci from th site of inf. or blood

     (but. nose or throat에서 발견되는 균주는 disease와 관계없다.)

# blood culture

  ; *obtained for all children with pneumonia, meningitis, arthritis, osteomyelitis, peritonitis, pericarditis, gangrenous skin lesion

       ② localized sign of inf. 이 없으면서 high fever와 leukocytosis를 가지는 1-24Mo child

  3. pneumococci

       ① Gram(+) lancet-shaped diplococci

       ② pneumococcal meningitis 초기

           --> many bacteria in a relatively acellular CSF

  4. the latex particle agglutination test

       ① rapid diagnosis

       ② Gram stain에서 보이는 경우는 필요없다

       ③ pneumococcal bacteremia를 Dx.하는데 sensitive

       ④ localized inf. --> negative

  5. leukocytosis

  6. ESR 증가

Prevention

# polyvalent pneumococcal vaccines

  ; *2세이하 childern에서 resposiveness는 unpredictable

    ; 23-valent pneumococcal vaccine이 사용된다.

         - purifed polysaccharide from 23 pneumococcal serotype

         - bacteremia, meningitis --> 95% response

           otitis media --> 85%

     3. vaccine에 대한 clinical efficacy는 controversial

     4. routine reimmunization is not recommanded

# ★Recommanded Immunization Indication After 2yr

          ① sickle cell anemia

          ② functional or anatomic asplenia

          ③ nephrotic syndrome

          ④ splenectomy following staging laparotomy for Hodgkin's ds.

          ⑤ CSF leakage

          ⑥ HIV infecton

       cf) recurrent otitis media or sinusitis의 예방에는 권하지 않음

     6. reimmunization

          : particular high risk patient

             optimal time interval --> unknown

# Penicillin prophylaxis

     1. pneumococcal sepsis risk가 있는 children

     2. Pc V potassium (125mg twice daily : 5세이하, 250mg twice daily : 5세이상)

     3. Benzathine Pc IM monthly

         - overwhelming sepsis 를 preventtion하는데 효과

     4. Erythromycin

         - Pc에 allergy가 있는 patient

Treatment

# ★Penicillin

    ; *Tx of choice

  Pc G : drug of choice for Pc-susceptable strains

    - 200.000-250.000U/kg/24hr, every 4-6hr

       : for bacteremia or pneumonia

    - 300.000U/kg/24hr, every 4-6hr

       : for meningitis

  oral Pc V

    - 50-100mg/kg/24hr, every 6-8hr

       : for minor infections

# Vancomycin (60mg/kg/24hr, every 6hr)

           : highly Pc resistent and for multipley resistent strains

    3. Cefotaxime and Cefotriaxone

           : 최근 resistant and Tx. failure가 보고되고 있다

    4. EM, cephalosporin, CM, bactrim

         --> effective for susceptible strain without meningitis

              alternate therapy for who are allergic to Pc.

Prognosis

     : depend on the

          ① integrity of host defense

          ② virulence of the infecting organism

          ③ age of the host

          ④ sithe of infection

          ⑤ adequacy of treat

Chapter 177. Haemophilus Influenza

(전반적으로 추가내용 많음 --> 새로 정리)

Microbiology

# H. influenza

         - fastidious, G(-) pleomorphic coccobacilli

         - require factor Ⅹ (hematin, heat stable)

                         Ⅴ (phosphophyridine nuclotide, heat stable)

                        for growth

# encapsulated strains

  ; surrounded by polysaccharide capsule

    ; *serotyed into six antigenitically & biochemically distinct type

           - designaged a-f

           - *type b : ▲virulent

# classified into 8 biotypes

 indole & urea metabolism and ornithin decarboxylase

 important in epidemiology & pathogenesis

    ① biotype Ⅰ

          : the most isolated form

            94% of serotype b

    ② biotype Ⅱ Ⅲ Ⅳ

          : genitourinary tract

    ③ biotype Ⅳ : neonatal inf.

    ④ biotype Ⅴ

          : otitis media or aSx. resp. inf.

Epidemiology

# serotype b

    ; major cause of invasive disease in children

    ; more than 95%

# ★Non-Encapsulated (Nontypable) H. Influenza

    ; *invasive ds. in the neonate, immunocompromised children, child in certain developing country

    ; *common etiologic agent for certain mucosal infection such as otitids media, sinusitis

    ; *asso. with chronic bronchitis in adults

    3. human is the only natural host for H. influenza

         - normal respiratory flora in 60-90% of healthy children

         - non-typable

              cf) serotype b --> infrequent (2-5%)

    4. H. influenza type b vaccine사용후

         --> invasive ds. incidence가 이전보다 90%이상 감소

    5. age distribution

         - 5세이하-->90%, 2세이하-->69-82%, 1세이하-->50%

         - peak age : 6mo-12mo

         - male>female

    6. increased risk

          ① sickle cell ds.

          ② asplenia

          ③ cong. & acquired immunodeficiency

          ④ malignancy

    7. Socioeconomic risk factor

          ① day care outside home

          ② the presence of sibling of elementary school age or younger

          ③ short duration of breat feeding

          ④ parental smoking

          ⑤ prev. hospitalization for invasive H. influenza type b

          ⑥ history of otitis media

    8. mode of transmission

         : direct contact or inhalation of respiratory tract droplets

    9. attack rate for secondary H. influenza type b ds. in househol contact

          --> high in susceptible children less 24mo (3.2%)

Pathogenesis

    1. attach to non-ciliated colummnar epithelial cell

           --> within the cell or intercellular space

           --> entravascular compartment

         # type b PRP --> resistent intravascular clearance mechanism

    2. non-invasive H. influenza

        : direct invasion from the pharynx

            --> otitis media, sinusitis, bronchitis

Antibiotics Resistance  

    1. Ampicillin

       ① 1988. USA : 29.5% of H. influenza type b

                     --> B-lactamase 생성, ampicillin resistence

       ② a few isolates

             --> non produce B-lactamase but ampicillin resistance

 

    2. CM

       ① chloramphenicol acetyl transferase (CAT) --> CM resistance

       ② both ampicillin and CM resistance --> 1%이하

    3. TMP-SMX, or amoxacillin calvulanate - 1%이하

Immunity  

    1. Anti PRP antibody

         ① Age related fashion

         ② facilitates clearance of H. influenza type b from blood

    2. The mechanism of action of anti-PRP antibodies

         ① opsonization

         ② classic & alternative complement pathway

         ③ macrophage of the reticuloendothelial system

# concentration of circulating anti-PRP antibody

  ; 0.15-1.0ug/ml

       --> prtect against invasive infection

    ; infant

       - lower anti PRP Ab. conc.

    - ♥Why ?

                   / *maturation delay in the immunologic responses to thymus-independent type 2 (TI-2) antigens such as PRP

                   / PRP imunization depends on age

                           : 6mo이하 --> anti-PRP antibody생성이 거의 없다.

