Mikroba Patogen penyebab ISK

Mekanisme sal kemih

dalam pertahanan tubuh
Anatomi Saluran Urinary
• Warna Urine yang sehat
dan normal :
kuning pucat hingga
kuning keemasan
• berasal dari zat yang
disebut dengan urokrom.
• Makanan dan obat tertentu
dapat mengubah warna
urine
 Penyakit Sistem Urinaria
1. Infeksi saluran kemih (ISK)
• adalah infeksi yang terjadi pada bagian sistem urinaria yaitu
dari ginjal hingga saluran kemih. A urinary tract infection (UTI)
is an infection in any part of your urinary system — your
kidneys, ureters, bladder and urethra. Most infections involve
the lower urinary tract — the bladder and the urethra.

• Wanita berisiko lebih besar terkena ISK daripada kaum pria.

Women are at greater risk of developing a UTI than are men.
Infection limited to your bladder can be painful and annoying.
• However, serious consequences can occur if a UTI spreads to
your kidneys.
 2. Batu saluran kemih
Batu saluran kemih ( urolithiatis ) adalah proses pembentukan batu di
sistem urinaria, seperti pada batu ginjal, kandung kemih, atau uretra.

3. Inkontinensia urine
Inkontinensia urine adalah kondisi di mana kontrol dalam berkemih
mengalami penurunan. Keadaan ini bisa membuat tiba-tiba mengompol ketika
batuk atau bersin. sering terjadi pada lansia, namun tidak menutup
kemungkinan terjadi pada orang yang lebih muda.

4. Uretritis
Uretritis adalah peradangan pada uretra, namun berbeda dengan ISK.
Keadaan ini biasanya menyebabkan rasa sakit saat buang air kecil dan adanya
dorongan yang meningkat untuk buang air kecil. Penyebab utamanya adalah
infeksi bakteri.
 Gejala-Gejala
• A strong, persistent urge to urinate
• A burning sensation when urinating
• Passing frequent, small amounts of urine
• Urine that appears cloudy
• Urine that appears red, bright pink or cola-colored — a sign of blood
in the urine
• Strong-smelling urine
• Pelvic pain, in women — especially in the center of the pelvis and
around the area of the pubic bone
Patogenesis infeksi sal kemih
 Tipe infeksi sal kemih
Part of urinary tract affected Signs and symptoms

Kidneys (acute pyelonephritis) •Upper back and side (flank) pain

•High fever
•Shaking and chills
•Nausea
•Vomiting

Bladder (cystitis) •Pelvic pressure

•Lower abdomen discomfort
•Frequent, painful urination
•Blood in urine

Urethra (urethritis) •Burning with urination

•Discharge
 Mikroba penyebab infeksi sal kemih

• Escherichia coli
• Klebsiella species,
• Proteus species,
• Pseudomonas aeruginosa,
• Enterococcus species.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2082698/
 Escherichia coli
Strain E.coli:
• Enterotoxigenic E. coli (ETEC)
• Enteroinvasive E. coli (EIEC)
• Enterohemorrhagic E. coli (EHEC)
• Enteropathogenic E. coli (EPEC)
• Enteroaggregative E. coli (EAEC)
• Neonatus meningitis E.coli (NMEC)
• Infeksi uretra
Beberapa Strain E.coli
 E.coli uropatogenik ( UPEC)
• Penyebab 90% ISK, bakteri yg berkolonisasi
berasal dr tinja, daerah perineum,
• Perempuan terkena ISK 14x pria, krn sal uretra
lebih pendek, bakteri pd periuretral tsb akan
masuk kedlm kandung kemih mell hub seksual.
• Adhesin membantu UPEC berkolonisasi di
K.Kemih.
• Proein adhesin penting: P-fimbria /PAP
pyelonefritis,
• Hemolisin dihasilkan: α dan ß hemolisin : melisis
limfosit, menghambat fagositosis
 Spesies Klebsiella
Klebsiella pneumonia is the most relevant human
pathogen within genus Klebsiella, causing many
infections in hospitals, long-term care facilities and
communities worldwide, including lung, urinary
tract, abdominal cavity, surgical sites and soft
tissues infections, even bacteremia [1,2].
This capsulated Gram-negative bacterium is found
in normal flora of the mouth, skin and intestine, and
it is also the third most frequently isolated
microorganism in the blood cultures from sepsis
patients [3].
 The species Klebsiella pneumoniae
• has three subspecies:
• K. pneumoniae subsp. ozaenae,
• K. pneumoniae subsp. rhinoscleromatis
• K. pneumoniae subsp. pneumoniae.