           : 18-24mo이상 -->geometric mean anti PRP respose (>1ug/ml)

           - *conjugate vaccine으로 immunization해야 한다.

# conjugate vaccine

  ; *acts as thymus- dependent (TD) antigen

        - *exception) PRP-OMP : thymus independent type 1 (TI-1) properties

        - ★Table 177-1

  ; in child

           - *memory response occur rapidly on exposure to PRP

           --> *15개월이후에는 1회만 접종 가능

# Immunity to non-typable H. influenza

    ; outer membrane protein(OMP)에 대한 Ab.

          ① P6 (major OMP)

          ② P2

Laboratory Diagnosis

    1. direct exam.

        a) Gram staining

        b) staining with methylene blue

    2. culture

        a) primary isolation

            - chocolate agar

            - Hemophilus isolation agar

            - blood agar plates using staphylococcus streak technique

        b) serotyping

            - slide agglutination with type specific antisera

        c) detection of PRP

       # rapid Dx. H. influenza type b by detect capsular polysaccharide

             ① CIE

             ② latex particle agglutination --> most sensitive

             ③ Co-A ( staphylococcal protein A coagglutination )

             ④ ELISA

Clinical menifestation & Treatment  

    1. initial empric antibiotic Tx.

        - should include agent against ampicilline resistent strain

        - normal sterile site에서 분리된 H. type b  dml 20-40%에서 ampicilline resistent

            --> cefotamie or cefotriaxone이 intial Tx.

    2. etiologic agent 분리후

        - ampicillin susceptable strain

            --> ampicillin

        - oral antibiotics

            : parenteral route로 initialehls Tx.의 complete

            : amoxicilline, amoxicillin-clavulanate, cefixime, CM

Meningitis

# *Type b

    ; leading cause

    ; N. meningitidis or S. pneumoniae등의 meninigitis와 구별이 어렵다.

  ; lung, joint, pericardium globe에 complication동반

# antibiotics

           - 7-14day

           - cefotaxime, ceftriaxone, ampicillin, CM

      3. prognosis

          : depend on

              ① age of presentation

              ② duration of illness before appropriate antimicrobial Tx.

              ③ CSF state

              ④ rapidity of capsular polysaccharide conc. clearing from CSF, blood & urine

      4. complication

           ① SIADH

           ② focal neurologic deficit

                # hearing impairment (6%)

                    : inflammation of cochlea and labyrinth

                # Dexamethasone (0.6mg/kg/24hr #4, #6)

                    - antimicrobial Tx.직전에 투여

                    - bilat. hearing loss의 incidence 감소

           ③ behavior problems, language disorders

           ④ impaired vision, mental retardation, motor abnormality, ataxia,

              seizure, hydrocephalus

Cellulitis

        - young children cellulitis의 5-14%, 2세이하의 85%

        - frequent associated with URI but no trauma history

        - most common infected site : cheek, preseptal region

        - lesion : indistinct margin, tender, indulated

                     violaceous or bluish purple color

        - complecated with meningitis or septic arthritis

        - antibiotics : Sx. & Sg이 사라진후 1주 후 까지 투여

       cf) celluitis에서 prolonged fever --> concomitant inf 의심

Orbit Or Preseptal Infection

        1. red swollen eye

            ① with inf of superficial tissue layers ant. to the orbit

                  --> preseptal cellulitis

            ② with inf of orbit & it's content

                  --> orbital cellulitis or abscess

                        subperiosteal abscess

        2. Sx. & Sg.

             : fever, edema, tenderness, warmth of the lid & purple discoloration

        3. DDx.

           ① S.pneumoniae

           ② S. aureus

           ③ group A B-hemolytic streptococcus

            --> no fever , interruption of integument (insect bite)

        4. Inf. involving the orbit : rare

             - lid edema

             - proptosis, chemosis, impaired vision, limitation of extracellular movement

             - CT, USG --> inf. extent 확인

         5. Tx.

             ① preseptal cellulitis without meningitis

                  --> 5days parenteral Tx until no fever & eythema

             ② orbital inf. --> 전 치료기간을 parenteral

            # total 10일 이상

             ③ abscess --> I & D and more prolonged Tx.

Suprglottitis Or Acue Epiglottitis

         : 2-7세 , almost --> type b H. influenza

Uvulitis

        - rare

        - alone or aoncomitant of pharyngitis or epiglottitis

Pneumonia

        - 4세이하

        - common associated with meningitis, epiglottitis

Septic Arthritis

        - most common affected site : knee, hip, elbow, .ankle

        - associated with meningitis

Osteomyelitis

Pericarditis

        - children에서 pericaditis의 15% 차지

        - 2-4세

        - meningitis에 준해서 치료

Bacteremia Without Associated Focus

       ① risk factor for occult bacteremia

           - fever (>39℃)

           - leukocytosis (>15.000)

       ② H. influenza type b. bacteremia의 26% --> meningitis

       ③ initial parenteral antibiotic Tx (2-5일).후 P.O로 7-10일 치료

Invasive Ds. Of Neonate

       ① nontypable H. influenza --> more common

       ② 생후 24시간 이내에 산모의 amnionitis나 PROM과 연관되어 infection이 나타나면

            organism의 transmission은 maternal tract을 통해서이다.

Non-Invasive Ds.

Otitis Media

      a) most common bacterial pathogen

           ① S pneumoniae

           ② H. influenza (nontypable)

           ③ Moraxella catarrhalis

      b) first line antibiotics --> amoxicillin or ampicillin , ceftriaxine

      c) treatment failure or B-lactamase producing isolates

           ① cefaclor

           ② amoxicillin-clavulanate

           ③ SMX-TMP

           ④ EM-sulfisoxazole

Conjunctivitis

Sinusitis

      a) acute sinusitis

          cause --> otitis media와 동일

      b) chronic sinisitis

          : 1년이상 severe sinusitis

        - cause

             ① S.aureus

             ② anaerobs

                  : peptococcus, peptostreptococcus, bacteroides

             ③ non-typable H. influenza

             ④ streptococcus viridance

      c) Tx.

           ① amoxicillin

           ② amoxicillin-clavuanate

           ③ EM-sulfisoxazole

Prevention Of Serotype B Infection

Chemophylaxis

    1. Ix.

       ① invasive H. influenza Pt.와 접촉한 48mo이하의 unvaccinated close contact

       ② secondary ds.의 risk는 age에 반비례

       ③ use of high efficacy conjugate vaccine --> chemoprophylaxis의 요구 감소

    2. the goal of chemoprophylaxis

         : close contact내의 colonization 제거

    3. Rifampin

          : 0-1mo. 10mg/kg/dose,  >1mo, 20mg/kg/dose,  max.600mg

             4days

    4. full immunization of H. influenza typ b conjugate vaccine

         ① 15mo이상 --> 1 dose

         ② 12mo-14mo --> 2 dose

         ③ 12mo이전 1dose & 12mo이후 1 booster dose

Immunoprophylaxis Vaccines

    1. 4 licenced H. influenza type b. conjugate vaccine (Table 177-1)

        : differ in the carrier protein, the saccharide molecular size,

                    and the method of conjugate the saccharide to protein

       ① PRP-D (ProHIBit)

            : diphtheria toxoid as the carrer protein

       ② HbOC (HIBTITER)

            : an oligosaccharide linked to a non-toxic mutant diphtheria toxin (CRM197)

       ③ PRP-OMP

            : outer membrane protein complex of N. menigitidis group B as the carrier

       ④ PRP-T (Act HIB/OmniHib)

            : tetanus toxoid carrier

    2. combine vaccines contain H.influenza thyp b

       ① HbOC with DTP (TETRAMUNE)

       ② PRP-T 와 DTP를 주사직전에 혼합

Chapter 178. Meningococcal Infection

Etiology

# N. meningitidis

    ; *G(-) diplococcus (0.6 x 0.8um), biscuit shape

  ; common commensal organism of the human nasopharynx

  ; not isolated from animal or environmental source

      . 5-10% CO2의 atmosphere 에서 35-37도의 moist environment에서 잘 자람

      . growth media

        : supplemental chocolate agar, Mueller-Hinton agar, blood agar base,

          trypticase soy agar

    ^신 . cell wall : cytochrome oxidase 포함

                -> positive oxidase test result

    ^신 . glucose or maltose를 acid로  ferment 시킬 수 있는지 그리고 sucrose or lactose

        를 ferment 시킬 수 없는 지에 따라 N. meningitidis는 identify된다

    ^신 . indole & hydrogen sulfide : not formed

  2) serogroups

     : capsular polysaccharide에서 antigenic difference에 따라 divide된다

       . 적어도 13 serogroups이 identified

       . gr. A, B, C, W, Y : most meningococcal disease야기

Epidemiology

 ^신1)meningococcal dissemination

      : 주로 endemic disease로 발생

       a. endemic disease

           - caused by heterogenous gr. of serotype

           - geographically clustered area에서 잘 발생

       b. epidemics

           - developed countries에서는 rare, but developing countries에서

               significant problem야기

           - caused by single serotype

           - multilocus enzyme genetic method

              : caused by strains derived from single clonotype

# highest attack rate

    ; winter & early spring

  ; male 55%

    ; younger than 1yr 29%

           - *younger than 4mo : 26/100,000 infants, peak incidence

    ; younger than 2yr 46%

    ; older than 30yr 25%

# incidence among serogroup

    ; ★serogroup B disease 46%

  ;    "     C   "    45%(69% older than 2yr)

    ;    "     A   "   

           - major health problem in developing world

# meningitis : 48% of case

# isolation rate

  ; blood (66%), CSF(51%), joint fluid(1%)

Pathogenesis

   1) N. meningitidis : acquired by respiratory route

       a. colonization of nasopharynx

          -> lead to aSx carriage (dissemination : rare)

          -> persist for weaks to months

         ^신 # carriage rate

               nonepidemic period

                  - normal population : variable (2-30%)

                  - day-care center & crowding condition : higher

               epidemic period

                  - 100% in closed population

   2) colonization of nasopharynx

        -> evade mucosal IgA & adhere to epithelial cell by secretion of protease

            # protease : a. protein-rich ring & region of IgA를 cleave시키고 nonfunctional

                        b. meningococci & gonococci (+)

                           nonpathogenic Neisseria (-)

        -> nonciliated epithelial cell에 selectively bind

            (by parasite-directed endocytotic process)

 

   3) dissemination in blood-stream

       . serum Ab

           : lead to complement-mediated bacterial lysis

              -> block the dissemination

           : directed against

               a. capsular polysaccharide

               b. subcapsular protein

               c. lipooligosaccharide Ag

 

  ^신4) newborn infants

        . protective Ab (maternal origin IgG)

        . 3-24Mo경 Ab감소 -> highest incidence

          (most adulthood : natural immunity developed)

        . source of immunity

           # infants - high carriage rate of unencapsulated, nonpathogenic neisserial strain,

                       N. lactamiaca

                   -> development of bactericidal Ab against meningococcus

    5) meningococcal dis.의 risk 증가 하는 경우

        . primary or

           acquired complement deficiency( SLE, nephrotic synd., multiple myeloma, hepatic failure)

        . properdin, factor D or terminal-component deficiency가 있는 individual의 50-60%

# ★Group B Capsule

  ; *homopolymer of sialic acid

  ; *inhibit alternative complement pathway activation

    ; ★그러므로 serotype B meningococci가 young children에 흔하다.

Pathology

    1) intravascular coagulation with deposition of fibrin in small vessels

        -> hemorrhage & necrosis in any organ system

    2) meningococcemia시 involved되는 major organ system

         . heart

         . CNS

         . skin

         . mucous & serous membrane

         . adrenals

   

        a. myocarditis

           : 사망환아의 50%이상

        b. cutaneous hemorrhage (petechia to purpura)

           - occur in most fetal inf.

           - asso. with acute vasculitis with fibrin deposition in arterioles and capillaries

        c. diffuse adrenal hemmorrhage

           - occur in fulminant meningococcemia

            (Waterhouse-Friderichsen synd.)

        d. meningitis

           - acute inflammatory cells in the leptomeninges & perivascular spaces

           - focal cerebral involve : uncommon

  ^신3) interaction of endotoxin & complement system

       : key in the pathogenesis of cl. manifestation

        a. C' activation

           : correlates with concentration of meningococcal lipooligosaccharide in the plasma

        b. concentration of circulating endotoxin

           : directly correlated with

              . activation of the fibrinolytic system

              . development of DIC

              . multiple organ system failure

              . septic shock

              . death

        c. level of endotoxemia

           : correlates with the concentration of circulating cytokines

             (endotoxin-stimulated monocyte & macrophages에서 release)

        d. concentration of tumor necrosis factor-alpha and interleukins

           : directly asso. with fatal meningococcal diseases

Clinical Manifestation

    1) disease spectrum

       : vary widely from fever and occult bacteremia to sepsis, shock & death

        # recognized pattern

            a. bacteremia without sepsis

            b. meningococcemia sepsis without meningitis

            c. meningitis with or without meningococcemia

            d. meningoencephalitis

            e. inf. of specific organs

    2) . well-recognized entity : occult bacteremia in a febrile child

       . upper resp. or G-I Sx or maculopapular rash : (+)