• K. pneumoniae, mainly serotype K1 and K2, is responsible for pneumonia,

septicemia, nosocomial infections, urinary tract and neonatal, while K.
ozaenae causes atrophic rhinitis ozena and K. rhinoscleromatis called the
rhinoscleroma, granulomatous infection of the upper airway.
• Although very similar, these three sub-species to cause respiratory tract
infections very different and is more or less virulent.

• More:https://klebsiella-
pneumoniae.org/klebsiella_pneumoniae_urinary_tract_infection.html
• Klebsiella is also found in the urine and is the origin of some urinary tract
infections acquired in hospitals (nosocomial infection), particularly in
certain at-risk services such as surgical services, intensive care or long stays.
• It seems that inadequate cleaning of the hands of hospital staff, perhaps a
poor sterilization of objects used, but also the use of broad spectrum
antibiotics (used to fight many bacteria) and an altered anatomical barrier
explain this phenomenon. The alteration of anatomical barriers may be due
to extensive burns or therapeutic interventions (tracheotomy, intubation,
urinary catheter, intravenous catheter, prosthesis etc.).

• The urinary tract infection is defined by the multiplication and thus the
presence of more than 100,000 (10 power 5) cells per ml of a urine sample
collected in the middle of urination that is to say during urination.
 Proteus species
Proteus species are part of the Enterobacteriaceae
family of gram-negative bacilli.
Proteus organisms are implicated as serious causes
of infections in humans, along
with Escherichia, Klebsiella, Enterobacter, and Serra
tia species.
 Pseudomonas aeruginosa
• Pseudomonas infection is caused by strains of bacteria found
widely in the environment; the most common type causing
infections in humans is called Pseudomonas aeruginosa.
• Patients in hospitals, especially those on breathing machines,
those with devices such as catheters, and patients with wounds
from surgery or from burns are potentially at risk for serious,
life-threatening infections.
 PAUTI
• Within the hospital setting, 7–10% of urinary
tract infections are caused by Pseudomonas
aeruginosa (P. aeruginosa)
• P. aeruginosa is a non-fermenter gram-negative
bacilli with a large intrinsic resistance to multiple
antibiotics.
• Pseudomonas aeruginosa urinary tract infection
(PAUTI)
 Enterococcus species
• Enterococcus species are facultative anaerobic
organisms that can survive temperatures of 60°C
for short periods and that grow in high salt
concentrations.
• In the laboratory, enterococci are distinguished
by their morphologic appearance on Gram stain
and culture (gram-positive cocci that grow in
chains)
• and their ability to (1) hydrolyze esculin in the
presence of bile, (2) their growth in 6
 Enterococcal bacteremia
• portal of entry of enterococcal bacteremia :
 Intravascular catheter infections
 Localized enterococcal infections
 Intestinal translocation

• Intravascular catheter infections

• Intravascular catheter infections are a major cause of nosocomial and
healthcare associated bacteremia being the most prevalent microorganisms
Staphylococci and Enterococci, albeit with lesser extent.
• Among patients with nosocomial enterococcal bacteremia, an intravascular
catheter infection may be the portal of entry in more than 20% of cases.
Enterococcal catheter-related bacteremia occur mainly in ICU patients,
severely immunocompromised or those with dialysis.
 Prevention
• Drink plenty of liquids, especially water. Drinking water helps
dilute your urine and ensures that you'll urinate more frequently
— allowing bacteria to be flushed from your urinary tract before
an infection can begin.
• Drink cranberry juice. Although studies are not conclusive that
cranberry juice prevents UTIs, it is likely not harmful.
• Urinate after sexual activity.
• Stay well hydrated and urinate regularly.
• Take showers instead of baths.
• Avoid potentially irritating feminine products . Minimize
douching, sprays, or powders in the genital area.
• Teach girls when potty training to wipe front to back.
• Change your birth control method. Diaphragms, or unlubricated
or spermicide-trea
 Treatment UTI
• Trimethoprim-sulfamethoxazole
• Inhibition of microbial DNA synthesis by inhibiting the folic acid
synthesis and consequently the purines required for DNA
• Fluoroquinolones
• Inhibition of microbial DNA synthesis by blocking DNA gyrase and
topoisomerase IV needed for successful DNA replication and
transcription.
• Nitrofurantoin
• The mechanism is not fully understood, but it directly causes
selective damage to microbial DNA, which metabolises the toxic
intermediates of nitrofurantoin more rapidly than human cells.
• UTIs are common infections that happen
when bacteria, often from the skin or rectum,
enter the urethra, and infect the urinary tract.
The infections can affect several parts of the
urinary tract, but the most common type is a
bladder infection (cystitis).