       . spontaneous recovery without Abc 가능하지만 일부는 meningitis developed

    3) acute meningococcemia

        : viral-like illness와 유사

           - pharyngitis, fever, myalgia, weakness, headache

        a. with widespread hematogenoous dissemination

           - rapidly progress to septic shock

               . hypotension

               . DIC

               . acidosis

               . adrenal hemorrhage

               . renal failure

               . myocardial failure

               . coma

           - meningitis : may or may not develope

           - pneumonia, myocarditis, purulent pericarditis, septic arthritis

        b. seizure & focal neurologic sg. in the meningitis

           - pneumococcus, or H. influenza보다 less frequent

        c. meningoencephalitis

           - rarely, diffuse brain involve

  ^신4) presenting sx & sg

          . fever(71%)

          . hypothermia(4%)

          . shock(42%)

          . petechia or purpura (71%), both(49%)

          . purpura fulminans(16%)

          . maculopapular, pustular, bullous lesion

          . irritability(21%), lethargy(30%), emesis(34%)

          . diarrhea, cough, rhinorrhea, seizure, arthritis : less frequent(6-10%)

 

   5) Lab

          . leukopenia(21%), low platelet count(14%)

          . WBC count range : 0.9-46/mm3 x 10³

          . blood culture : 48% (+), meningitis에서는 55%(+)

   ^신6) a. CSF pleocytosis(-), hypoglycorrhachia(-) or G. stain상 detect되는 organism이 없는

         경우에 있어서 6%에서 CSF상 균 isolated

       b. arthritis pt 8명중 5명 : joint fluid -> isolated

       c. 8%에서 x-ray 상 pneumonia (+)

           - primary meningococcal pn.중 15%에서 pleural effusion or empyema동반

    7) chronic meningococcemia

          . rare, occur in children & adult

          . sx : fever, nontoxic apperance, arthralgia, headache, rash

               (rash - disseminated gonococcal inf.과 유사)

          . blood culture : initially sterile

          . Cx : specific Tx 하지 않는 경우 -> meningitis

Diagnosis

# ★Isolation Of Organism

  ; blood, CSF, synovial fluid

           - usually used

    ; nasopharynx - not diagnostic

    ; petechial or purpuric lesion

           - variable successful

# Counterimmunoelectrophoresis & latex agglutination test

    ; detection of meningococcal capsular polysaccharide

    ; CSF, serum, joint fluid, urine

    ; false(-) occur

         . cross-reactive Ag(E.coli K1)

             -> gr.B meningococcus와 cross-react

             -> specificity감소

# antisera & monoclonal Ab

         . identify different serogroup

         . useful

            - early in inf.

            - received Abc

            - rendering cultures sterile

# ancillary data

         . ESR & CRP 증가

         . leukocytopenia or leukocytosis

         . proteinuria, hematuria

         . thrombocytopenia

         . pts with DIC

             - prothrombin & fibrinogen감소

         . complement deficiency

Differential Diagnosis

     a. acute bacterial or viral meningitis

     b. mycoplasma inf.

     c. leptospirosis    

     d. syphilis     

     e. acute hemorrhagic encephalitis

     f. encephalopathies 

     g. serum sickness    

     h. collagen-vascular disease

     i. H-S purpura   

     j. hemolytic uremic synd.  

     k. congestion of various poisons

 

   # the morbilliform rash : confused with any macular or maculopapular viral exanthem

      -  meningococcemia때의 rash와 감별해야 할 질환

         a. septicemia due to many G(-) organism

         b. overwhelming septicemia with G(+) organisms

         c. bacterial endocarditis

         d. Rocky Mountain spotted fever

         e. epidemic typhus

         f. Ehrlichia canis inf.

         g. inf. with echoviruses(esp. types 6, 9, 16)

         h. coxsackievirus infecions(esp. type A2, A4, A9, A16)

         i. rubella

         j. rubeola & atypical rubella

         k. H-S purpura

         l. Kawasaki ds.

         m. idiopathic thrombocytopenia

         n. erythema multiforme or erythema nodosum

              due to drugs or infectious or non infectious ds. process

Complication

     1) acute Cx : related to

         +- . inflammatory change

         |  . vasculitis

         |  . DIC

         +- . hypotension of invasive meningococcal disease

         1. meningococcemia

              . adrenal hemorrhage

              . arthritis

              . myocarditis

              . pneumonia

              . lung abscess

              . peritonitis

              . renal infarcts

         2. vasculitis

              . skin loss with secondary inf.

              . tissue necrosis

              . gangrene

         3. bone involvement

              . growth disturbance

              . late skeletal deformities secondary to epiphyseal avascular necrosis

                 & epiphyseal-metaphyseal defects

         4. meningitis : rarely

              . subdural effusion

              . empyema

              . brain abscess

         5. deafness : mc neurologic sequale 0-38%

            ataxia, seizure, blindness, cranial n. palsies, hemiparesis or quadriparesis, 

            obstructive hydrocephalus

 

     2) late Cx

         . due to immune complex mediated

         . apparent 4-9day after the onset of illness

         . usual manifestation

            - arthritis & cutaneous vasculitis

         . arthritis

            - monoarticular or oligoarticular

            - effusion : sterile & respond to NSAID

            - permanent joint deformity : uncommon

         . Abc Tx 5일 후에도 persistence of fever

            : immune complex-mediated Cx에 대해 evaluation

Prevention

# prophylaxis Ix

  ; house-hold, day-care, & nursery school contacts

  ; contact with pt's oral secretion

  ; intimate exposure

   - mouth to mouth resuscitation

   - intubation

   - suctioning before Abc Tx

# rifampin

   : *10mg/kg (max 600mg) po every 12hr for 2days (total 4 dose)

   : very young infant - 5mg/kg

# sulfonamide : sensitive 한 경우

# vaccination

    ; quadrivalent vaccine

        - composed of capsular polysaccharide of menigococcal group A, C, Y and W-135

    ; *immunogenic in adult, but unreliable in children under 2yr

    ; group B polysaccharides

           - *poor immunogenic in chidren & adults

    ; *not recommended as routine

Treatment

    ; ★aqueous PC G

           - drug of choice

       - *250,000 to 300,000 u/kg/24hr IV in six divided dose

  ; CM sodium succinate

    - 75-100mg/kg/24hr IV 4 divided dose

       - pc에 allergy 있는 경우

  ; cefotaxime (200mg/kg/24hr) & ceftriaxone (100mg/kg/24hr)

    - empirical Tx & pc에 allergy 있을때

  ; duration

           - ★7days

Prognosis

# mortality rate

    ; 8-12%

# ★Poor Px Factor

  ; hypothermia

    ; hypotension

    ; purpura fulminance

    ; *seizure or shock on presentation

    ; leukopenia

    ; thrombocytopenia 

    ; high circulating level of endotoxin & tumor necrosis factor

    ; some studies, included

        - petechia within 12hr of admission

        - hyperpyrexia

        - *absence of meningitis

Chapter 179. Gonococcal Infections

Etiology

  1) N. gonorrhea

       . nonmotile, aerobic, non-spor-forming, G(-)intracellular diplococcus

       . optimal growth

          : 35-37도 & PH 7.2-7.6 in an atmosphere of 3-5% CO2

       . Thayer-Martin or Transgrow media

       . other Neisseria와 감별점

           gonococci - fermentation of glucose but not maltose, sucrose, or lactose

  2) most widely used serotyping system

     : based on antigenic difference in protein I found in the outer membrane

        protein I : 1A

                   1B

  3) monoclonal Ab

         1A-1

         1B-12

Epidemiology

  1) occur only in humans

  2) highest incidence : male : 20-24세 july-september > january-april

                       female :15-19세

  3) risk factor

       . nonwhite race

       . homosexuallity

       . No. of sexual partner증가

       . prostitution

       . STD(+)

       . unmarried state

       . poverty

       . failure to use of condom

 ^신4) gonococcal inf. of neonate

       . peripartum exposure to infected exudate from cervix

       . begin 2 to 5 days after birth

       . incidence

          : preg. woman 에 있어서 prenatal screening for gonorrhea

           & ophthalmic prophylaxis 유무에 좌우됨

       . prevalance

          : < 1% in US prenatal populations

Pathology

1) mucosal invasion by gonococci

   -> local inflammatory responce

   -> purulent exudate (PMNL + desquamated epithelium)

2) lipooligosaccharide (endotoxin)

   . direct cytotoxicity -> ciliostasis & sloughing of ciliated epithelial cell

   . bind bactericidal IgM Ab & serum C'

     -> subepithelial space에서 acute inflammatory response

   . tumor necrosis factor & other cytokines

     -> cytotoxicity

3) purulent discharge

     -> block ducts of paraurethral(Skene) or vaginal (Bartholin)glands

     -> cysts or abscess

4) gonococci

      -> ascend the urogenital tract

      -> endometritis, salpingitis, peritonitis : postpubertal females

      -> urethritis, epididymitis : postpubertal males

# ♥Fitz-Hugh-Curtis Syndrome

    ; perihepatitis

    ; dissemination through peritoneum from fallopian tube to liver capsules

Pathogenesis

   1. selective pressure from different mucosal environment

     -> change in the outer membrane of the organism

          . exposure of variants of pili

          . opacity or Opa protein(protein II)

          . lipooligosaccharide

     -> gonococcal attachment

         invasion of human cell

         replication

         evasion of the host's immune response

   2. gonococcal IgA protease

      . cleaving the molecule in the hinge region

        -> inactivate IgA1

      . colonization or invasion of host mucosal surface에 관여

   3. gonococci

      : adhere to microvilli of nonciliated epithelial cell by hairlike protein structure(pili)

        # pili : . high frequency antigenic variation

               . protect the gonococcus from phagocytosis and complement-

                 mediated killing

 ^신4. other phenotypic changes

       . iron-repressible protein for binding transferrin or lactoferrin

       . anaerobically expressed protein

       . synthesis of protein-mediated by contact with epithelial cells

   5. 24hr after attachment

      epithelial cell invaginate & surround the gonococcus in a phagocytic vacuole

       (by the gonococcal outer membrane protein I)

     -> alteration in membrane permeability

     -> phagocytic vacuole

          : exocytosis에 의해 subepithelial space내로 gonococci을 release

     -> local disease(salpingitis)

          or disseminate (blood stream or lymphatics)

   6. host factor

      1) influence the incidence & manifestation of gonococcal inf.

      2) prepubertal female

          . vulvovaginitis

          . rarely salpingitis

      3) neonate & mature female

           : resist inf.

      4) postpubertal female

           : salpingitis esp. menses

   7. population at risk for DGI

      1) aSx carrier

      2) neonates

      3) menstruating, pregnant, & postpartum female

      4) homosexual

      5) immunocompromised hosts

   8. PC resistant gonococci 증가 이유

      1) plasmid-mediated B-lactamase (penicillinase) production

         : absolute resistance

      2) chromosomally mediated resistance

         : relative resistance

 ^신 9. PPNG : all PC & 1st cepha 에 resist

              but not to 2nd & 3rd cephalosporin

      # PC or TC에 resist : 32%

         : PPNG - 11%

           TRNG - 5-7%

           PPNG & TRNG - 2%

         : chromosomally mediated resistance - 14%

Clinical Manifestation

Asymptomatic Gonorrhea

      a. isolated oropharynx of young (2-9yr of age)

          : abused sexually by male contacts

      b. oropharyngeal Sx : abscent

      c. 12-19yr females : 12%

                          most of girl - asymtomatic

      d. 68% of infected United States military men : asymtomatic

      e. 80% of sexually mature females with urogenital gonorrheal inf.

          : asymtomatic

      f. 20% of rectal inf. & 78% of pharyngeal gonococcal inf.

        : asymtomatic in homosexual men

Uncomplicated Gonorrhea

      a. genital gonorrhea

         : incubation period - 2-5 days in men

                              5-10 days in women

         : primary inf.  - urethra of the male

                        - vulva & vagina of the prepubertal females

                        - cervix of the postpubertal females

      b. urethritis

          : purulent discharge

          : burning on urination without urgency or frequency

      c. vulvovaginitis

          : prepubertal female

          : purulent vaginal discharge

          : dysuria

      d. cervicitis & urethritis

          : purulent discharge, suprapubic pain, dysuria, intermenstrual bleeding, dyspareunia

          : cervix - inflamed & tender

      e. gonococcal ophthalmitis

          : unilateral or bilateral

          : ophthamia neonatorum - 1-4days after birth

          : if treatment not promptly - corneal ulceration, rupture, blindness

Disseminated Gonoccal Infection

    ; hematogenous dissemination : 1-3% of all gonococcal inf.

 women : Sx. beginning 7-30 days after inf.

         and within 7 days of menstruation

 most common manifestation

 : arthritis, tenosynovitis, dermatitis

 : rarely carditis, meningitis, osteomyelitis

 most common initial sx

 : polyarthralgias with fever

 25% : complain of skin lesion

 80-90% of cervical culture : positive in women with DGI

 50-60% of urethral culture : positive in male

 pharyngeal culture : positive in 50-60%

 rectal culture : positive in 15%

 classification

 . tenosynovitis-dermatitis Sd.

    : more common

    : fever, chill, skin lesion, polyarthralgia

    : blood culture-positive(30-40%)

    : synovial fluid culture - negative

 . suppurative arthritis sd.