• Kidney infection (pyelonephritis) is another

type of UTI. They’re less common, but more
serious than bladder infections.
 Risk Factors
• Some people are at higher risk of getting a UTI. UTIs are more common in women and
girls because their urethras are shorter and closer to the rectum, which makes it easier
for bacteria to enter the urinary tract.
• Other factors that can increase the risk of UTIs:
• A previous UTI
• Sexual activity, and especially a new sexual partner
• Changes in the bacteria that live inside the vagina (vaginal flora), for example caused
by menopause or use of spermicides
• Pregnancy
• Age (older adults and young children are more likely to get UTIs)
• Structural problems in the urinary tract, such as prostate enlargement.
• Poor hygiene, particularly in children who are potty-training
• Keterangan.
• The innate immune responses of bladder epithelium to bacterial infections.
(A) The bladder epithelium; (B) adherent bacteria are internalized along with
Rab27b+ fusiform vesicles; (C) exocytosis of RAB27b+ vesicles harboring
UPEC and expulsion of the intracellular UPEC back into the lumen of the
bladder; (D) transient receptor potential mucolipin 3 Ca2+ channel
(TRPML3) triggers the spontaneous expulsion of the defective lysosomes
and its contents out into the extracellular space; (E) soluble factors are also
secreted by BECs, including antimicrobial peptides (AMP, such as
cathelicidin and β-defensin 1), antimicrobial proteins [such as pentraxin 3
(PTX3)] and chemokines [such as CXC-chemokine ligand 1 (CXCL1) and
CC-chemokine ligand 5 (CCR5)]. (F) Exfoliation is accompanied by rapid
renewal of superficial BECs through active proliferation of basal progenitor
mast cells. Intimate crosstalk between macrophages ensures the precise
initiation of neutrophil responses.
 UPEC antibiotic susceptibility and resistance

• The efficacy of antibiotic treatment depends on the identification and antimicrobial resistance
pattern of uropathogens responsible for UTI (Bartoletti et al., 2016). The practice of
prescribing antibiotics to treat UTI without bacterial characterization led to increased
resistance among uropathogens and to decreased effectiveness of oral therapies. Despite
clinical symptoms of UTIs have been ameliorated by numerous antibiotics, UPEC
persistence and resistance to antibiotics represent a serious problem (Blango and Mulvey,
2010). According to the 2015 guidelines of the European Association of Urology, the
recommendations for the prevention of recurrent UTI are first aimed at behavioral changes
and immediately after toward non-antibiotic measures. If these two recommendations are
not sufficiently effective then the antibiotic prophylaxis should be considered, in order to
prevent the adverse events and collateral damages that the long-term and not necessary
use of antibiotics may cause (Vahlensieck et al., 2016). In Europe, resistance to UPEC
isolates shows average values of 11.8% for third-generation cephalosporins and 22.3% for
fluoroquinolones. In the U.S., fluoroquinolone-resistant UPEC represented the 31.3% of
isolates among hospitalized patients between the years 2007 and 2010 (Edelsberg et al.,
2014). These data confirm the general consideration that number of effective antibiotic
compounds availability and the prevalence of antibiotic resistance are worsening, as
demonstrated by an increased number of clinical studies (Bartoletti et al., 2016).
• New antibiotics, such as colistin (Cui et al., 2016),
finafloxacin, and cefiderocol (S-649266), which are
currently in early clinical development, might be useful
in the treatment of UTIs (Zacché and Giarenis, 2016).
• Figure ​Figure44 shows the structure formulae of the
most representative antibiotics for which UPEC
resistance has been demonstrated (red background)
and those showing susceptibility to UPEC (green
background). The yellow background shows antibiotics
that already show resistance in some UPEC strains.
•
Alternative antimicrobial remedies
• Antibiotics will continue to be an unavoidable source
for the prevention of UTIs on a case-by-case basis.
However, the excessive use of antibiotics and the
long-term interference with intestinal microbiota,
require to search for alternative remedies. A plethora
of molecules has been tested to reduce UPEC
infections by exploiting their ability either to
stimulate the immune system or to interfere with the
UPEC ability to adhere and invade the urothelium.
Here we briefly summarize the most effective
alternative remedies to fight UPECs.
 Vaccines