    : monoarticualar arthritis (knee)

    : synovial fluid culture-positive(45-55%)

    : blood culture-negative

 DGI in neonate : polyarticular septic arthritis

 dermatologic lesion

 . painful discrete

 . 1-20mm pink or red macules

   -> maculopapular, vesicular, bullous, pustule, petechial lesion

 . lesion number : 5-40

 . 20-30% of lesion : contain gonococci

 acute endocarditis

 : uncommon(1-2%)

 : fetal manifestation of DGI - rapid destruction of aortic valve

 meningitis

 : documented

Complication

    1) result from the spread of gonococci from a local site of invasion

    2) postpubertal females

       1. endometritis

       2. salpingitis, peritonitis(pelvic inflammatory disease)

       3. manifestation of PID

           . sign of lower genital tract inf.

              -- vaginal discharge, suprapubic pain, cervical tenderness

           . upper genital tract inf.

              -- fever, leukocytosis, elevated ESR, adnexal tenderness or mass

       4. DDX

           . gynecologic

              -- ovarian cyst, ovarian tumor, ectopic preg.

           . intraabdomial

              -- appendicitis, UTI, inflammatory bowel ds.

       5. Fitz-Hugh-Curtis Sd.

           : perihepatitis

           : RUQ pain, with or without signs of salpingitis

       6. perihepatitis due to Chlamydia trachomatis

       7. progression to PID

           . 20% of cases of gonococcal cervicitis

           . isolated in 40% of cases of PID

           . untreated

              : hydrosalpinx, pyosalpinx, tubo-ovarian abscess, sterility

           . treated

              : risk of sterility

                  - 20% after one episode of salpingitis

                  - 60% with three or more episodes

           . risk of ectopic preg.

              : 7-fold after one or more episodes of salpingitis

           . additional sequelae of PID

              : chronic pain, dyspareunia, inc. risk of recurrent PID

       8. high risk of septic abortion

           : urogenital gonococcal inf. acquired during the 1st trimester

       9. after 16weeks

           : inf. --> chorioamnionitis, PROM, premature delivery

Diagnosis & Differential Diagnosis

# definitive Dx

  ; isolation of N. gonorrhea

    2) DDx of gonococcal urethritis & vulvovaginitis

        : beta-hemolytic streptococci, C. trachomatis, Mycoplasma hominis,

          Trichomonas vaginalis, Candida albicans

        : rare - Herpesvirus hominis type 2

# identification of G(-) intracellular diplococci(within leukocytes) in urthral discharge

    ; male - presumptive Dx

  ; female

           - *not sufficient

       - *due to Mima polymorpha & Moraxella (normal vaginal flora) : similar appearance

# bacteriologic culture

  ; gold standard for the Dx of N. gonorrhea

  ; *specimen from cervix, rectum, pharynx

           - *use Tayer-Martin medium (selective culture media)

    ; specimen from synovial fluic, blood, CSF

           - use chocolate agar medium

    ; DGI suspect

           - blood, pharynx, rectum, urethra, cervix, synovial fluid에서 culture

        : colonies of N. gonorrhoeae -- oxidase positive

           DDx of M. polymorpha & N. lactamica : carbohydrate utilization test

        : gonococci -- fermentation glucose

                       but not maltose, lactose, sucrose

                   -- tested for beta-lactamase production

    5) rapid slide coagglutination test (Phadebact)

        : sensitivity of 96-98%

        : cross reacts with commensial N. species

    6) enzyme immunoassay test(Gonozyme)

        : more sensitive than G stain(80-92%)

        : cannot be used for rectal or pharyngeal infections

    7) DDx of gonococcal arthritis

        : other forms of septic arthritis

           -- rhematic fever, rheumatoid arthritis, Reitier Sd., inflammatory bowel ds.,

              arthritis secondary to rubella or rubella immunization

    8) DDx of gonococcal conjunctivitis in the newborn

        : chemical conjuctivitis by silver nitrate drop

        : by C. trachomatis, S. aureus, group A or B streptococcus, P. aeruginosa,

           herpesvirus type 2

Prevention

# gonococcal opthalmia neonatum

  ; *conjunctival sac에 1% silver nitrate solution

  ; EM(0.5%) or TC(1%) ophthalmic ointment

    2) Gono(+) mother --> infant (high risk for gonococcal ophthalmitis)

       - ceftriaxone : 125mg IM single

                    : 25-50mg IM single IM LBWI

Treatment

# general principles

    ; ★ceftriaxone recommended as initial Tx for all ages

# uncomplicated gonorrhea in penicillin-allergic individuals

    ; spectinomycin 40mg/kg single im

    ; ciprofloxacin 500mg orally for 1 dose

    ; EM

       - during preg. added to spectinomycin or ceftriaxone

# DGI

    ; ★ceftriaxone

           - initial Tx

    - *50mg/kg/24hr(max. 1g/24hr) iv or im for 7day

    ; endocarditis or meningitis

         - ceftriaxone 50mg/kg(max, 2g) iv

           - endocarditis : 4wks

         - meningitis : 10-14days

    ; penicillin sensitive DGI

         - aqueous PCG 100,000-200,000 U/kg/24hr six divided dose iv for 7-10 days

    - meningitis & endocarditis

           / 250,000 U/kg/24hr for same duration

4. concurrent Tx with doxycyclin

          : Tx of genital chlamydia inf.

    6) infants born to mothers with known gonococcal inf.

      1. evaluated for sepsis with blood & CSF cultures

      2. ceftriaxone : drug of choice,  50ug/kg IM or IV once, max 125mg

                   : topical prophylaxis - not adequate

    7) neonates with gonococcal ophthalmitis

      1. evaluated for DGI

      2. ceftriaxone 25-50mg/kg/D IV or IM every day for 7 days

      3. concomittant saline irrigation of eye

    8) PID

      1. due to N. gonorrhoeae, C. trachomatis,

            endogenous flora(streptococci, anaerobes, G(-)bacilli)

      2. cefoxitin 2g IV every 6hr + doxycycline 100mg oral or IV every 12hr or

        cefotetan 2g IV every 12hr +            "

      3. at least 48hr after the pt. shows improvement

      4. oral doxycycline : total of 10-14 days

      5. alternative

         : clindamycin, 900mg IV every 8hr + loading dose of gentamicin

                                            (2mg/kg IM or IV)

                                           maintenance dose 1.5mg/kg every 8hr

Chapter 180. Diphtheria

Etiology

# Corynebacterium species

  ; aerobic, nonencapsulated, non-spore-forming, nonmotile, pleomorphic, G(+) bacilli

  ; cystinetellurite blood agar

# 3 biotypes

  ; mitis

    ; gravis

  ; intermedius

      -> capable of causing diphtheria

# demonstration of diphtheritic toxin

  ; in vitro

           - *agar immunoprecipitin technique(Elek test)

    - PCR

    ; in vivo

           - toxin neutralization test (lethality test)

# *toxigenic strains 는 colony type, microscopy, biochemical test로 구분할 수 없다.

Epidermiology

   1) C. diphtheria

      : exclusive inhabitant of human mucous membrane & skin

   2) spread

        . airborne resp. droplets

        . symptomatic individuals 의 resp. secretion or infected skin lesion의 exudate와 direct contact

        . asymptomatic resp. carrier

            : important in transmission

# incidence

    ; begin to fall

    ; primarily affected children younger than 15yr

           --> *최근에는 vaccination을 하지 않은 adult로 shift endemic onset

# survery of antitoxin level in Sweden

    ; childhood - 95% protective rate

    ; younger than 20yr - 81%

    ; older than 60yr

           - female 19%, male 44%

# cutaneous infection

    ; infrequently complication

    ; ★compared with mucosal infection

           - more prolonged bacterial shedding

    - increased contamination of environment

    - increased transmission to pharynx & skin of close contacts

# ★Outbreaks Associated Factors

    ; homelessness

  ; crowding

  ; poverty

  ; alcoholism

  ; poor hygiene

  ; contaminated fomites

  ; underlying dermatosis

    ; introduction of new strain from exogenous sources

Pathogenesis

# toxigenic and nontoxigenic C. diphtheria organisms

    ; skin & mucosal infection or distant infection after bacteremia

           --> superficial layer of skin lesion or resp. mucosa

           --> *produce 62-KD polypeptide exotoxin

       --> inhibit protein synthesis

    --> cause local tissue necrosis

# resp. tract infection

    ; dense necrotic coagulation of organism, epithelial cell, fibrin, leukocyte & erythrocyte within first few days

           --> become gray-brown adherent pseudomembrane

       --> removal - difficult

    - reveals a bleeding edematous submucosa

   5) early local effect of toxin

      : paralysis of palate & hypopharynx

   6) toxin absorption 시 Cx

      . necrosis of kidney tubules

      . thrombocytopenia

      . myocardiopathy         -+

      . demyelination of nerves -+  --> occur 2-10wks after mucocutaneous inf.

Clinical Manifestation

Resp. Tract Diphtheria

# primary focus

    ; tonsil or pharynx (94%)

  ; nose & larynx (2nd common sites)

# *IP for 2-4 days

# fever : 39도 이상은 rare

# ★Infection Of The Ant. Nares

  ; *more common in infants

  ; *serosanguinous, purulent, erosive rhinitis with memb. formation

  ; *shallow ulceration of the external nares & upper lip

# tonsilar & pharyngeal diphtheria

          . sore throat : universal early sx

          . fever : 50%에서

          . dysphagia, hoarseness, malaise or headache : fewer

      7. mild pharyngeal injection

          -> unilat. or bilat. tonsilar memb. formation

          -> extend to uvula, soft palate, post. oropharynx, hypopharnx, and glottic areas

      8. underlying soft tissue edema & enlarged lymph nodes

          -> bull-neck appearance

      9. degree of local extension에 따라서

          . profound prostration

          . bull-neck appearance

          . fatality from airway compromise or toxin-mediated Cx

 

       10. DDx

           a. exudative phayngitis due to strep. pyogenes & E-B virus

              : leather-like adherent memb., extension beyond the facial area,

                relative lack of fever, dysphagia

                 -> diphtheria

           b. vincent angina, infective phlebitis & thrombosis of the jugular vein.

              & mucositis in pts undergoing cancer chemoTx

              : clinical setting에 의해

           c. inf. of the larynx, trachea & bronchi

              : pharyngeal inf.에 의한 primary or secondary extension

              : hoarseness, stridor, dyspnea, & croupy cough

           d. bacterial epiglottitis, severe viral laryngotracheobronchitis,

              & staphylococcal or strep. tracheitis

              : diphtheria pt에서의 Sx & Sg은 비교적 적고

                laryngobronchoscopy & intubation때 adherent pseudomemb.을 직접 관찰하여 감별

# laryngeal diphtheria

  ; *highly prone to suffocation

    ; edema of soft tissue, obstructing dense cast of resp. epithelium & necrotic coagulation

Cutaneous Diphtheria

     1. classic cutaneous diphtheria

         . indolent, nonprogressive inf.

         . superficial, ecthymic, nonhealing ulcer with gray-brown memb.

     2. diphtheric skin inf.

         . strep. or sta. impetigo와 DDx 힘들다

         . frequently coexist

     3. underlying dermatoses, laceration, burn, bites or impetigo

        : secondarily contaminated

     4. site : extrimity (more common), trunk, head

     5. sx  a. pain, tenderness, erythema, & exudate : typical

            b. local hyperesthesia or hypesthesia : unusual

     6. resp. tr. colonization or symptomatic inf. & toxic Cx

         : 소수의 환아에서 (+)

Infection At Other Sites

      - ear (otitis externa)

      - eye(purulent and ulcerative conjunctivitis)

      - genital tract (purulent & ulcerative vulvovaginitis)

Toxic Myocardiopathy

      1. pt중 10-25%, 사망원인 중 50-60%

      2. risk for significant Cx

          . extent & severity of exudative local oropharyngeal ds.

          . delay in adminstration of antitoxin

      3. first evidence of cardiac toxicity

          : 2nd to 3rd wk. of illness as pharyngeal ds. improve

            (but 1wk or 6wks 경에도 나타날 수 있다.)

      4. tachycardia

         . fever와 비례하지 않음

         . may be evidence of cardiac toxicity or autonomic n. system dysfunction

      5. EKG

         . prolonged P-R interval

         . changes in the ST-T wave

         . single or progressive dysrhythmia

             - 1st, 2nd, 3rd degree heart block

             - atrioventricular dissociation

             - ventricular tachycardia

      6. echocardiogram

          : dilated & hypertrophic cardiomyopathy

      7. CHF : incidious or acute onset

      8. elevation of serum aspartate aminotransferase conc.

          : parallels the severity of myonecrosis

Toxic Neuropathy

     1. neurologic Cx

        . parallel the extent of primary inf.

        . multiphasic in onset

     2. acutely or 2-3wk after onset of oropharyngeal inflammation

        -> hypesthesia, & local paralysis of soft palate

     3. weakness of the post. pharyngeal, laryngeal & facial n.

        -> nasal quality in the voice, difficulty in swallowing

            & risk of death from aspiration

     4. cranial neuropathy

         . occure in the 5wks

         . oculomotor & ciliary paralysis

            - strabismus, blurred vision, difficulty with accommodation

     5. symmetric polyneuropathy

         . 10days to 3 Mo after oropharyngeal inf.

         . motor deficit with diminished deep tendon reflex

     6. prox. muscle weakness of the extrimity

        -> progressing distally

       distal weakness (more common)

        -> progressing proximally

        -> clinical & CSF finding

             : G-B synd.과 감별 힘듦

     7. paralysis of the diaphragm

     8. complete recovery is likely

     9. rarely, 2 or 3 wk after onset of illness

        -> dysfunction of the vasomotor centers

        -> hypotension or cardiac failure

Management

The Patient

Diagnostic Test

      . specimen for culture

          : nose, throat & other mucocutaneous lesion

Antitoxin

    ; *mainstay of therapy

    ; *adminstered on the basis of clinical diagnosis

        - ★Why ?