• The development of new strategies to fight UTI has focused on the development of vaccines based on bacterial
components with the aim of identifying specific UPEC factors for potential use as vaccine antigens (McLellan and
Hunstad, 2016).
• Among candidate antigens, potential targets are adhesins, antimicrobial peptides (AMPs), and siderophores
(Spaulding and Hultgren, 2016).
• However, the use of vaccines may alter the proteobacteria populations of E. coli in the gut and may find a difficult
way to reach the bladder lumen.
• Furthermore, vaccine use might be more efficient to treat upper rather than lower urinary tracts (McLellan and
Hunstad, 2016). Recently, healthy adult women with a history of recurrent UTI where the subject of a multicentre
phase 1b trial where a single intramuscular injection of either a bioconjugate vaccine containing the O-antigens of
four E. coli serotypes (ExPEC4V) or placebo were administered.
• Vaccination induced significant IgG responses for all serotypes; moreover, the vaccine group showed significantly
lower UTIs caused by UPEC of any serotype when compared with the placebo group (Huttner et al., 2017). In a
meta-analysis of about 900 patients, the oral vaccine OM-89 (Uro-Vaxom®) reduced the mean number of UTIs by
half, whereas a vaginal vaccine (Urovac) showed a scanty reduction in recurrent UTIs and caused a vaginal
irritation in nearly 28% of patients (Beerepoot et al., 2013). An alternative strategy to elicit protective immunity is
to select as antigens small molecules, rather than proteins or peptides. The use of siderophore-protein conjugates
was found to elicit immune responses targeted to bacterial siderophores and to successfully protect against UTI
(Mike et al., 2016). A reverse-vaccinology approach in combination with proteomics and genomics was used to
identify putative broadly protective vaccine antigens (Moriel et al., 2016). Currently, no UTI vaccines are approved
in the United States but among current strategies, immunotherapeutic formulation OM-89 (marketed in Europe by
EurimPharm GmbH as UroVaxom), which is a bacterial extract prepared from 18 strains of E. coli, is really
promising (Neto et al., 2016). The identification of potential vaccine targets has been recently reviewed (O'Brien et
al., 2016; Poolman and Wacker, 2016).
 Probiotics
• Women with recurrent UTIs often show alterations in their vaginal or periurethral
microbiota (Czaja et al., 2009). Probiotics have been extensively used as alternative
approaches to reduce recurrent UTIs (Zacché and Giarenis, 2016).
• Several Lactobacilli strains showed UPEC inhibitory activity between that of
sensitive and resistant antibiotics (Shim et al., 2016). One of the major roles of
Lactobacilli is their ability to clear potential UPEC reservoirs, thus preventing
recurrences. Lactobacillus-mediated protection from UTI is not clear, and may
involve hydrogen peroxide, surfactants, and anti-adhesive molecules production
(O'Brien et al., 2016).
• However, contrasting results have been reported. For instance, Lactobacilli
prophylaxis did not decrease the rate of UTI recurrence in several open
randomized trials with women who had a UTI caused by UPEC (Kontiokari et al.,
2001; Beerepoot et al., 2013; Schwenger et al., 2015).
• On the other hand, Lactobacilli were shown to actively stimulate the immune
system by up- and down-regulation of NF-κB activity (Karlsson et al., 2012), and to
colonize and protect the vagina (Reid, 2000), thus suggesting some sort of indirect-
cooperative function
 Estrogens
• The vaginal epithelium and its acidic microenvironment provide substantial inhibition of bacterial
growth of enteric microorganisms. Estrogen is an important modulator of urothelium cell growth
and differentiation.
• Estrogen may constitute a risk factor for infections in young women; however, after menopause the
low estradiol levels have been related to recurrent infections (Mody and Juthani-Mehta, 2014).
• Estrogen application modulates two epithelial defense mechanisms: induction of AMPs and
reduction of epithelial exfoliation (Luthje et al., 2013).
• Furthermore, increased epithelial integrity and higher expression of AMPs may reduce the
formation of QIRs as the source of recurrent infections (Luthje and Brauner, 2016).
• However, oral estrogen therapy failed to be effective at reducing UTI risk compared with placebo,
whereas vaginal estrogen application reduced UTI (Perrotta et al., 2008; Matulay et al., 2016).
Vaginal estrogen therapy was found to be effective in preventing recurrent UTI of postmenopausal
women when used in combination with hyaluronic acid, chondroitin sulfate, curcumin, and
quercetin administered per os (Torella et al., 2016).

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559502/