                   / *neutralizes only free toxin

             / *diminished effect after onset of mucocutaneous Sx

    ; degree of toxicity, site & size of the memb. & duration of illness에 따라 투여

      ★Table 180-1

        - once at empiric dosage

        - 주로 IV route

        - infusion over 30-60min

    4) local manifestation of cutaneous diphtheric 에는 no valuable

       but toxic sequalae 나타날수 있기 때문에 사용하는 것이 좋다

    5) 8% of Pt. given equine antitoxin

       -> serum sickness develope

 

    6) 10% of individuals

       : pre-existing hypersensitivity to horse protein

       -> infusion전에 test시행해야 함

       -> negative control(saline) & positive control (histamine)with

           epinephrine & available resuscitative equipment

 

    7) intradermal test

       a. 0.02 ml of 1:100 saline-diluted antitoxin

       b. if animal allergy Hx(+), or prior exposure to animal serum,

        -> 1:1000 saline-diluted antitoxin

       c. immediate reaction

          : wheal with surrounding erythema at least 3mm larger than the negative control test result,

             lead at 15 to 20min

    8) desensitization

        (table 180-2)

       - immediate reaction을 보이는 경우 protocol에 따라서

       - with successive dose every 15min

       - negative test results

        : physiologic saline or 5% glucose solution 10ml로 dilution된 prelimimary dose of 0.5ml of antitoxin

             -> 30min observation하면서 가능한 slowly given

             -> remainder : diluted 1:20 & 1ml/min초과하지 않게 투여

    9) IV immunoglobulin

        : contain Ab to diphtheria toxin

    10) antitoxin

       : asymptomatic carrier에는 not recommend

Antimicrobial Therapy

    ; halt toxin production, treat localized inf., prevent transmission of the organism to contacts

    ; EM

           - *nasopharyngeal carrier시 PC보다 superior

    - 40-50mg/24hr max. 2g/24hr, oral or parenteral for 14days

    ; PC

        - *aqueous crystalline PC 100,000-150,000 u/kg/24hr #4 IM or IV for 14days

           - procaine PC 25,000-50,000u/kg/24hr #2 IM for 14days

    ; cutaneous diphtheria

       : 7-10일 치료

    ; Tx 종결 후 24hr 간격으로 nose & throat (or skin) culture에서 negative나와야 함

        if culture (+) -> EM therapy repeat

Other Measures

    1) pharyngeal diphtheria

          - strict isolation

       cutaneous diphtheria

          - Tx 종결 후 negative culture  나올 때까지 contact isolation

    2) cutaneous wound

        - soap & water로 cleaning

    3) bed rest

        - acute phase동안

        - return of physical activity guided by the degree of toxicity

           & cardiac involvement

    4) orophayngeal & laryngeal diphtheria

        - artificial airway로 airway obstruction & aspiration을 avoid

    5) steroid Tx : not recommend

    6) myocarditis 시 digitalis therapy

         : dysrrhythmia 주의 요함

    7) Px: depend on

        . virulence of organism

            : subspecies gravis가 highest fatality

        . age

        . immunization status

        . site of inf.

        . speed of administration of the toxin

    8) Cx of most diphtheria-related death

        . mechanical obstruction from laryngeal or bull-neck diphtheria

        . myocarditis

    9) case fatality rate

        : 10% for resp. tract diphtheria

    ; *administration of diphtheria toxoid

           - at recovery

           - *not all patients develop antibodies after infection

Esposed Persons

Asymptomatic Case Contacts

  ^신1) several steps

      a. 7day 의 IP동안 closely monitored

      b. nose, throat, & cutaneous lesion culture

      c. immunization status와 상관없이 antimicrobial prophylaxis

          - oral EM(40-50mg/kg/24hr for 7-10day, max 2g/24hr)

          - if intolerant of EM, or if complete compliance is not assured

               : benzathine PC IM

                 < 30kg : 60만 u

                 > 30kg : 120만 u

          - presumed but not proved

      d. diphtheria toxoid vaccine, in age-appropriate conc.

          - 5년 이내에 booster dose을 받지 않은 immunized individual

          - 4th dose 받지 않은 children

               : should be vaccinated

          - 3 dose of diphtheria toxoid 이하       -+

            immunization status 을 잘 모르는 경우 -+ --> primary schedule에 따라

                                                          immunized 시킴

Asymptomatic Carrier

   ^신1) several steps

        a. antimicrobial prophylaxis : 7-10 day

        b. age-appropriate preparation of diphtheria toxoid

            : 1년 이내 booster dose 받지 않은 경우 즉시 투여

        c. Tx종결후 24hr 간격으로 culture 시행 - 2회 이상 negative나올 때까지 isolation

              strict isolation : resp. tr. colonization

              contact isolation : cutaneous colonization only

        d. case & carrier의 Tx 종결후 2주경 repeat culture

            if positive - oral EM for 10days & follow up culture

    2) antitoxin

        : inadequately immunized 일지라도 asymptomatic close contacts or

          carrier 에는 not recommend

Prevention

    * serum antitoxin conc.

         0.01 IU/ml : minimum protective level

         0.1 IU/ml  : certain protective level

Preparation

     1) diphtheric toxoid

          prepared by  . formaldehyde treatment of toxin

                       . standardized for potency

                       . absorbed to aluminum salts

              -> enhanced immunogenecity

     2) pediatric preparation

           - DTP, DT, DTaP

           - contain 6.7-12.5 Lf units of diphtheria toxoid per 0.5 ml dose

        adult preparation

           - Td

           - contain no more than 2 Lf unit of toxoid per 0.5ml dose

     3) 6세까지

           higher-potency(i.e. D) formulation of toxoid

              : primary series and booster doses

                -> superior immunogenicity & minimal reactogenicity

        7세 이상

           Td : primary series & booster doses

                ∵ lower conc. of diphtheria toxoid

                      . adequately immunogenic

                      . increasing content of toxoid

                           -> age 증가할수로 reactogenicity 증가

Schedules

     1) 6wk-7세 까지

         : 5회 0.5ml dose of diphtheria containing(D) vaccine

         a. primary series

            : 2, 4, 6 Mo

         b. 4th dose

            : 3dose 후 6-12Mo

         c. booster : 4-6세

     2) 7세 이상

         : 3회 0.5ml dose of diphtheria containing vaccine

          . primary series

              : 4-8주 간격으로 2dose

                3rd dose는 2nd dose 후 6-12Mo

     3) 1세 전에 DTP or DT 접종시

           - 6세까지 total 5회 0.5ml dose of diphtheria containing vaccine

        1세 이후

            primary series : 3회 0.5ml dose

            booster : 4-6세